Search

Background: Thoracic radiation intensification is debated in patients with stage III non-small-cell lung cancer (NSCLC). We aimed to assess the activity and safety of a boost radiotherapy dose up to 74 Gy in a functional sub-volume given according to on-treatment [ 18 F]fluorodeoxyglucose ([ 18 F]FDG)-PET results., Methods: In this multicentre, randomised, controlled non-comparative phase 2 trial, we recruited patients aged 18 years or older with inoperable stage III NSCLC without EGFR mutation or ALK rearrangement with an Eastern Cooperative Oncology Group performance status of 0-1, and who were affiliated with or a beneficiary of a social benefit system, with evaluable tumour or node lesions, preserved lung function, and who were amenable to curative-intent radiochemotherapy. Patients were randomly allocated using a central interactive web-response system in a non-masked method (1:1; minimisation method used [random factor of 0·8]; stratified by radiotherapy technique [intensity-modulated radiotherapy vs three-dimensional conformal radiotherapy] and by centre at which patients were treated) either to the experimental adaptive radiotherapy group A, in which only patients with positive residual metabolism on [ 18 F]FDG-PET at 42 Gy received a boost radiotherapy (up to 74 Gy in 33 fractions), with all other patients receiving standard radiotherapy dosing (66 Gy in 33 fractions over 6·5 weeks), or to the standard radiotherapy group B (66 Gy in 33 fractions) over 6·5 weeks. All patients received two cycles of induction platinum-based chemotherapy cycles (paclitaxel 175 mg/m 2 intravenously once every 3 weeks and carboplatin area under the curve [AUC]=6 once every 3 weeks, or cisplatin 80 mg/m 2 intravenously once every 3 weeks and vinorelbine 30 mg/m 2 intravenously on day 1 and 60 mg/m 2 orally [or 30 mg/m 2 intravenously] on day 8 once every 3 weeks). Then they concomitantly received radiochemotherapy with platinum-based chemotherapy (three cycles for 8 weeks, with once per week paclitaxel 40 mg/m 2 intravenously and carboplatin AUC=2 or cisplatin 80 mg/m 2 intravenously and vinorelbine 20 mg/m 2 intravenously on day 1 and 40 mg/m 2 orally (or 20 mg/m 2 intravenously) on day 8 in 21-day cycles). The primary endpoint was the 15-month local control rate in the eligible patients who received at least one dose of concomitant radiochemotherapy. This RTEP7-IFCT-1402 trial is registered with ClinicalTrials.gov (NCT02473133), and is ongoing., Findings: From Nov 12, 2015, to July 7, 2021, we randomly assigned 158 patients (47 [30%] women and 111 [70%] men) to either the boosted radiotherapy group A (81 [51%]) or to the standard radiotherapy group B (77 [49%)]. In group A, 80 (99%) patients received induction chemotherapy and 68 (84%) received radiochemotherapy, of whom 48 (71%) with residual uptake on [ 18 F]FDG-PET after 42 Gy received a radiotherapy boost. In group B, all 77 patients received induction chemotherapy and 73 (95%) received radiochemotherapy. At the final analysis, the median follow-up for eligible patients who received radiochemotherapy (n=140) was 45·1 months (95% CI 39·3-48·3). The 15-month local control rate was 77·6% (95% CI 67·6-87·6%) in group A and 71·2% (95% CI 60·8-81·6%) in group B. Acute (within 90 days from radiochemotherapy initiation) grade 3-4 adverse events were observed in 20 (29%) of 68 patients in group A and 33 (45%) of 73 patients in group B, including serious adverse events in five (7%) patients in group A and ten (14%) patients in group B. The most common grade 3-4 adverse events were febrile neutropenia (seven [10%] of 68 in group A vs 16 [22%] of 73 in group B), and anaemia (five [7%] vs nine [12%]). In the acute phase, two deaths (3%) occurred in group B (one due to a septic shock related to chemotherapy, and the other due to haemotypsia not related to study treatment), and no deaths occurred in group A. After 90 days, one additional treatment-unrelated death occurred in group A and two deaths events occurred in group B (one radiation pneumonitis and one pneumonia unrelated to treatment)., Interpretation: A thoracic radiotherapy boost, based on interim [ 18 F]FDG-PET, led to a meaningful local control rate with no difference in adverse events between the two groups in organs at risk, in contrast with previous attempts at thoracic radiation intensification, warranting a randomised phase 3 evaluation of such [ 18 F]FDG-PET-guided radiotherapy dose adaptation in patients with stage III NSCLC., Funding: Programme Hospitalier de Recherche Clinique National 2014., Competing Interests: Declaration of interests EM declared payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Varian Medical Systems, AstraZeneca, MSD, Janssen, and Sanofi; support for attending meetings or travel, or both, from Ipsen, Janssen, and AstraZeneca; and participation on a data safety monitoring board or advisory board for AstraZeneca and Janssen. IB-R declares payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Novartis 3A and Curium; payment for expert testimony from Curium; and support for attending meetings or travel, or both, from Novartis 3A. CLP declares payment or honoraria to her institution for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AstraZeneca and Amgen; support for attending meetings or travel, or both, paid to her institution from Janssen and Roche; and participation on a data safety monitoring board or advisory board paid to her institution for AstraZeneca, Varian, MSD, and Roche. EG-L declares payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Amgen, AstraZeneca, Ipsen, Janssen, Lilly, MSD, Novartis, Pfizer, Sanofi, and Takeda; and support for attending meetings or travel, or both, from Takeda, MSD, AstraZeneca, and Roche. CA-V declares support for attending meetings or travel, or both, from Roche, Sanofi, MSD, BMS, Lilly, Pfizer, AstraZeneca, Janssen, and Abbvie; and participation on a data safety monitoring board or advisory board for Roche, Sanofi, MSD, BMS, Lilly, Pfizer, AstraZeneca, Janssen, and Abbvie. ALan and EA are employees of the French Intergroup (Intergroupe Francophone de Cancérologie Thoracique). GZ declares consulting fees paid to his institution from AstraZeneca, BMS, Takeda, and Roche; payment or honoraria to his institution for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AstraZeneca, Inventiva, BMS, and Pfizer; support for attending meetings or travel, or both, from Roche, BMS, Abbvie, Pfizer, and AstraZeneca; and receipt of equipment, materials, drugs, medical writing, gifts, or other services to his institution by Foundation Roche. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Competing Interests: Disclosure Daisuke Shibahara reports a funding grant from Eli Lilly Japan KK. Yoshimasa Shiraishi reports a funding grant from Chugai Pharmaceutical Co Ltd, and speaking and lecture fees from Ono Pharmaceutical Co Ltd, Bristol-Myers Squibb Co, AstraZeneca Pharmaceuticals LP, Taiho Pharmaceutical Co Ltd, Chugai Pharmaceutical Co Ltd, and Kyowa Kirin. Eiji Iwama reports speaking and lecture fees from Chugai Pharmaceutical Co Ltd and AstraZeneca Pharmaceuticals LP. Kentaro Tanaka reports speaking and lecture fees from AstraZeneca Pharmaceuticals LP, Chugai Pharmaceutical Co Ltd, Ono Pharmaceutical Co Ltd, Bristol-Myers Squibb Co, MSD, Novartis Pharmaceuticals, Eli Lilly Japan KK, Daiichi Sankyo Co Ltd, Pfizer, Merck and Co Inc, and Takeda Pharmaceutical Co Ltd. Isamu Okamoto reports funding grants from Chugai Pharmaceutical Co Ltd, AstraZeneca Pharmaceuticals LP, Daiichi Sankyo Co Ltd, Merck and Co Inc, Takeda Pharmaceutical Co Ltd, Eli Lilly Japan KK, Ono Pharmaceutical Co Ltd, Bristol-Myers Squibb Co, Taiho Pharmaceutical Co Ltd, and Nippon Boehringer Ingelheim Co Ltd, and speaking and lecture fees from Chugai Pharmaceutical Co Ltd, AstraZeneca Pharmaceuticals LP, Takeda Pharmaceutical Co Ltd, Eli Lilly Japan KK, Ono Pharmaceutical Co Ltd, Bristol-Myers Squibb Co, Taiho Pharmaceutical Co Ltd, Nippon Boehringer Ingelheim Co Ltd, and Novartis Pharmaceuticals.

Introduction: Stereotactic body radiation therapy (SBRT) is a treatment for patients with early-stage non-small cell lung cancer (ES-NSCLC). Surveillance guidelines vary after treatment. While patients are more likely to locally recur within 2 years of treatment, there remains a paucity of data on the benefit of frequent and long-term surveillance. We evaluated a cohort of NSCLC patients to evaluate surveillance patterns and outcomes., Materials and Methods: Patients with ES-NSCLC treated with SBRT were retrospectively evaluated. Imaging was reviewed after SBRT for evidence of recurrence or new malignancy. The median scan interval (MSI) was calculated as the median number of months between surveillance scans. The MSI between patients with or without new disease was compared by t-test. New disease development and survival between patients with =T2 disease and with or without prior malignancy was compared using χ², Kaplan-Meier analysis, and Gray's test., Results: A cohort of 168 patients with median follow up of 23.4 months met criteria for review with 50% developing new disease. MSI did not differ between patients with or without new disease. Patients with >=cT2 tumors had worse overall survival and trended towards higher incidence of new disease. New disease continued to occur, even 5 years after treatment., Conclusion: Increased scan frequency did not increase detection of new disease. Patients continued to fail 5 years after treatment. Larger tumors trended toward more frequent failures and those patients experienced worse OS. Surveillance guidelines should be optimized to prevent over surveillance after treatment and to continue long-term surveillance., Competing Interests: Disclosure The authors have stated that they have no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: In the era of personalized medicine, individualized prognostic models with tumor characteristics are needed to inform patients about survival. Before clinical use, external validation of such models by an independent group is needed. An updated version of the graded prognostic assessment (GPA) estimates survival in patients with brain metastases (BMs) of non-small cell lung cancer (NSCLC). This is the first external validation of the updated Lung-molGPA in patients treated with stereotactic radiotherapy (SRT) for one or more BMs., Materials and Methods: Patients treated with SRT for BMs from NSCLC adenocarcinoma were retrospectively included. GPA score was calculated for each patient based on six prognostic factors including age, Karnofsky Performance Status, number of BMs, extracranial metastases, EGFR/ALK status, and PD-L1 expression. Kaplan-Meier analysis evaluated survival probability. Impact of individual prognostic factors on survival was assessed by univariate and multivariate analyses using the Cox proportional hazard model. Predictive performance was evaluated using discrimination (C-statistic) and calibration (Brier test)., Results: The cohort (n = 241) was divided into four prognostic groups. Overall median survival was 15 months. Predicted and observed median survival were similar between the original and validation cohorts, apart from the most favorable prognostic group. With adequate C-statistics and Brier scores, the Lung-molGPA provided accurate survival predictions., Conclusion: The Lung-molGPA accurately predicted survival in our European population, except for an overestimation of survival in the small most favorable prognostic group. This prognostic model was externally validated and is therefore useful for counseling of patients with BMs of NSCLC adenocarcinoma., 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 The Author(s). Published by Elsevier B.V. All rights reserved.)

Purpose: Stereotactic body radiation therapy (SBRT) versus surgery for operable early-stage non-small cell lung cancer (ES-NSCLC) remains highly debated. Herein, we used spatial proteomics to identify whether any molecular biomarker(s) associate with the efficacy of either modality, in efforts to optimize treatment selection between surgery and SBRT for this population., Methods and Materials: We evaluated biopsy tissue samples from 44 patients with ES-NSCLC treated with first-line SBRT (cohort 1) by GeoMx Digital Spatial Profiling (DSP) with a panel of 70 proteins in 5 spatial molecular compartments: tumor (panCK+), leukocyte (CD45+), lymphocyte (CD3+), macrophage (CD68+), and stroma (α-SMA+). To validate the findings in cohort 1, biopsy samples from 52 patients with ES-NSCLC who received SBRT (cohort 2) and 62 patients with ES-NSCLC who underwent surgery (cohort 3) were collected and analyzed by multiplex immunofluorescence (mIF)., Results: In cohort 1, higher CD44 expression in the lymphocyte compartment was associated with poorer recurrence-free survival (RFS) (DSP: P < .001; mIF: P < .001) and higher recurrence rate (DSP: P = .001; mIF: P = .004). mIF data from cohort 2 validated these findings (P < .05 for all). From cohort 3, higher lymphocyte CD44 predicted higher RFS after surgery (P = .003). Intermodality comparisons demonstrated that SBRT was associated with significantly higher RFS over surgery in CD44-low patients (P < .001), but surgery was superior to SBRT in CD44-high cases (P = .016)., Conclusions: Lymphocyte CD44 may not only be a predictor of SBRT efficacy in this population but also an important biomarker (pending validation by large prospective data) that could better sharpen selection for SBRT versus surgery in ES-NSCLC., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose: Disparities in access to a multidisciplinary cancer consultation (MDCc) persist, and the role of physician relationships remains understudied. This study examined the extent to which multilevel factors, including patient characteristics and patient-sharing network measures reflecting the structure of physician relationships, are associated with an MDCc and receipt of stereotactic body radiation therapy versus surgery among patients with early-stage non-small cell lung cancer (NSCLC)., Methods and Materials: In this cross-sectional study, we analyzed Surveillance, Epidemiology, and End Results (SEER)-Medicare data for patients diagnosed with stage I-IIA NSCLC from 2016 to 2017. We assembled patient-sharing networks and identified cancer specialists who were locally unique for their specialty, herein referred to as linchpins. The proportion of linchpin cancer specialists for each hospital referral region (HRR) was calculated as a network-based measure of specialist scarcity. We used multilevel multinomial logistic regression to estimate associations between study variables and receipt of an MDCc and multilevel logistic regression to examine the relationship between patient receipt of an MDCc and initial treatment., Results: Our study included 6120 patients with stage I-IIA NSCLC, of whom 751 (12.3%) received an MDCc, 1729 (28.3%) consulted only a radiation oncologist, 2010 (32.8%) consulted only a surgeon, and 1630 (26.6%) consulted neither specialist within 2 months of diagnosis. Compared with patients residing in an HRR with a low proportion of linchpin surgeons, those residing in an HRR with a high proportion of linchpin surgeons had a 2.99 (95% CI, 1.87-4.78) greater relative risk of consulting only a radiation oncologist versus receiving an MDCc and a 2.70 (95% CI, 1.68-4.35) greater relative risk of consulting neither specialist versus receiving an MDCc. Patients who received an MDCc were 5.32 times (95% CI, 4.27-6.63) more likely to receive stereotactic body radiation therapy versus surgery., Conclusions: Physician networks are associated with receipt of an MDCc and treatment, underscoring the potential for leveraging patient-sharing network analysis to improve access to lung cancer care., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Despite the importance of radiation therapy as a non-surgical treatment for non-small cell lung cancer (NSCLC), radiation resistance has always been a concern, due to poor patient response and prognosis. Therefore, it is crucial to uncover novel targets to enhance radiotherapy and investigate the mechanisms underlying radiation resistance. Previously, we demonstrated that NRP1 was connected to radiation resistance in NSCLC cells. In the present study, bioinformatics analysis of constructed radiation-resistant A549 and H1299 cell models revealed that transcription coactivator YAP is a significant factor in cell proliferation and metastasis. However, there has been no evidence linking YAP and NRP1 to date. In this research, we have observed that YAP contributes to radiation resistance in NSCLC cells by stimulating cell proliferation, migration, and invasion. Mechanistically, YAP dephosphorylation after NSCLC cell radiation. YAP acts as a transcription co-activator by binding to the transcription factor TEAD4, facilitating TEAD4 to bind to the NRP1 promoter region and thereby increasing NRP1 expression. NRP1 has been identified as a new target gene for YAP/TEAD4. Notably, when inhibiting YAP binds to TEAD4, it inhibits NRP1 expression, and Rescue experiments show that YAP/TEAD4 influences NRP1 to regulate cell proliferation, metastasis and leading to radiation resistance generation. According to these results, YAP/TEAD4/NRP1 is a significant mechanism for radioresistance and can be utilized as a target for enhancing radiotherapy efficacy., (© 2024. The Author(s).)

Purpose: The most appropriate time of primary tumor radiotherapy in non-small cell lung cancer(NSCLC) with EGFR-TKIs remains unclear. The aim of this study was to investigate the effect of the time factor of primary tumor radiotherapy on long-term overall survival(OS)and provide a theoretical basis for further clinical research., Patients and Methods: In total, 238 patients with EGFR-TKIs and OS ≥ 12 months were statistically analysed. Patients were grouped: the D group without primary tumor radiotherapy and the R group with it.The R group were divided into three groups according to the interval between the start of EGFR-TKIs and the start of primary tumor radiotherapy: R 0 - 30 (<30 days), R 30 - PD (≥ 30 days and disease stable), and R PD (radiotherapy after disease progression). The Kaplan-Meier method and log-rank test were used for survival analyses. Exploratory landmark analyses were investigated., Results: The OS rates at 1, 2, 3, 5 years for the R group and D group were 96.8%, 62.9%, 38.3%, 17.1%, and 95.6%, 37.7%, 21.8%, 2.9%, respectively; the corresponding MST was 29 months(95% CI: 24.3-33.7) for the R group and 22 months(95% CI: 20.4-23.6) for the D group (χ 2  = 13.480, p<0.001). Multivariate analysis revealed that primary tumor radiotherapy was independent predictors of prolonged OS.Among the four groups, The R 30 - PD appeared to have the best OS (D, χ 2  = 19.307, p<0.001;R 0 - 30 , χ 2  = 11.687, p = 0.01; R PD , χ 2  = 4.086, p = 0.043). Landmark analyses(22 months) showed the R 30 - PD group had a significant long-term OS.The incidence of radiation pneumonitis ≥ grade 2 was17.3%(n = 19)and radiation esophagitis ≥ grade 2 was observed in 32 patients(29.1%)., Conclusions: Our results showed that primary tumour radiotherapy may prolong long-term OS with acceptable toxicities. Appropriate delay(R 30 - PD )of primary tumour radiotherapy may be the best choice.Premature radiotherapy(R 0 - 30 ) and radiotherapy after disease progression (R PD )may not be reasonable for long-term OS., (© 2024. The Author(s).)

This single-arm, multicenter, phase 2 trial (NCT04106180) investigated the triple combination of sintilimab (anti-PD1 antibody), stereotactic body radiotherapy (SBRT) and granulocyte-macrophage colony-stimulating factor (GM-CSF) in metastatic non-small cell lung cancer (NSCLC). With a median follow-up of 32.1 months, 18 (36.7%, 90% CI 25.3%-49.5%) of the 49 evaluable patients had an objective response, meeting the primary endpoint. Secondary endpoints included out-of-field (abscopal) response rate (ASR), progression-free survival (PFS), overall survival (OS), and treatment-related adverse events (TRAEs). The ASR was 30.6% (95% CI 18.3%-45.4%). The median PFS and OS were 5.9 (95% CI 2.5-9.3) and 18.4 (95% CI 9.7-27.1) months, respectively. Any grade and grade 3 TRAEs occurred in 44 (86.3%) and 6 (11.8%) patients, without grade 4-5 TRAEs. Moreover, in pre-specified biomarker analyses, SBRT-induced increase of follicular helper T cells (Tfh) in unirradiated tumor lesions and patient's blood, as well as of circulating IL-21 levels, was found associated with improved prognosis. Taken together, the triple combination therapy was well tolerated with promising efficacy and Tfh may play a critical role in SBRT-triggered anti-tumor immunity in metastatic NSCLC., (© 2024. The Author(s).)

Background: Adaptive therapy has been enormously improved based on the art of generating adaptive computed tomography (ACT) from planning CT (PCT) and the on-board image used for the patient setup. Exploiting the ACT, this study evaluated the dose delivered to patients with non-small-cell lung cancer (NSCLC) patients treated with stereotactic ablative radiotherapy (SABR) and derived relationship between the delivered dose and the parameters obtained through the evaluation procedure., Methods: SABR treatment records of 72 patients with NSCLC who were prescribed a dose of 60 Gy (D prescribed ) to the 95% volume of the planning target volume (PTV) in four fractions were analysed in this retrospective study; 288 ACTs were generated by rigid and deformable registration of a PCT to a cone-beam computed tomography (CBCT) per fraction. Each ACT was sent to the treatment planning system (TPS) and treated as an individual PCT to calculate the dose. Delivered dose to a patient was estimated by averaging four doses calculated from four ACTs per treatment. Through the process, each ACT provided the geometric parameters, such as mean displacement of the deformed PTV voxels (Warp mean ) and Dice similarity coefficient (DSC) from deformation vector field, and dosimetric parameters, e.g. difference of homogeneity index (ΔHI, HI defined as (D 2% -D 98% )/D prescribed *100) and mean delivered dose to the PTV (D mean ), obtained from the dose statistics in the TPS. Those parameters were analyzed using multiple linear regression and one-way-ANOVA of SPSS ® (version 27)., Results: The prescribed dose was confirmed to be fully delivered to internal target volume (ITV) within maximum difference of 1%, and the difference between the planned and delivered doses to the PTV was agreed within 6% for more than 95% of the ACT cases. Volume changes of the ITV during the treatment course were observed to be minor in comparison of their standard deviations. Multiple linear regression analysis between the obtained parameters and the dose delivered to 95% volume of the PTV (D 95% ) revealed four PTV parameters [Warp mean , DSC, ΔHI between the PCT and ACT, D mean ] and the PTV D 95% to be significantly related with P-values < 0.05. The ACT cases of high ΔHI were caused by higher values of the Warp mean and DSC from the deformable image registration, resulting in lower PTV D 95% delivered. The mean values of PTV D 95% and Warp mean showed significant differences depending on the lung lobe where the tumour was located., Conclusions: Evaluation of the dose delivered to patients with NSCLC treated with SABR using ACTs confirmed that the prescribed dose was accurately delivered to the ITV. However, for the PTV, certain ACT cases characterised by high HI deviations from the original plan demonstrated variations in the delivered dose. These variations may potentially arise from factors such as patient setup during treatment, as suggested by the statistical analyses of the parameters obtained from the dose evaluation process., (© 2024. The Author(s).)

Background: Radiation therapy is an effective local therapy for lung cancer. However, the interaction between genes and radiotherapy is multifaceted and intricate. Therefore, we explored the role of miR-93-5p in the proliferation, apoptosis, and migration abilities of A549 cells. Simultaneously, we also investigated the interactions between miR-93-5p and ionizing radiation (IR)., Methods: Cell Counting Kit-8, transwell, and apoptotic assay were performed to measure the proliferation, migration, and apoptosis abilities. The expression levels of miR-93-5p and its target gene in lung cancer were predicted using starBase v3.0. Then, data were validated using qPCR and western blot., Results: miR-93-5p significantly promoted the proliferation ( P < 0.01) and migration abilities ( P < 0.001) of A549 cells. Gasdermin E (GSDME) was identified to be a putative target of miR-93-5p and had a negative correlation with miR-93-5p ( P < 0.001). Overexpression of miR-93-5p significantly decreased GSDME in A549 ( P < 0.001). Interestingly, miR-93-5p decreased cell proliferation ( P < 0.01) and cell migration ( P < 0.01) and increased apoptosis ( P < 0.01) in A549 cells after exposure to IR., Conclusions: miR-93-5p is presumed to play an oncogenic role in lung cancer by enhancing A549 cell proliferation and migration. It can enhance the sensitivity of radiotherapy under IR conditions. We speculate that the miR-93-5p/GSDME pathway was inhibited, activating the GSDME-related pyroptosis pathway when the cells were exposed to IR. Therefore, miR-93-5p can overcome resistance to radiotherapy and improve the efficacy of radiotherapy., Competing Interests: The authors report no competing interests., (Copyright © 2024 Qingtao Ni et al.)

Introduction: The estimated dose of radiation to immune cells (EDRIC) has been shown to correlate with the overall survival (OS) of patients who receive definitive thoracic radiotherapy. However, the planning target volume (PTV) may be a confounding factor. We assessed the prognostic value of EDRIC for non-small cell lung cancer (NSCLC) in patients who underwent postoperative radiotherapy (PORT) with homogeneous PTV., Methods: Patients with NSCLC who underwent PORT between 2004 and 2019 were included. EDRIC was computed as a function of the number of radiation fractions and mean doses to the lungs, heart, and remaining body. The correlations between EDRIC and OS, disease-free survival (DFS), locoregional-free survival (LRFS), and distant metastasis-free survival (DMFS) were analyzed using univariate and multivariate Cox models. Kaplan-Meier analysis was performed to assess the survival difference between low- and high-EDRIC groups., Results: In total, 345 patients were analyzed. The mean EDRIC was 6.26 Gy. Multivariate analysis showed that higher EDRIC was associated with worse outcomes in terms of OS (hazard ratio [HR] 1.207, P = .007), DFS (HR 1.129, P = .015), LRFS (HR 1.211, P = .002), and DMFS (HR 1.131, P = .057). In the low- and high-EDRIC groups, the 3-year OS was 81.2% and 74.0%, DFS 39.8% and 35.0%, LRFS 70.4% and 60.5%, and DMFS 73.9% and 63.1%, respectively., Conclusions: EDRIC is an independent prognostic factor for survival in patients with NSCLC undergoing PORT. Higher doses of radiation to the immune system are associated with tumor progression and poor survival. Organs at risk for the immune system should be considered during radiotherapy planning., (© 2024. The Author(s).)

New treatment paradigms for resectable nonsmall cell lung cancer (NSCLC), with an emphasis on personalised care and a multidisciplinary approach, have significantly improved patient outcomes. The incorporation of immune checkpoint inhibitors into neoadjuvant, perioperative and adjuvant treatment algorithms is reshaping the standard of care for resectable NSCLC. Adjuvant targeted therapy trials have also paved the way for a much-needed personalised approach for patients with actionable genomic alterations. Innovative surgical techniques and judicious use of postoperative radiotherapy may mitigate the toxicity associated with a multimodality approach. Amid the many new treatment options, questions remain about the best approach to consider for each patient. Measurement of minimal residual disease and achievement of pathological complete response are emerging biomarkers of interest to help further refine treatment selection. This review summarises the current management of resectable NSCLC, focusing on ongoing and recent advances in surgical approaches, the role of postoperative radiotherapy and the rapidly changing field of systemic therapies., Competing Interests: Conflict of interest: M-F. D'Amours has received honoraria for an educational presentation from Pfizer. C. Ho has received research grants from AstraZeneca and Roche; and honoraria for advisory boards from Abbvie, Amgen, AstraZeneca, Bayer, BMS, Eisai, EMD Serono, Janssen, Jazz, Merck, Novartis, Pfizer, Roche, Sanofi and Takeda. F.T.H. Wu has received honoraria for an educational presentation from Bristol Myers Squibb. A. McGuire has received an educational grant from Johnson & Johnson; and honoraria for advisory boards from AstraZeneca, Bristol Myers Squibb and Medtronic. The remaining authors have no potential conflicts of interest to disclose., (Copyright ©The authors 2024. For reproduction rights and permissions contact permissions@ersnet.org.)

Objective: There is a lack of evidence to support a consensus on whether surgery or radiotherapy is optimal for elderly or very elderly patients with early-stage non-small cell lung cancer (NSCLC). We aimed to assess the impact of surgery or radiotherapy on survival in elderly (≥70 years) and very elderly (≥80 years) patients with early-stage NSCLC., Methods: Patients aged ≥70 years diagnosed with early-stage NSCLC between January 1, 1975, and December 31, 2018, were identified in the Surveillance, Epidemiology, and End Results (SEER) database. Overall survival (OS) and cancer-specific survival (CSS) were assessed based on surgery, radiotherapy, and no-treatment groups., Results: Data for 15,224 NSCLC patients aged ≥70 years were collected, which consisted of 6949 (45.6%) patients who underwent surgery alone, 5014 (32.9%) who underwent radiotherapy alone, and 3261 (21.5%) who received no treatment. Surgery significantly improved patient survival compared with no treatment (MST: 74 months vs. 7 months, HR: 0.201, 95% CI: 0.186-0.217, P < 0.001), as did radiotherapy (MST: 28 months vs. 7 months, HR: 0.440; 95% CI: 0.413-0.469, P < 0.001). Surgery also resulted in improved survival compared with radiotherapy (74 months vs. 28 months, HR: 0.455; 95% CI: 0.430-0.482, P < 0.001). A similar conclusion was made from the analysis of CSS. A subgroup analysis further confirmed the survival benefits., Conclusions: The results of this large-scale retrospective study indicate that both surgery and radiotherapy significantly enhance survival outcomes in patients aged ≥70 or ≥80 years with early-stage NSCLC. The survival benefits of surgery were particularly notable., (Copyright © 2024 Copyright: © 2024 Journal of Cancer Research and Therapeutics.)

Introduction: The present study sought to examine the relationships between systemic inflammatory composite ratios/cumulative scores, magnitude of systemic inflammatory response (SIR) and survival in good performance status patients (ECOG-PS 0/1) with advanced NSCLC receiving palliative radiotherapy., Methods: Systemic inflammatory composite ratios/cumulative scores included the neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), lymphocyte-monocyte ratio (LMR), C-reactive protein, (CRP)-albumin ratio (CAR), neutrophil- lymphocyte score (NLS), platelet-lymphocyte score (PLS), lymphocyte-monocyte score (LMS), neutrophil-platelet score (NPS), modified Glasgow prognostic score (mGPS). The magnitude of SIR was determined by serum CRP concentration, with a median CRP concentration of >10 m mg/L considered to be systemically inflamed. Relationships between systemic inflammatory composite ratios/ cumulative scores and clinicopathological characteristics were examined using chi-square analysis. Relationships between overall survival (OS) and systemic inflammatory composite ratios/ cumulative scores were examined using cox regression analysis., Results: 479 patients were included. 48% (n = 231) of patients were male and 70% (n = 338) were ≥65 years of age. 29% (n = 140) patients were ECOG-PS 0 and 71% (n = 339) were ECOG-PS 1. 98% (n = 469) of patients died during follow-up. The median survival was 5 months (2-11). A similar prevalence of systemic inflammation was noted across the various ratios/scores (NLR >3 68%; LMR <2.4 65%; PLR >150 70%; CAR >0.20 83%; NLS ≥1 66%; LMS ≥1 71%; NPS≥1 50%; PLS≥1 60% and mGPS≥1 75%). Despite not considered to be systemically inflamed, an NLR <3, LMR ≥2.4, PLR ≤150, NLS 0, LMS 0, NPS 0 and PLS 0 all had a median CRP concentration of >10 mg/L. When adjusted for ECOG-PS, CAR>0.40 (p < 0.001) and mGPS 2 (p < 0.05) remained significantly associated with OS., Conclusion: Liver-based measures of systemic inflammation (CAR and mGPS) appear more reliable for the quantification of the magnitude of SIR and have prognostic value in patients with advanced NSCLC., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

Introduction: Radiation induced lymphopenia (RIL) deteriorate survival and diminishes the benefit of immune checkpoint inhibitors in combined treatment of lung cancer. Given the inconsistent data across various studies on the predictors of RIL, we aim to methodically elucidate these predictors and formulate a practical guide for clinicians., Methods: We conducted observational cohort study in four tertiary cancer centers. Patients with non-small cell lung cancer and small cell lung cancer, without lymphopenia grade >1, who underwent standalone radiotherapy (RT) in minimum 15 fractions were eligible. Dose-volume parameters of structures and clinical factors were comprehensively analyzed using various predictors selection methods and statistical models (Linear Regressors, Elastic Net, Bayesian Regressors, Huber Regression, regression based on k-nearest neighbors, Gaussian Process Regressor, Decision Tree Regressor, Random Forest Regressor, eXtreme Gradient Boosting, Automated Machine Learning) and were ranked to predict lymphocytes count nadir (alc&#95;nadir)., Results: Two hundred thirty eight patients (stage I-3.4%, II-17.6%, III-75.2%, IV-3.8%) who underwent RT to median dose of 60 Gy were analyzed. Median alc&#95;nadir was 0.68K/mm 3 . The 60 feature sets were evaluated in 600 models (RMSE 0.27-0.41K/mm ³ ). The most important features were baseline lymphocyte count (alc&#95;1), mean lung&#95;dose, lung v05, lung v10, heart v05 and effective dose to immune cells (edic). In patients with alc&#95;1 ≤ 2.005K/mm 3 , median alc&#95;nadir predictions were 0.54K/mm3 for lung&#95;v05p > 51.8% and 0.76K/mm 3 for lung&#95;v05p ≤ 51.8%. Lymphopenia was rare in patients with alc&#95;1 > 2.005K/mm 3 ., Discussion: RIL was most severe in patients with low early lymphocyte counts, primarily triggered by low RT doses in the heart and lungs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Kuncman, Pajdziński, Smółka, Bilski, Socha, Stando, Peszyńska-Piorun, Korab, Jereczek-Fossa and Fijuth.)

Radiotherapy plays a critical role in the management of non-metastatic lung cancer, offering curative potential and symptom relief. It serves as a primary treatment modality or adjuvant therapy post-surgery, enhancing local control and survival rates. Modern techniques like Stereotactic Body Radiotherapy (SBRT) enable precise tumor targeting, minimizing damage to healthy tissue and reducing treatment duration. The synergy between radiotherapy and systemic treatments, including immunotherapy, holds promise in improving outcomes. Immunotherapy augments the immune response against cancer cells, potentially enhancing radiotherapy's efficacy. Furthermore, radiotherapy's ability to modulate the tumor microenvironment complements the immunotherapy's mechanism of action. As a result, the combination of radiotherapy and immunotherapy may offer superior tumor control and survival benefits. Moreover, the integration of radiotherapy with surgery and chemotherapy in multidisciplinary approaches maximizes treatment efficacy while minimizing toxicity. Herein we present an overview on modern radiotherapy and potential developments in the close future., Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht., (Thieme. All rights reserved.)

Background: There was limited research data on large-scale locally advanced non-small cell lung cancer (LA-NSCLC) radical radiotherapy (RT) reported in China. This study examined overall survival (OS), progression-free survival (PFS), treatment effectiveness, and toxicity in patients with LA-NSCLC treated with definitive RT in the pre-durvalumab era., Methods: A retrospective analysis of demographic information, clinical characteristics, treatment patterns, and clinical outcomes of 789 patients with LA-NSCLC who underwent radical RT at our center between January 2005 and December 2015 was performed. The Kaplan-Meier method and log-rank test were used for survival comparisons, and Cox regression was used for multivariate analysis., Results: There were 328 patients with stage IIIA disease and 461 with stage IIIB disease. By the last follow-up, there were 365 overall deaths and 576 cases of recurrence, metastasis, or death. The median survival time was 31 months. The OS rates at 1, 2, 5, and 10 years were 83.7%, 59.5%, 28.8%, and 18.9%, respectively. PFS rates at 1, 2, 5, and 10 years were 48%, 24.5%, 11.9%, and 5.5%, respectively. Rates of ≥grade 3 acute radiation pneumonitis or esophagitis were 7.6% and 1.9%, respectively. Rates of ≥grade 3 chronic radiation pneumonitis and esophagitis were 11% and 0.4%, respectively. Multivariate analysis showed that the Karnofsky Performance Status (KPS) score, smoking status, and combined chemotherapy were prognostic factors for OS (p < 0.05). Multivariate analysis revealed that combined chemotherapy and radiation dose were prognostic factors for PFS (p < 0.05)., Conclusions: Our center's data showed that the survival prognosis of locally advanced patients receiving RT and chemotherapy in China was consistent with international levels during the same period. Patients with a KPS score of 80 or higher, who had never smoked or received combined RT, had a more favorable prognosis than those with a KPS of less than 80, who had smoked, or only received RT. The combination of RT and chemotherapy, with a reasonable radiation dose, was the key to improving the therapeutic effect., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

Introduction: The use of stereotactic ablative radiotherapy (SABR) over conventional fractionated radiotherapy (CFRT) for early-stage non-small-cell lung cancer (NSCLC) has been advocated, but is also debated in the literature., Methods: In this retrospective cohort study, we adopted a target trial emulation framework to identify eligible patients diagnosed between 2011 and 2021 using the Taiwan Cancer Registry. In the primary analysis, the overall survival (OS) was the primary endpoint, whereas incidences of lung cancer mortality and radiation pulmonary toxicity were the secondary endpoints. Extensive supplementary analyses were also conducted., Results: We included 351 patients in the primary analysis and found that the OS was not significantly different between the SABR (n = 290) and CFRT (n = 61) groups. The propensity score weighting adjusted hazard ratio of death was 0.75 (95% confidence interval 0.53-1.07, p = 0.118). The secondary endpoints and supplementary analyses showed no significant differences., Conclusions: The OS of patients with early-stage NSCLC treated with SABR was not significantly different from that of patients treated with CFRT alone. The results of the relevant ongoing clinical trials are eagerly awaited., (© 2024 The Author(s). Thoracic Cancer published by John Wiley & Sons Australia, Ltd.)

Importance: The optimal radiotherapy technique for unresectable locally advanced non-small cell lung cancer (NSCLC) is controversial, so evaluating long-term prospective outcomes of intensity-modulated radiotherapy (IMRT) is important., Objective: To compare long-term prospective outcomes of patients receiving IMRT and 3-dimensional conformal radiotherapy (3D-CRT) with concurrent carboplatin/paclitaxel for locally advanced NSCLC., Design, Setting, and Participants: A secondary analysis of a prospective phase 3 randomized clinical trial NRG Oncology-RTOG 0617 assessed 483 patients receiving chemoradiotherapy (3D-CRT vs IMRT) for locally advanced NSCLC based on stratification., Main Outcomes and Measures: Long-term outcomes were analyzed, including overall survival (OS), progression-free survival (PFS), time to local failure, development of second cancers, and severe grade 3 or higher adverse events (AEs) per Common Terminology Criteria for Adverse Events, version 3. The percentage of an organ volume (V) receiving a specified amount of radiation in units of Gy is reported as V(radiation dose)., Results: Of 483 patients (median [IQR] age, 64 [57-70] years; 194 [40.2%] female), 228 (47.2%) received IMRT, and 255 (52.8%) received 3D-CRT (median [IQR] follow-up, 5.2 [4.8-6.0] years). IMRT was associated with a 2-fold reduction in grade 3 or higher pneumonitis AEs compared with 3D-CRT (8 [3.5%] vs 21 [8.2%]; P = .03). On univariate analysis, heart V20, V40, and V60 were associated with worse OS (hazard ratios, 1.06 [95% CI, 1.04-1.09]; 1.09 [95% CI, 1.05-1.13]; 1.16 [95% CI, 1.09-1.24], respectively; all P < .001). IMRT significantly reduced heart V40 compared to 3D-CRT (16.5% vs 20.5%; P < .001). Heart V40 (<20%) had better OS than V40 (≥20%) (median [IQR], 2.5 [2.1-3.1] years vs 1.7 [1.5-2.0] years; P < .001). On multivariable analysis, heart V40 (≥20%), was associated with worse OS (hazard ratio, 1.34 [95% CI, 1.06-1.70]; P = .01), whereas lung V5 and age had no association with OS. Patients receiving IMRT and 3D-CRT had similar rates of developing secondary cancers (15 [6.6%] vs 14 [5.5%]) with long-term follow-up., Conclusions and Relevance: These findings support the standard use of IMRT for locally advanced NSCLC. IMRT should aim to minimize lung V20 and heart V20 to V60, rather than constraining low-dose radiation bath. Lung V5 and age were not associated with survival and should not be considered a contraindication for chemoradiotherapy., Trial Registration: ClinicalTrials.gov Identifier: NCT00533949.

Radioresistance is an inevitable obstacle in the clinical treatment of inoperable patients with non-small cell lung cancer (NSCLC). Combining treatment with radiosensitizers may improve the efficacy of radiotherapy. Previously, the quinoline derivative 10E as new exporter of Nur77 has shown superior antitumor activity in hepatocellular carcinoma. Here, we aimed to investigate the radiosensitizing activity and acting mechanisms of 10E. In vitro, A549 and H460 cells were treated with control, ionizing radiation (IR), 10E, and 10E + IR. Cell viability, apoptosis, and cycle were examined using CCK-8 and flow cytometry assays. Protein expression and localization were examined using western blotting and immunofluorescence. Tumor xenograft models were established to evaluate the radiosensitizing effect of 10E in vivo. 10E significantly inhibited cell proliferation and increased their radiosensitivity while reducing level of p-BCRA1, p-DNA-PKs, and 53BP1 involved in the DNA damage repair pathway, indicating that its radiosensitizing activity is closely associated with repressing DNA damage repair. A549 cells showed low level of Nur77 and a low response to IR but 10E-treated A549 cells showed high level of Nur77 indicating that Nur77 is a core radiosensitivity factor and 10E restores the expression of Nur77. Nur77 and Ku80 extranuclear co-localization in the 10E-treated A549 cells suggested that 10E-modulated Nur77 nuclear exportation inhibits DNA damage repair pathways and increases IR-triggered apoptosis. The combination of 10E and IR significantly inhibits tumor growth in a tumor xenograft model. Our findings suggest that 10E acts as a radiosensitizer and that combining 10E with radiotherapy may be a potential strategy for NSCLC treatment., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: This study aimed to determine whether the combined use of bevacizumab could improve overall survival (OS) in patients with brain metastasis (BM), epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) undergoing cerebral radiotherapy., Materials and Methods: A total of 237 patients with EGFR-mutant lung adenocarcinoma and BM met the inclusion criteria for this retrospective study, including 102 patients in the bevacizumab treatment group and 135 in the non-bevacizumab group. The Kaplan-Meier method was used for survival analysis. Univariate and multivariate analyses were performed to identify EGFR-mutated BM prognostic factors for these patients., Results: At the end of the last follow-up period, 176 patients (74.3%) had died, and the median overall survival (OS) was 34.2 months. We observed a significant difference in the median OS between the bevacizumab and non-bevacizumab groups (45.8 months vs 30.0 months, P < 0.0001). Among the 178 (75.1%) patients who received cerebral radiotherapy, the median OS of patients in the bevacizumab + cerebral radiotherapy group was 45.8 months versus 32.0 months in the non-bevacizumab + cerebral radiotherapy group, respectively (P = 0.0007). Patients treated with bevacizumab after cerebral radiotherapy had a longer median OS than patients treated with bevacizumab before cerebral radiotherapy (59.4 months vs 33.7 months, P = 0.0198). In the univariate analysis, smoking status, Lung-molGPA scores, and bevacizumab therapy showed correlations (HR = 1.450, P = 0.045; HR = 0.700, P = 0.023; HR = 0.499, P < 0.001). Multivariate analysis showed that bevacizumab therapy alone (hazard ratio [HR] = 0.514; P < 0.001) was independently associated with improved OS., Conclusion: In patients with BM from EGFR-mutated NSCLC, cerebral radiotherapy with bevacizumab markedly improved OS. This improvement was more evident after cerebral radiotherapy., (© 2024. The Author(s).)

Purpose: To determine whether 4-dimensional computed tomography (4DCT) ventilation-based functional lung avoidance radiation therapy preserves pulmonary function compared with standard radiation therapy for non-small cell lung cancer (NSCLC)., Methods and Materials: This single center, randomized, phase 2 trial enrolled patients with NSCLC receiving curative intent radiation therapy with either stereotactic body radiation therapy or conventionally fractionated radiation therapy between 2016 and 2022. Patients were randomized 1:1 to standard of care radiation therapy or functional lung avoidance radiation therapy. The primary endpoint was the change in Jacobian-based ventilation as measured on 4DCT from baseline to 3 months postradiation. Secondary endpoints included changes in volume of high- and low-ventilating lung, pulmonary toxicity, and changes in pulmonary function tests (PFTs)., Results: A total of 122 patients were randomized and 116 were available for analysis. Median follow up was 29.9 months. Functional avoidance plans significantly (P < .05) reduced dose to high-functioning lung without compromising target coverage or organs at risk constraints. When analyzing all patients, there was no difference in the amount of lung showing a reduction in ventilation from baseline to 3 months between the 2 arms (1.91% vs 1.87%; P = .90). Overall grade ≥2 and grade ≥3 pulmonary toxicities for all patients were 24.1% and 8.6%, respectively. There was no significant difference in pulmonary toxicity or changes in PFTs between the 2 study arms. In the conventionally fractionated cohort, there was a lower rate of grade ≥2 pneumonitis (8.2% vs 32.3%; P = .049) and less of a decline in change in forced expiratory volume in 1 second (-3 vs -5; P = .042) and forced vital capacity (1.5 vs -6; P = .005) at 3 months, favoring the functional avoidance arm., Conclusions: There was no difference in posttreatment ventilation as measured by 4DCT between the arms. In the cohort of patients treated with conventionally fractionated radiation therapy with functional lung avoidance, there was reduced pulmonary toxicity, and less decline in PFTs suggesting a clinical benefit in patients with locally advanced NSCLC., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: The predictors of long-term survival and appropriate surrogate endpoints in unresectable stage III non-small cell lung cancer (NSCLC) treated with radiotherapy remain unclear, especially in the immune therapy era., Methods: This study retrospectively analyzed a prospective cohort of 822 patients treated at the Chinese National Cancer Center from 2013 to 2022. Cure fractions, surrogates for long-term survival, and associated factors were assessed using a mixture cure model, with validation against a matched Surveillance, Epidemiology, and End Results (SEER) dataset., Results: 27.3% of patients with unresectable stage III NSCLC can achieve long-term survival after treated by radiotherapy. 4-year PFS and 5-year OS, when 80% of patients were considered cured, showed significant correlations with cure rates based on background mortality-adjusted PFS and relative survival, with R-squared values exceeding 0.85. Independent predictors of long-term survival included non-squamous cell carcinoma (non-SCC) pathological type, N category, gross tumor volume, and treatment combination with immune checkpoint inhibitors (ICIs)., Conclusions: Radiotherapy, especially when combined with ICIs, offers a potential cure for a proportion of patients with unresectable stage III NSCLC. Tumor burden and ICIs are key predictors of long-term survival. The study suggested 4-year PFS and 5-year OS as surrogate endpoints for cure and long-term survival assessment., 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 Elsevier B.V. All rights reserved.)

Non-Small Cell Lung Cancer (NSCLC) remains one of the main causes of cancer death worldwide. In the urge of finding an effective approach to treat cancer, enormous therapeutic targets and treatment combinations are explored in clinical studies, which are not only costly, suffer from a shortage of participants, but also unable to explore all prospective therapeutic solutions. Within the evolving therapeutic landscape, the combined use of radiotherapy (RT) and checkpoint inhibitors (ICIs) emerged as a promising avenue. Exploiting the power of quantitative system pharmacology (QSP), we undertook a study to anticipate the therapeutic outcomes of these interventions, aiming to address the limitations of clinical trials. After enhancing a pre-existing QSP platform and accurately replicating clinical data outcomes, we conducted an in-depth study, examining different treatment protocols with nivolumab and RT, both as monotherapy and in combination, by assessing their efficacy through clinical endpoints, namely time to progression (TTP) and duration of response (DOR). As result, the synergy of combined protocols showcased enhanced TTP and extended DOR, suggesting dual advantages of extended response and slowed disease progression with certain combined regimens. Through the lens of QSP modeling, our findings highlight the potential to fine-tune combination therapies for NSCLC, thereby providing pivotal insights for tailoring patient-centric therapeutic interventions., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: The most common form of therapy for nonsmall cell lung cancer (NSCLC) in early stage is surgery-based combination therapy, including radiotherapy and immunotherapy. However, postoperative radiotherapy (PORT) of cancer is correlated with increasing risk of second primary malignancy (SPM), especially young-onset cancer cases. The authors aimed to quantify the risks of SPM associated with PORT treatment for young‑onset NSCLC in early stage., Methods: The authors screened for SPM that developed over 5 years since the diagnosis of NSCLC. Using the data from the Surveillance, Epidemiology, and End Results database, PORT-correlated risks were estimated with multivariate Logistic regression analysis. Moreover, Fine-Gray's competing risk regression analysis was used to calculate the cumulative incidence of SPMs., Results: Among the 30 308 young-onset NSCLC patients in early stage undergoing surgery, a total of 3728 patients have received PORT. Logistic regression analyses showed that PORT showed substantial correlation with elevated risks of second solid malignancies [relative risks (RR)=1.31; 95% CI: 1.17-1.46], lung cancer (RR=1.23; 95% CI: 1.07-1.42), breast cancer (RR=1.74; 95% CI: 1.16-2.74), and colon and rectum cancers (RR=1.37; 95% CI: 1.07-2.06) as well as a negligible risk of second hematologic malignancies (RR=1.15; 95% CI: 0.82-1.67). The cumulative incidence of SPMs revealed similar findings. Higher RR was obtained in NSCLC patients aged 60-69 years (RR=1.33), in white race (RR=1.36), diagnosed in 1975-2000 (RR=1.23) and 2001-2015 (RR=1.40), or diagnosed with lung adenocarcinoma (RR=1.55)., Conclusion: PORT for young-onset NSCLC in early stage was correlated with elevated risks of SPMs (lung cancer, breast cancer, as well as colon and rectum cancers), supporting the need for long-term surveillance of these patients., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Introduction: Limiting acute esophagitis remains a clinical challenge during the treatment of locally advanced non-small cell lung cancer (NSCLC)., Methods: Demographic, dosimetric, and acute toxicity data were prospectively collected for patients undergoing definitive radiation therapy +/- chemotherapy for stage II-III NSCLC from 2012 to 2022 across a statewide consortium. Logistic regression models were used to characterize the risk of grade 2 + and 3 + esophagitis as a function of dosimetric and clinical covariates. Multivariate regression models were fitted to predict the 50 % risk of grade 2 esophagitis and 3 % risk of grade 3 esophagitis., Results: Of 1760 patients, 84.2 % had stage III disease and 85.3 % received concurrent chemotherapy. 79.2 % of patients had an ECOG performance status ≤ 1. Overall rates of acute grade 2 + and 3 + esophagitis were 48.4 % and 2.2 %, respectively. On multivariate analyses, performance status, mean esophageal dose (MED) and minimum dose to the 2 cc of esophagus receiving the highest dose (D2cc) were significantly associated with grade 2 + and 3 + esophagitis. Concurrent chemotherapy was associated with grade 2 + but not grade 3 + esophagitis. For all patients, MED of 29 Gy and D2cc of 61 Gy corresponded to a 3 % risk of acute grade 3 + esophagitis. For patients receiving chemotherapy, MED of 22 Gy and D2cc of 50 Gy corresponded to a 50 % risk of acute grade 2 + esophagitis., Conclusions: Performance status, concurrent chemotherapy, MED and D2cc are associated with acute esophagitis during definitive treatment of NSCLC. Models that quantitatively account for these factors can be useful in individualizing radiation plans., 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 Elsevier B.V. All rights reserved.)

Background: Oligometastases in mediastinal nodes are increasingly prevalent, posing challenges for treatment with stereotactic body radiotherapy (SBRT) due to proximity to organs at risk (OARs). We report the results of a single prospective observational phase II trial on ablative SBRT for medically inoperable thoracic nodes metastases (NCT02970955)., Material and Methods: Since 2017, patients with < 3 nodal metastases were evaluated by the tumor board and included if deemed inoperable. SBRT was delivered using risk adaptive approach based on number, site and size of metastatic nodes (50 Gy/5fractions, 60 Gy/8fractions, 70 Gy/10 fractions). Planning target volume (PTV) partial underdosage was allowed. The primary end point was local control (LC) at 12 months. Secondary end points were: acute and late toxicities, overall survival (OS), progression free survival (PFS), and time to next systemic therapy (TTNS)., Results: Between 03/2017-11/2021, 32 patients (41 nodal metastases) were included. NSCLC (13pts), breast (5pts) and colorectal cancer (4pts) were the most represented primary tumour. In 66 % cases, partial PTV undercoverage was necessary. LC at 1 and 2 years was 93.5 % and 82.3 %, respectively. Treatment was well-tolerated with no acute or late toxicity ≥ G3. Median OS was 59.7 months. OS at 1 and 2 years was 96.9 % and 83.8 % respectively. Median PFS was 12.2 months. PFS at 1 and 2 years was 53.1 % and 31.3 %, respectively., Conclusion: This trial supported the feasibility and safety of ablative SBRT for thoracic nodes metastases thanks to risk adaptive approach allowing to delay of new systemic therapies. Larger studies are needed to confirm these observations., 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 Elsevier B.V. All rights reserved.)

Background: All known randomized trials of stereotactic radiotherapy (SRT) versus whole brain radiotherapy (WBRT) for brain metastases (BMs) comprise mixed histologies. The phase III HYBRID trial (NCT02882984) attempted to evaluate the non-inferiority of SRT vs. WBRT specifically for EGFR-mutated non-small cell lung cancer (EGFRm NSCLC) BMs., Methods: Inclusion criteria were ≤ 5 BMs (any size) from treatment-naïve EGFRm NSCLC. All patients started a first-generation tyrosine kinase inhibitor on the first day of WBRT (37.5 Gy/15 fractions) or SRT (25-40 Gy/5 fractions per tumor volume). The primary endpoint was 18-month intracranial progression-free survival (iPFS; intention-to-treat)., Results: The trial commenced in June 2015 and was closed in April 2021 after screening 208 patients but enrolling 85 (n = 41 WBRT, n = 44 SRT; median follow-up 31 and 36 months, respectively). Respectively, 9.5 % vs. 10.2 % of patients experienced intracranial progression at 18 months, and the median iPFS was 21.4 vs. 22.3 months (p > 0.05 for all). The SRT arm experienced higher overall survival and cognitive preservation (p < 0.05 for all). The most notable reason for low enrollment was patients not wishing to risk neurocognitive decline from WBRT., Conclusions: Although this phase III trial was underpowered, there was no evidence that SRT yielded outcome detriments compared to WBRT for EGFRm NSCLC BMs. Lessons from prematurely closed trials are valuable, as they often provide important experiential perspectives for investigators designing/executing future trials. In the current era, randomized trials involving WBRT without cognitive sparing measures may be at high risk of underaccrual; trial investigators are encouraged to carefully consider our experience when attempting to design such trials. However, trials of molecular-/biologically-stratified patients are highly recommended as the notion of "individualized medicine/oncology" continues to expand., 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 Elsevier B.V. All rights reserved.)

Non-small cell lung cancer (NSCLC) is a prevalent malignant tumor, and the commonly treatment modalities include surgery, radiotherapy, chemotherapy, etc. Currently, CT-guided percutaneous radiofrequency ablation (RFA) for the treatment of cancers has been widely performed. This study aimed to evaluate the safety and efficacy of this therapy in NSCLC patients. Thirty-five NSCLC patients were enrolled in this study and all received CT-guided percutaneous RFA therapy. The outcome measures included the changes in forced respiratory volume in the first second (FEV1), total lung volume (TLC), lesion size and computed tomography (CT) values of the region of interest (ROI) before and after treatment. The main efficacy measures comprised complete tumor ablation and local recurrence after initial treatment, as well as the objective response rate (ORR) and disease control rate (DCR) after 6 months of treatment. After receiving CT-guided percutaneous RFA therapy, the target lesion was effectively controlled and CT values gradually decreased. Besides, no significant changes were observed in the patient's lung function, postoperative complications were experienced by a total of 10 patients, primarily including pneumothorax, infection, lung hollowing. Fortunately, all these complications were successfully managed with appropriate treatment. Following the initial RFA treatment, 31 patients (88.57%) achieved complete ablation, while 6 patients experienced local recurrence. After 6 months of treatment, the ORR and DCR were found to be 68.57% and 82.86% respectively. CT-guided percutaneous RFA has demonstrated favorable safety and efficacy in the treatment of patients with NSCLC at different stages, which represented a promising therapeutic modality., (© 2024. The Author(s), under exclusive licence to Springer-Verlag London Ltd., part of Springer Nature.)

Radiotherapy is one of the predominant treatment modalities for almost all kinds of malignant cancers, including non-small cell lung cancer (NSCLC). Increasing evidence shows that ionizing radiation (IR) induces reactive oxygen species (ROS) leading to lipid peroxidation and subsequently ferroptosis of cancer cells. However, cancer cells evolve multiple mechanisms against ROS biology resulting in resistance to ferroptosis and radiotherapy, of which NRF2 signaling is one of the most studied. In the current research, we identified that microRNA-139 (miR-139) could be a novel radiosensitizer for NSCLC by inhibiting NRF2 signaling. We found that miR-139 possessed great potential as a diagnostic biomarker for NSCLC and multiple other types of cancer. Overexpression of miR-139 increased radiosensitivity of NSCLC cells in vitro and in vivo. MiR-139 directly targeted cJUN and KPNA2 to impair NRF2 signaling resulting in enhanced IR-induced lipid peroxidation and cellular ferroptosis. We proved KPNA2 to be a binding partner of NRF2 that involved in nuclear translocation of NRF2. Moreover, we found that IR induced miR-139 expression through transcriptional factor EGR1. EGR1 bound to the promoter region and transactivated miR-139. Overall, our findings elucidated the effect of EGR1/miR-139/NRF2 in IR-induced ferroptosis of NSCLC cells and provided theoretical support for the potential diagnostic biomarkers and therapeutic targets for the disease., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Lung cancer is the leading cause of cancer-related deaths globally, with non-small cell lung cancer (NSCLC) accounting for over 85% of cases and poor prognosis in advanced stages. This study explored shifts in circulating metabolite levels in NSCLC patients versus healthy controls and examined the effects of conventionally fractionated radiation therapy (CFRT) and stereotactic body radiation therapy (SBRT). We enrolled 91 NSCLC patients (38 CFRT and 53 SBRT) and 40 healthy controls. Plasma metabolite levels were assessed using semi-targeted metabolomics, revealing 32 elevated and 18 reduced metabolites in patients. Key discriminatory metabolites included ethylmalonic acid, maltose, 3-phosphoglyceric acid, taurine, glutamic acid, glycocolic acid, and d-arabinose, with a combined Receiver Operating Characteristics curve indicating perfect discrimination between patients and controls. CFRT and SBRT affected different metabolites, but both changes suggested a partial normalization of energy and amino acid metabolism pathways. In conclusion, metabolomics identified distinct metabolic signatures in NSCLC patients with potential as diagnostic biomarkers. The differing metabolic responses to CFRT and SBRT reflect their unique therapeutic impacts, underscoring the utility of this technique in enhancing NSCLC diagnosis and treatment monitoring.

Objective. Vital rules learned from fluorodeoxyglucose positron emission tomography (FDG-PET) radiomics of tumor subregional response can provide clinical decision support for precise treatment adaptation. We combined a rule-based machine learning (ML) model (RuleFit) with a heuristic algorithm (gray wolf optimizer, GWO) for mid-chemoradiation FDG-PET response prediction in patients with locally advanced non-small cell lung cancer. Approach. Tumors subregions were identified using K-means clustering. GWO+RuleFit consists of three main parts: (i) a random forest is constructed based on conventional features or radiomic features extracted from tumor regions or subregions in FDG-PET images, from which the initial rules are generated; (ii) GWO is used for iterative rule selection; (iii) the selected rules are fit to a linear model to make predictions about the target variable. Two target variables were considered: a binary response measure (ΔSUVmean ⩾ 20% decline) for classification and a continuous response measure (ΔSUVmean) for regression. GWO+RuleFit was benchmarked against common ML algorithms and RuleFit, with leave-one-out cross-validated performance evaluated by the area under the receiver operating characteristic curve (AUC) in classification and root-mean-square error (RMSE) in regression. Main results. GWO+RuleFit selected 15 rules from the radiomic feature dataset of 23 patients. For treatment response classification, GWO+RuleFit attained numerically better cross-validated performance than RuleFit across tumor regions and sets of features (AUC: 0.58-0.86 vs. 0.52-0.78, p = 0.170-0.925). GWO+Rulefit also had the best or second-best performance numerically compared to all other algorithms for all conditions. For treatment response regression prediction, GWO+RuleFit (RMSE: 0.162-0.192) performed better numerically for low-dimensional models ( p = 0.097-0.614) and significantly better for high-dimensional models across all tumor regions except one (RMSE: 0.189-0.219, p < 0.004). Significance . The GWO+RuleFit selected rules were interpretable, highlighting distinct radiomic phenotypes that modulated treatment response. GWO+Rulefit achieved parsimonious models while maintaining utility for treatment response prediction, which can aid clinical decisions for patient risk stratification, treatment selection, and biologically driven adaptation. Clinical trial: NCT02773238., (© 2024 Institute of Physics and Engineering in Medicine.)

Radiotherapy (RT) treatment is an important strategy for the management of non-small cell lung cancer (NSCLC). Local recurrence amongst patients with late-stage NSCLC remains a challenge. The loss of PTEN has been associated with radio-resistance. This study aimed to examine the efficacy of RT combined with ataxia telangiectasia-mutated Rad3-related (ATR) inhibition using Ceralasertib in phosphatase and tensin homolog (PTEN)-depleted NSCLC cells and to assess early inflammatory responses indicative of radiation pneumonitis (RP) after combined-modality treatment. Small hairpin RNA (shRNA) transfections were used to generate H460 and A549 PTEN-depleted models. Ceralasertib was evaluated as a single agent and in combination with RT in vitro and in vivo. Histological staining was used to assess immune cell infiltration in pneumonitis-prone C3H/NeJ mice. Here, we report that the inhibition of ATR in combination with RT caused a significant reduction in PTEN-depleted NSCLC cells, with delayed DNA repair and reduced cell viability, as shown by an increase in cells in Sub G1. Combination treatment in vivo significantly inhibited H460 PTEN-depleted tumour growth in comparison to H460 non-targeting PTEN-expressing (NT) cell-line-derived xenografts (CDXs). Additionally, there was no significant increase in infiltrating macrophages or neutrophils except at 4 weeks, whereby combination treatment significantly increased macrophage levels relative to RT alone. Overall, our study demonstrates that ceralasertib and RT combined preferentially sensitises PTEN-depleted NSCLC models in vitro and in vivo, with no impact on early inflammatory response indicative of RP. These findings provide a rationale for evaluating ATR inhibition in combination with RT in NSCLC patients with PTEN mutations.

Background: Many patients with early-stage lung cancer are not candidates for lobectomy because of various factors, with treatment options including sublobar resection or stereotactic body radiation therapy (SBRT). Limited information exists regarding patient-centered outcomes after these treatments., Methods: Subjects with stage I-IIA non-small cell lung cancer (NSCLC) at high risk for lobectomy who underwent treatment with sublobar resection or SBRT were recruited from five medical centers. Quality of life (QOL) was compared with the Short Form 8 (SF-8) for physical and mental health and Functional Assessment of Cancer Therapy-Lung (FACT-L) surveys at baseline (pretreatment) and 7 days, 30 days, 6 months, and 12 months after treatment. Propensity score methods were used to control for confounders., Results: Of 337 subjects enrolled before treatment, 63% received SBRT. Among patients undergoing resection, 89% underwent minimally invasive video-assisted thoracic surgery or robot-assisted resection. Adjusted analyses showed that SBRT-treated patients had both higher physical health SF-8 scores (difference in differences [DID], 6.42; p = .0008) and FACT-L scores (DID, 2.47; p = .004) at 7 days posttreatment. Mental health SF-8 scores were not different at 7 days (p = .06). There were no significant differences in QOL at other time points, and all QOL scores returned to baseline by 12 months for both groups., Conclusions: SBRT is associated with better QOL immediately posttreatment compared with sublobar resection. However, both treatment groups reported similar QOL at later time points, with a return to baseline QOL. These findings suggest that sublobar resection and SBRT have a similar impact on the QOL of patients with early-stage lung cancer deemed ineligible for lobectomy., (© 2024 American Cancer Society.)

Purpose: Chemoradiotherapy (CRT) combined with immune checkpoint inhibitors (ICIs) is the standard of care for patients with unresectable and locally advanced non-small cell lung cancer. This study aimed to determine whether the addition of ICIs to CRT is associated with an increased risk of pneumonitis., Methods and Materials: The PubMed, Embase, Cochrane Library, and Web of Science databases were searched for eligible studies published between January 1, 2015, and July 31, 2023. The outcome of interest was the incidence rate of pneumonitis. A random-effects model was used for statistical analysis., Results: A total of 185 studies with 24,527 patients were included. The pooled rate of grade ≥2 pneumonitis for CRT plus ICIs was significantly higher than that for CRT alone (29.6%; 95% CI, 25.7%-33.6% vs 20.2%; 95% CI, 17.7%-22.8%; P < .0001) but not that of grade ≥3 (5.7%; 95% CI, 4.8%-6.6% vs 5.6%; 95% CI, 4.7%-6.5%; P = .64) or grade 5 (0.1%; 95% CI, 0.0%-0.2% vs 0.3%; 95% CI, 0.1%-0.4%; P = .68). The results from the subgroup analyses of prospective studies, retrospective studies, Asian and non-Asian studies, concurrent CRT (cCRT), and durvalumab consolidation were comparable to the overall results. However, CRT or cCRT plus PD-1 inhibitors not only significantly increased the incidence of grade ≥2 but also that of grade ≥3 pneumonitis compared to CRT alone or cCRT plus PD-L1 inhibitors., Conclusions: Compared with CRT alone, durvalumab consolidation after CRT appears to be associated with a higher incidence of moderate pneumonitis and CRT plus PD-1 inhibitors with an increased risk of severe pneumonitis. Nevertheless, these findings are based on observational studies and need to be validated in future large head-to-head studies., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Stereotactic ablative radiotherapy (SABR) is increasingly used for the treatment of early-stage non-small cell lung cancer (ES-NSCLC) and for pulmonary metastases. In patients with ES-NSCLC, SABR is highly successful with reported 5-year local control rates of approximately 90%. However, the assessment of local control following lung SABR can be challenging as radiological changes arising from radiation-induced lung injury (RILI) can be observed in up to 90% of patients. These so-called 'benign' radiological changes evolve with time and are often asymptomatic. Several radiological and metabolic features have been explored to help distinguish RILI from local recurrences (LR). These include the Response Evaluation Criteria for Solid Tumors (RECIST), high-risk features (HRF's) and maximum standardized uptake value (SUVmax) on FDG-PET-CT. However, use of some of these approaches have poor predictive values and low specificity for recurrence. A proposed new workflow for the evaluation of post-lung SABR radiological changes will be reviewed which uses the presence of so-called 'actionable radiological features' to trigger changes to imaging schedules and identifies the need for a multidisciplinary board review. Furthermore, this critical review of post-lung SABR imaging will highlight current challenges, new insights, and unknowns in this field., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Louie Alexander has received honoraria from AstraZeneca for speaker's bureau and advisory board participation, unrelated to the present work. Palma David reports a Clinician-Scientist Grant from the Ontario Institute for Cancer Research, royalties from Uptodate.com, and has a consultant role with equity from Need Inc, all unrelated to the present work. Senan Suresh has received honoraria from ViewRay Inc and the Department of Radiation Oncology at the Amsterdam University Medical Center has funded research agreements with ViewRay Inc. and Varian Medical Systems, unrelated to the present work. All other authors declare no conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Purpose: Predicting recurrence following stereotactic body radiotherapy (SBRT) for non-small cell lung cancer provides important information for the feasibility of the individualized radiotherapy and allows to select the appropriate treatment strategy based on the risk of recurrence. In this study, we evaluated the performance of both machine learning models using positron emission tomography (PET) and computed tomography (CT) radiomic features for predicting recurrence after SBRT., Methods: Planning CT and PET images of 82 non-small cell lung cancer patients who performed SBRT at our hospital were used. First, tumors were delineated on each CT and PET of each patient, and 111 unique radiomic features were extracted, respectively. Next, the 10 features were selected using three different feature selection algorithms, respectively. Recurrence prediction models based on the selected features and four different machine learning algorithms were developed, respectively. Finally, we compared the predictive performance of each model for each recurrence pattern using the mean area under the curve (AUC) calculated following the 0.632+ bootstrap method., Results: The highest performance for local recurrence, regional lymph node metastasis, and distant metastasis were observed in models using Support vector machine with PET features (mean AUC = 0.646), Naive Bayes with PET features (mean AUC = 0.611), and Support vector machine with CT features (mean AUC = 0.645), respectively., Conclusions: We comprehensively evaluated the performance of prediction model developed for recurrence following SBRT. The model in this study would provide information to predict the recurrence pattern and assist in making treatment strategies., (© 2024 The Authors. Journal of Applied Clinical Medical Physics is published by Wiley Periodicals, Inc. on behalf of The American Association of Physicists in Medicine.)

Background and Purpose: The ultimate challenge in dose-escalation trials lies in finding the balance between benefit and toxicity. We examined patient-reported outcomes (PROs), including health-related quality of life (HRQoL) in patients with locally advanced non-small cell lung cancer (LA-NSCLC), treated with dose-escalated radiotherapy., Materials and Methods: The international, randomised, phase 2 ARTFORCE PET-Boost study (NCT01024829) aimed to improve 1-year freedom from local failure rates in patients with stage II-III NSCLC, with a ≥ 4 cm primary tumour. Treatment consisted of an individualised, escalated fraction dose, either to the primary tumour as a whole or to its most FDG-avid subvolume (24 x 3.0-5.4 Gy). Patients received sequential or concurrent chemoradiotherapy, or radiotherapy only. Patients were asked to complete the EORTC QLQ-C30, QLQ-LC13, and the EuroQol-5D at eight timepoints. We assessed the effect of dose-escalation on C30 sum score through mixed-modelling and evaluated clinically meaningful changes for all outcomes., Results: Between Apr-2010 and Sep-2017, 107 patients were randomised; 102 were included in the current analysis. Compliance rates: baseline 86.3%, 3-months 85.3%, 12-months 80.3%; lowest during radiation treatment 35.0%. A linear mixed-effect (LME) model revealed no significant change in overall HRQoL over time, and no significant difference between the two treatment groups. Physical functioning showed a gradual decline in both groups during treatment and at 18-months follow-up, while clinically meaningful worsening of dyspnoea was seen mainly at 3- and 6-months., Conclusion: In patients with LA-NSCLC treated with two dose-escalation strategies, the average patient-reported HRQoL remained stable in both groups, despite frequent patient-reported symptoms, including dyspnoea, dysphagia, and fatigue., 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 Elsevier B.V. All rights reserved.)

Aims: To assess the robustness and to define the dosimetric and NTCP advantages of pencil-beam-scanning proton therapy (PBSPT) compared with VMAT for unresectable Stage III non-small lung cancer (NSCLC) in the immunotherapy era., Material and Methods: 10 patients were re-planned with VMAT and PBSPT using: 1) ITV-based robust optimization with 0.5 cm setup uncertainties and (for PBSPT) 3.5 % range uncertainties on free-breathing CT 2) CTV-based RO including all 4DCTs anatomies. Target coverage (TC), organs at risk dose and TC robustness (TCR), set at V95%, were compared. The NTCP risk for radiation pneumonitis (RP), 24-month mortality (24MM), G2 + acute esophageal toxicity (ET), the dose to the immune system (EDIC) and the left anterior descending (LAD) coronary artery V15 < 10 % were registered. Wilcoxon test was used., Results: Both PBSPT methods improved TC and TCR (p < 0.01). The mean lung dose and lung V20 were lower with PBSPT (p < 0.01). Median mean heart dose reduction with PBSPT was 8 Gy (p < 0.001). PT lowered median LAD V15 (p = 0.004). ΔNTCP > 5 % with PBSPT was observed for two patients for RP and for five patients for 24 MM. ΔNTCP for ≥ G2 ET was not in favor of PBSPT for all patients. PBSPT halved median EDIC (4.9/5.1 Gy for ITV/CTV-based VMAT vs 2.3 Gy for both ITV/CTV-based PBSPT, p < 0.01)., Conclusions: PBSPT is a robust approach with significant dosimetric and NTCP advantages over VMAT; the EDIC reduction could allow for a better integration with immunotherapy. A clinical benefit for a subset of NSCLC patients is expected., 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 Associazione Italiana di Fisica Medica e Sanitaria. Published by Elsevier Ltd. All rights reserved.)

Purpose: Radiotherapy planning incorporating functional lung images has the potential to reduce pulmonary toxicity. Free-breathing 4DCT-derived ventilation image (CTVI) may help quantify lung function. This study introduces a novel deep-learning model directly translating planning CT images into CTVI. We investigated the accuracy of generated images and the impact on functional avoidance planning., Materials and Methods: Paired planning CT and 4DCT scans from 48 patients with NSCLC were randomized to training (n = 41) and testing (n = 7) data sets. The ventilation maps were generated from 4DCT using a Jacobian-based algorithm to provide ground truth labels (CTVI 4DCT ). A 3D U-Net-based model was trained to map CT to synthetic CTVI (CTVI Syn ) and validated using fivefold cross-validation. The highest-performing model was applied to the testing set. Spearman's correlation (r s ) and Dice similarity coefficient (DSC) determined voxel-wise and functional-wise concordance between CTVI 4DCT and CTVI Syn . Three plans were designed per patient in the testing set: one clinical plan without CTVI and two functional avoidance plans combined with CTVI 4DCT or CTVI Syn , aimed at sparing high-functional lungs defined as the top 50% of the percentile ventilation ranges. Dose-volume (DVH) parameters regarding the planning target volume (PTV) and organs at risk (OARs) were recorded. Radiation pneumonitis (RP) risk was estimated using a dose-function (DFH)-based normal tissue complication probability (NTCP) model., Results: CTVI Syn showed a mean rs value of 0.65 ± 0.04 compared to CTVI 4DCT . Mean DSC values over the top 50% and 60% of ventilation ranges were 0.41 ± 0.07 and 0.52 ± 0.10, respectively. In the test set (n = 7), all patients' RP-risk benefited from CTVI 4DCT -guided plans (Risk mean&#95;4DCT&#95;vs&#95;Clinical : 29.24% vs. 49.12%, P = 0.016), and six patients benefited from CTVI Syn -guided plans (Risk mean&#95;Syn&#95;vs&#95;Clinical : 31.13% vs. 49.12%, P = 0.022). There were no significant differences in DVH and DFH metrics between CTVI Syn and CTVI 4DCT -guided plan (P > 0.05)., Conclusion: Using deep-learning techniques, CTVI Syn generated from planning CT exhibited a moderate-to-high correlation with CTVI 4DCT . The CTVI Syn -guided plans were comparable to the CTVI 4DCT -guided plans, effectively reducing pulmonary toxicity in patients while maintaining acceptable plan quality. Further prospective trials are needed to validate these findings., (© 2024. The Author(s) under exclusive licence to Japan Radiological Society.)

Radiotherapy (RT) in non-small cell lung cancer (NSCLC) triggers cellular senescence, complicating tumor microenvironments and affecting treatment outcomes. This study examines the role of lymphocyte immunoglobulin-like receptor B2 (LILRB2) in modulating RT-induced senescence and radiosensitivity in NSCLC. Through methodologies including irradiation, lentivirus transfection, and various molecular assays, we assessed LILRB2's expression and its impact on cellular senescence levels and tumor cell behaviors. Our findings reveal that RT upregulates LILRB2, facilitating senescence and a senescence-associated secretory phenotype (SASP), which in turn enhances tumor proliferation and resistance to radiation. Importantly, LILRB2 silencing attenuates these effects by inhibiting the JAK2/STAT3 pathway, significantly increasing radiosensitivity in NSCLC models. Clinical data correlate high LILRB2 expression with reduced RT response and poorer prognosis, suggesting LILRB2's pivotal role in RT-induced senescence and its potential as a therapeutic target to improve NSCLC radiosensitivity., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Immunotherapy, particularly immune checkpoint inhibitors (ICIs), is undoubtedly one of the major breakthroughs in lung cancer research. Patient survival and prognosis have all been improved as a result, although numerous patients do not respond to immunotherapy due to various immune escape mechanisms of the tumor cells. Recent preclinical and clinical evidence has shown that stereotactic body radiotherapy (SBRT), also known as stereotactic ablative radiotherapy, has a prominent immune priming effect that could elicit antitumor immunity against specific tumor antigens and destroy distant tumor cells, thereby achieving the elusive abscopal effect, with the resulting immuno‑active tumor environment also being more conducive to ICIs. Some landmark trials have already demonstrated the survival benefit of the dynamic duo of SBRT plus immunotherapy in metastatic non‑small‑cell lung cancer, while others such as PEMBRO‑RT further suggest that the addition of SBRT to immunotherapy could expand the current indication to those who have historically responded poorly to ICIs. In the present review, the biological mechanisms that drive the synergistic effect of SBRT and immunotherapy were first briefly outlined; then, the current understanding from clinical trials was summarized and new insight into the evolving role of immunotherapy and SBRT synergy in lung cancer treatment was provided. Finally, novel avenues for discovery were highlighted. The innovation of the present review lies in the inclusion of non‑ICI immunotherapy in the discussion, which provides a more comprehensive view on the current development and future trend of SBRT + immunotherapy synergy.

Background and Purpose: To evaluate modern clinical outcomes for patients with brain-only metastatic non-small cell lung cancer (NSCLC) treated with intracranial stereotactic radiosurgery (SRS) with or without definitive treatment of the primary site., Materials and Methods: Patients with synchronously diagnosed NSCLC and brain-only metastatic disease treated with intracranial SRS at a single institution were retrospectively identified. Patients were stratified based on whether they did (A) or did not (B) receive definitive primary site treatment. Patient characteristics and clinical outcomes were compared., Results: From 2008 to 2022, 103 patients were identified, 53 of whom received definitive primary site treatment. Median follow-up was 2.1 y (A) and 0.8 y (B) (p < 0.001). 28 (53 %) patients in Group A received immune checkpoint inhibitor (ICI) therapy versus 19 (38 %) in Group B (p = 0.13) and there were no other statistically significant baseline or treatment characteristic differences between the groups. 5-year local-PFS was 34.5 % (A) versus 0 % (B) (p < 0.001). 5-year regional-PFS was 33.0 % (A) versus 0 % (B) (p < 0.001). 5-year distant body-PFS was 34.0 % (A) versus 0 % (B) (p < 0.001). 5-year CNS-PFS was 14.7 % (A) versus 0 % (B) (p = 0.12). 5-year OS was 40.2 % (A) versus 0 % (B) (p = 0.001). 5-year CSS was 67.6 % (A) versus 0 % (B) (p = 0.002). On multivariable analysis, lack of definitive treatment to the primary site (HR = 2.40), AJCC T3-4 disease (HR = 2.73), and lack of ICI therapy (HR = 2.86) were significant predictors of death., Conclusion: Definitive treatment to the thoracic primary site in patients with brain-only metastatic NSCLC after intracranial radiosurgery was associated with slower progression of disease and improved survival., 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 Elsevier B.V. All rights reserved.)