Purpose Meningiomas (MNGs) occur in different histopathological subtypes. The WHO grading system classifies a subset as grade 2 and 3, indicating a more aggressive course. Recent advances in risk stratification introduces an integrated molecular-morphological score (IntS), offering improved risk prediction over the traditional WHO classification. This study aims to evaluate the prognostic utility of IntS in the context of the timing of adjuvant radiotherapy (RT). Methods This retrospective study analyzed 55 patients with histologically diagnosed WHO grade 2 and 3 MNG treated with adjuvant RT. Molecular analyses using Illumina 450k Human BeadChip and Illumina 850k EPIC stratified patients into 3 risk groups (low, intermediate and high) using an integrated model that combines WHO grading, Copy Number Variations (CNVs), and Methylation Families (MF). Results After 5 years a local failure-free survival (LFFS) rate of 0% in MF-malignant MNG contrasts with a LFFS rate of 77% and 58% in MF-benign and MF-intermediate MNG. A significant correlation between CNVs and LFFS was also observed in the adjuvant setting. The IntS model revealed distinct 5-year LFFS disparities across different risk categories, underscoring the impact of combined morphological and molecular characteristics on outcome. Conclusion The integration of DNA-methylation and CNV-profiles into the IntS unified risk score offer an enhanced prognostic differentiation of MNG patients. This approach shows a promising direction for guiding the optimal timing of adjuvant RT, offering a path toward more tailored treatment strategies for meningiomas.

Background:Evidence on the influence of eloquent brain areas on the effectiveness and side effects of radio-therapy (RT) remains limited. This study evaluated the relationship between eloquent brain regions, radiation dose, and tumor recurrence patterns in glioma patients. Methods:Preoperative navigated transcranial magnetic stimulation (nTMS) mapping of language and motor function, complemented by nTMS-based tractography, was performed. Magnetic resonance imaging of tumor recurrence was co-registered with RT treatment plans and functional nTMS data. Tumor growth direction, radiation dose to eloquent structures, and clinical outcomes were analyzed. Results:Seventy-two patients with glioblastoma, aged 57.7 ± 14.8 years, were included. Tumor recurrence toward eloquent brain areas, assessed either by volumetric or linear measurements, indicated growth affecting motor function in 68.1% and language function in 79.3% of patients. Following RT, new motor deficits occurred in 3/48 patients (6.3%) and language deterioration in 3/20 (15.0%). The mean dose to the corticospinal tract was 10.1 Gy in patients with motor decline versus 3.7 Gy in those without (P = .137). For language fiber tracts, corresponding doses were 34.1 Gy and 15.1 Gy (P = .073). Conclusions:Tumor recurrence toward eloquent brain areas was observed, with high radiation doses to eloquent brain areas being associated with higher rates of neurological deterioration. These findings create an ambiguous situation regarding the application of high radiation doses to the resection cavity facing eloquent brain areas while simultaneously ensuring optimal dose gradients to spare those.

Background: The optimal management of locoregional breast cancer recurrence after prior radiotherapy remains challenging. Reirradiation (ReRT) may allow repeat breast-conserving surgery as an alternative to mastectomy; however, prospective evidence is scarce, and existing data are largely retrospective, with the strongest support for brachytherapy. Despite this, external beam reirradiation (EBreRT) is widely used because of its availability. This systematic review evaluated the feasibility, oncologic outcomes, toxicity, and patient-reported outcomes of external-beam ReRT for locoregional breast cancer recurrence. Methods: Following the PRISMA guidelines (PROSPERO CRD420251003760), seven databases were searched until November 2025 to identify studies evaluating adjuvant external beam reirradiation for locoregional breast cancer recurrence. The outcomes of interest included disease control, survival, toxicity, and patient-reported outcomes, which were summarized descriptively. Results: Twenty-four studies published between the mid-1980s and 2024, comprising 1252 patients, were included; most were retrospective, heterogeneous, single-institution cohorts with moderate quality. Reirradiation was predominantly delivered as partial-breast photon-based EBreRT using conventional fractionation. Conclusions: Evidence on EBreRT for locoregional breast cancer recurrence remains insufficient to define optimal dose regimens, treatment intervals, or standardized patient selection criteria, as the available studies are predominantly retrospective and heterogeneous. Nevertheless, the available data suggest that EBreRT may be a feasible therapeutic option, provided that careful case-by-case patient selection is applied.

Purpose To evaluate the relationship between cardiac radiation dose and progression of subclinical coronary artery disease using cardiac CT at baseline and 24 months after breast cancer radiation therapy. Materials and Methods This secondary analysis of the prospective multicenter EARLY-HEART study (ClinicalTrials.gov identifier: NCT03297346) included asymptomatic participants with breast cancer treated with radiation therapy after lumpectomy who underwent cardiac CT before radiation therapy (T0) and at 24-month follow-up (T24). Cardiac radiation dose to the whole heart, left ventricle, right ventricle, and left anterior descending coronary artery was quantified using mean dose and volume-based metrics. Coronary artery calcium (CAC) progression was assessed as changes in CAC score between T0 and T24 at noncontrast CT, and stenosis progression was assessed at coronary CT angiography using Coronary Artery Disease Reporting and Data System classification. Associations between cardiac radiation dose and imaging-based progression were evaluated using multivariable linear and logistic regression models adjusted for cardiovascular risk factors. Results The final analysis included 224 participants (58.4 years ± 8.0; all female participants). CACS was higher at T24 than at T0 (median, 0 [IQR, 0-25] vs 0 [IQR, 0-17]; P < .001). Among 88 participants with CAC scores greater than 0 at T24, CACS increased more from T0 in the highest quartile of cardiac radiation dose compared with the remaining participants (whole heart mean dose, P < .001). The proportion of participants with CAC progression above the cohort median (16 participants) was also greater in those receiving the highest radiation doses (relative risk: whole heart, 2.0 [95% CI: 1.5, 2.8]; left ventricle, 1.8 [95% CI: 1.2, 2.5]; right ventricle, 1.7 [95% CI: 1.2, 2.5]; left anterior descending coronary artery, 1.5 [95% CI: 1.0, 2.3]). In contrast, progression of coronary stenosis at coronary CT angiography (36 of 224) was not associated with cardiac radiation dose but was strongly associated with higher baseline CACS and greater CAC progression (both P < .001). Conclusion Higher cardiac radiation dose during breast cancer radiation therapy was associated with increased CAC progression at 2-year follow-up, particularly in participants with preexisting calcification, whereas coronary stenosis progression was unrelated to dose. Keywords: Radiotherapy, Cardiac CT, Atherosclerosis, Coronary Artery Plaque Supplemental material is available for this article. ClinicalTrials.gov identifier: NCT03297346 © RSNA, 2026.

Purpose:/Objectives: Older adults with WHO grade 4 glioma face distinct therapeutic challenges due to age-related comorbidities, treatment intolerance and tumor aggressiveness. This retrospective study evaluates the prognostic value of the Onco-Functional Outcome (OFO) classification, which integrates extent of resection and postoperative functional status, in the context of radiotherapy (RT) for patients with grade 4 glioma. Materials:/Methods: 139 patients aged ≥ 60 years treated between 2001 and 2021 were included. Patients were grouped into four OFO categories based on Karnofsky Performance Status, National Institutes of Health Stroke Scale, and resection extent. Survival outcomes were assessed using Kaplan-Meier and compared by log-rank test. Univariate and multivariable analyses were performed using Cox proportional hazards model. Results:Median OS decreased across OFO groups (OFO1-4: 22.6, 20.5, 12.6, and 11.2 months respectively, log-rank, p = 0.0026). PFS followed a similar pattern (12.2, 9.3, 6.7, and 5.7 months respectively; p = 0.0030). Among 119 patients with known MGMT status, methylation (n = 49) was associated with significantly prolonged OS (36.3 vs. 12.6 months, p < 0.00001) and PFS (14.1 vs 5.9 months, p < 0.00001). Survival advantage of NF-RT showed a a strong trend in both univariate (OS HR = 0.47, 95 % CI 0.28-0.82; p = 0.007) and multivariate models (OS HR = 0.57, 95 % CI 0.33-1.00, 0.051). In multivariable analysis, the OFO classification retained independent prognostic value, with OFO Group 4 associated with a significantly increased risk of both death (OS: HR = 2.91, p = 0.003) and disease progression (PFS: HR = 3.08, p = 0.0005) compared to OFO Group 1. Conclusions:OFO classification effectively stratifies survival in elderly grade 4 glioma patients. Its integration with MGMT methylation status and RT regimen refines risk assessment, supporting personalized treatment strategies in this vulnerable patient group.

The aim of this review is to give an overview of the results of prospective and retrospective studies using allogenic reconstruction and postmastectomy radiotherapy (PMRT) in breast cancer and to make recommendations regarding this interdisciplinary approach. A PubMed search was conducted to extract relevant articles from 2000 to 2024. The search was performed using the following terms: (breast cancer) AND (reconstruction OR implant OR expander) AND (radiotherapy OR radiation). Data from the literature on allogenic breast reconstruction and radiation are presented and discussed in relation to toxicity and cosmesis. Breast reconstruction is also feasible if PMRT is necessary. Patients need to be informed about the relevant risk of capsular fibrosis and implant failure. A planned reconstruction is no reason to forgo PMRT nor is an indication for PMRT a reason to forego implant-based breast reconstruction if desired by the patient. It is important to provide detailed information here to enable shared decision-making. There is still no clear consensus regarding implant-based reconstruction (IBR) and PMRT. However, in clinical practice, both a one-stage (immediate “implant-direct” IBR) procedure with PMRT up to the final implant and a two-stage (immediate-delayed IBR) procedure with PMRT up to the tissue expander (TE) and later exchange of the TE are used; both approaches have their specific advantages and disadvantages. Depending on patient-specific factors and the surgeon’s experience and estimates, both IBR procedures are also possible in combination with PMRT. When using a TE/implant approach, completing skin stretching by adequately filling the expander before PMRT may be favorable. This approach is particularly practical when adjuvant chemotherapy is planned but may lead to postponement of radiotherapy when primary systemic therapy is given. According to the latest data, moderate hypofractionation also appears to be safe in the context of the IBR approach. It is important to have a closely coordinated interdisciplinary approach and to fully inform patients about the increased rate of potential side effects.

PurposeGeneral practitioners (GPs) play a crucial role in providing interdisciplinary care for radiation oncology patients. This study aims to understand the specific needs and challenges faced by general practitioners in Germany when treating oncology patients.MethodsA comprehensive web-based questionnaire with 24 items was disseminated to GPs in Germany via email using survio.com. The survey collected data on demographics, qualifications, clinical experiences, decision-making involvement, and symptom recognition. It specifically examined post-radiotherapy care and the use of specialized palliative homecare networks (SAPV). Statistical analyses were descriptive. The survey was open from July 4 to August 9, 2023.ResultsA notable majority of general practitioners displayed confidence in their understanding of cancer-related symptoms, with over half (54.6%) rating their knowledge with 4 out of 5. This level of self-assessed expertise extended to their capacity to address the needs of cancer patients (53.8%), although 67% express a need for further education in specifically radiotherapeutic side effects. Satisfaction with SAPV networks was high, and 72.3% of respondents were actively involved in palliative care, compared to only 45.6% in managing radiation therapy. Notable challenges included inadequate communication with specialists, insufficient staffing, and under-recognition of GPs' roles in oncology care.ConclusionThe study highlights a paradox where GPs show high engagement in palliative care but limited involvement in radiation therapy management due to communication gaps and professional development needs. Addressing these disparities through targeted initiatives and fostering a collaborative care model is essential to amplify the important role of GPs, ensuring more integrated and effective patient care.

Elderly high-grade glioma (HGG) or glioblastoma (GBM) patients face challenging treatment conditions due to comorbidities and age-related factors. The age-adjusted Charlson Comorbidity Index (ACCI) accounts for age and comorbidities and serves as a tool for predicting survival rates in various clinical scenarios. This study examined its prognostic value in elderly HGG patients undergoing radiotherapy (RT) and concurrent chemoradiotherapy (CRT). We retrospectively analyzed 163 elderly HGG patients (≥ 60 years) treated with radiotherapy (RT) or chemo-RT (CRT) at TUM University Hospital (2001–2021). Kaplan-Meier analysis estimated median overall survival (OS) by ACCI group (≤ 5 vs. ≥6). Multivariate Cox regressions assessed OS and progression-free-survival (PFS) based on fractionation and treatment strategies. Further Cox models evaluated ACCI scores, age, comorbidities, and mortality. A random survival forest (RSF) identified key survival predictors, using permutation importance with bootstrapped confidence intervals. Among the 163 HGG patients, those with greater comorbidities (ACCI ≥ 6) had a shorter median OS (14.8 months) than did those with ACCI ≤ 5 (22.6 months) (log-rank p = 0.463). In the ACCI ≤ 5 subgroup, hypofractionated RT (hRT) alone was significantly associated with worse OS than Stupp was (HR = 85.7, 95

BACKGROUND:Approximately 25-50% of patients undergoing radiotherapy (RT) experience psychological distress and anxiety, which can detrimentally affect both their quality of life and treatment outcomes. While previous research has demonstrated that relaxation exercises can enhance the tolerability of RT and alleviate associated stress and anxiety, the specific needs for such therapies in radiation oncology remain under-explored. This study aims to investigate the demand for and preferences toward relaxation exercises among radiotherapy patients, addressing a critical gap in patient-centered care.METHODS:A prospective pseudonymized survey study using a one-time paper-based questionnaire was conducted from 2022 to 2023 among patients undergoing curative-intent RT for breast cancer or patients undergoing palliative RT for bone metastases. Patients were asked in a 11-item questionnaire about their anxiety, pre-existing practice of relaxation exercises/interventions, their interest in relaxation exercises, and preferences on the type and format of instruction. Data were analyzed descriptively.RESULTS:100 patients (74 female and 26 male) responded, of whom 68 received curative-intent adjuvant RT and 32 palliative RT. Median age was 62 years. 78% of patients indicated a desire to be actively involved in their radiotherapy, but only 27% had used relaxation exercises prior to RT. 44.8% of both curatively and palliatively treated patients who wanted to be actively involved in their therapy desired to learn how to best relax. 56.4% of respondents were willing to spend extra time learning offered exercises.CONCLUSION:The survey indicates that patients undergoing RT, both for curative or palliative intent, desire relaxation exercises to relieve stress and anxiety from RT. It is therefore important to assess the need for relaxation interventions in individual patients and to develop suitable programs or collaborate with other healthcare professionals to meet these needs.

PURPOSE Rapidly expanding medical literature challenges oncologists seeking targeted cancer therapies. General-purpose large language models (LLMs) lack domain-specific knowledge, limiting their clinical utility. This study introduces the LLM system Medical Evidence Retrieval and Data Integration for Tailored Healthcare (MEREDITH), designed to support treatment recommendations in precision oncology. Built on Google's Gemini Pro LLM, MEREDITH uses retrieval-augmented generation and chain of thought . METHODS We evaluated MEREDITH on 10 publicly available fictional oncology cases with iterative feedback from a molecular tumor board (MTB) at a major German cancer center. Initially limited to PubMed -indexed literature (draft system), MEREDITH was enhanced to incorporate clinical studies on drug response within the specific tumor type, trial databases, drug approval status, and oncologic guidelines. The MTB provided a benchmark with manually curated treatment recommendations and assessed the clinical relevance of LLM-generated options (qualitative assessment). We measured semantic cosine similarity between LLM suggestions and clinician responses (quantitative assessment). RESULTS MEREDITH identified a broader range of treatment options (median 4) compared with MTB experts (median 2). These options included therapies on the basis of preclinical data and combination treatments, expanding the treatment possibilities for consideration by the MTB. This broader approach was achieved by incorporating a curated medical data set that contextualized molecular targetability. Mirroring the approach MTB experts use to evaluate MTB cases improved the LLM's ability to generate relevant suggestions. This is supported by high concordance between LLM suggestions and expert recommendations (94.7% for the enhanced system) and a significant increase in semantic similarity from the draft to the enhanced system (from 0.71 to 0.76, P = .01). CONCLUSION Expert feedback and domain-specific data augment LLM performance. Future research should investigate responsible LLM integration into real-world clinical workflows.

PURPOSE:The identification of internal mammary lymph node metastases and the assessment of associated risk factors are crucial for adjuvant regional lymph node irradiation in patients with breast cancer. The current study aims to investigate whether tumor contact with internal mammary perforator vessels is associated with gross internal mammary lymph node involvement. METHODS AND MATERIALS:We included 297 patients with primary breast cancer and gross internal mammary (IMN+) and/or axillary metastases as well as 230 patients without lymph node metastases. Based on pretreatment dynamic contrast-enhanced magnetic resonance imaging, we assessed contact of the tumor with the internal mammary perforating vessels (IMPV). RESULTS:A total of 59 patients had ipsilateral IMN+ (iIMN+), 10 patients had contralateral IMN+ (cIMN+), and 228 patients had ipsilateral axillary metastases without IMN; 230 patients had node-negative breast cancer. In patients with iIMN+, 100% of tumors had contact with ipsilateral IMPV, with 94.9% (n = 56) classified as major contact. In iIMN- patients, major IMPV contact was observed in only 25.3% (n = 116), and 36.2% (n = 166) had no IMPV contact at all. Receiver operating characteristic analysis revealed that "major IMPV contact" was more accurate in predicting iIMN+ (area under the curve, 0.85) compared with a multivariate model combining grade of differentiation, tumor site, size, and molecular subtype (area under the curve, 0.65). Strikingly, among patients with cIMN+, 100% of tumors had contact with a crossing contralateral IMPV, whereas in cIMN- patients, IMPVs to the contralateral side were observed in only 53.4% (iIMN+) and 24.8% (iIMN-), respectively. CONCLUSIONS:Tumor contact with the IMPV is highly associated with risk of gross IMN involvement. Further studies are warranted to investigate whether this identified risk factor is also associated with microscopic IMN involvement and whether it can assist in the selection of patients with breast cancer for irradiation of the internal mammary lymph nodes.

Skin inflammation with the potential sequel of moist epitheliolysis and edema constitute the most frequent breast radiotherapy (RT) acute side effects. The aim of this study was to compare the predictive value of tissue-derived radiomics features to the total breast volume (TBV) for the moist cells epitheliolysis as a surrogate for skin inflammation, and edema. Radiomics features were extracted from computed tomography (CT) scans of 252 breast cancer patients from two volumes of interest: TBV and glandular tissue (GT). Machine learning classifiers were trained on radiomics and clinical features, which were evaluated for both side effects. The best radiomics model was a least absolute shrinkage and selection operator (LASSO) classifier, using TBV features, predicting moist cells epitheliolysis, achieving an area under the receiver operating characteristic (AUROC) of 0.74. This was comparable to TBV breast volume (AUROC of 0.75). Combined models of radiomics and clinical features did not improve performance. Exclusion of volume-correlated features slightly reduced the predictive performance (AUROC 0.71). We could demonstrate the general propensity of planning CT-based radiomics models to predict breast RT-dependent side effects. Mammary tissue was more predictive than glandular tissue. The radiomics features performance was influenced by their high correlation to TBV volume.

Purpose: Randomized studies demonstrated the oncological equivalence of (ultra-)hypofractionation compared to a 5-week schedule in postoperative radiotherapy of breast cancer. Due to the low incidence and long latency of secondary malignancies, there are currently no reliable clinical data regarding the influence of fractionation regimens on the development of secondary malignancies. Material and methods: For 20 patients with right or left-sided breast cancer, postoperative treatment plans were created using 3D-CRT (n = 10) or VMAT (n = 10) for three different fractionation schedules: 5-week schedule with 50.4Gy in 1.8Gy (28fx), hypofractionation with 40.05Gy in 2.67Gy (15fx) and ultra-hypofractionation with 26Gy in 5.2Gy (5fx). The EARs (absolute additional cases of disease per 10,000 patient-years) for secondary malignancies in the lung, contralateral breast, esophagus, liver, thyroid, spinal cord, bones and soft tissue were calculated using a fraction-dependent dose-response model. Results: Based on risk modulation, (ultra-)hypofractionation resulted in significantly lower EARs for lung cancer (LC), contralateral breast cancer (CBC) and soft tissue sarcoma (STS) (p < .001). For the ultra-hypofractionated dose concept the median EARs for LC, CBC and STS were 42.8 %, 39.4 % and 58.1 % lower compared to conventional fractionation and 31.2 %, 25.7 % and 20.3 % compared to hypofractionation. The influence of fractionation on the risk of secondary malignancies for LC and CBC was less pronounced with 3D-CRT than with VMAT. For STS, however, the influence of fractionation was greater with 3D-CRT than with VMAT. Conclusion: Based on this simulation study (ultra-)hypofractionated postoperative breast cancer irradiation may be associated with a lower risk of secondary malignancies compared to a 5-week schedule.

Metastasis -directed therapy has the potential to improve progressionfree and overall survival in oligometastatic disease (OMD). For breast cancer, however, randomized trials have failed so far to confirm this finding. Because the concept of metastasis -directed therapy in OMD is highly dependent on the accuracy of the imaging modality, we aimed to assess the impact of 18 F-FDG PET/CT on the definition of OMD in breast cancer patients. Methods: Eighty patients with a total of 150 18 F-FDG PET/CT images (between October 2006 and January 2022) were enrolled in this retrospective study at the Technical University of Munich. The inclusion criteria were OMD, defined as 1-5 distant metastases, at the time of 18 F-FDG PET/CT. For the current study, we systemically compared the metastatic pattern on 18 F-FDG PET/CT with conventional CT. Results: At the time of 18 F-FDG PET/CT, 21.3% of patients ( n = 32) had a first-time diagnosis of metastatic disease, 40.7% ( n = 61) had a previous history of OMD, and 38% ( n = 57) had a previous history of polymetastatic disease. In 45.3% of cases, the imaging modality ( 18 F-FDG PET/CT vs. conventional CT) had an impact on the assessment of whether OMD was present. An identical metastatic pattern was observed in only 32% of cases. 18 F-FDG PET/CT detected additional metastases in 33.3% of cases, mostly in the nonregional lymph node system. Conclusion: The use of 18 F-FDG PET/CT had a substantial impact on the definition of OMD and detection of metastatic pattern in breast cancer. Our results emphasize the importance of establishing a standardized definition for imaging modalities in future trials and clinical practices related to metastasisdirected therapy in breast cancer patients.

The aim of this review was to evaluate the existing evidence for radiotherapy for brain metastases in breast cancer patients and provide recommendations for the use of radiotherapy for brain metastases and leptomeningeal carcinomatosis. For the current review, a PubMed search was conducted including articles from 01/1985 to 05/2023. The search was performed using the following terms: (brain metastases OR leptomeningeal carcinomatosis) AND (breast cancer OR breast) AND (radiotherapy OR ablative radiotherapy OR radiosurgery OR stereotactic OR radiation). Despite the fact that the biological subtype of breast cancer influences both the occurrence and relapse patterns of breast cancer brain metastases (BCBM), for most scenarios, no specific recommendations regarding radiotherapy can be made based on the existing evidence. For a limited number of BCBM (1–4), stereotactic radiosurgery (SRS) or fractionated stereotactic radiotherapy (SRT) is generally recommended irrespective of molecular subtype and concurrent/planned systemic therapy. In patients with 5–10 oligo-brain metastases, these techniques can also be conditionally recommended. For multiple, especially symptomatic BCBM, whole-brain radiotherapy (WBRT), if possible with hippocampal sparing, is recommended. In cases of multiple asymptomatic BCBM (≥ 5), if SRS/SRT is not feasible or in disseminated brain metastases (> 10), postponing WBRT with early reassessment and reevaluation of local treatment options (8–12 weeks) may be discussed if a HER2/Neu-targeting systemic therapy with significant response rates in the central nervous system (CNS) is being used. In symptomatic leptomeningeal carcinomatosis, local radiotherapy (WBRT or local spinal irradiation) should be performed in addition to systemic therapy. In patients with disseminated leptomeningeal carcinomatosis in good clinical condition and with only limited or stable extra-CNS disease, craniospinal irradiation (CSI) may be considered. Data regarding the toxicity of combining systemic therapies with cranial and spinal radiotherapy are sparse. Therefore, no clear recommendations can be given, and each case should be discussed individually in an interdisciplinary setting.

Background and purpose: In a relevant number of primary breast cancer patients, lymphatic drainage to the contralateral internal mammary nodes (cIMN) is being observed. Nevertheless, so far lymphatic drainage pathway to the cIMN is largely neglected during adjuvant radiotherapy. Materials and methods: This study evaluated the incidental dose to the cIMN for 120 volumetric modulated arc therapy (VMAT) treatment plans for node positive breast in dependence of internal mammary node irradiation (IMNI) and deep inspiration breath hold (DIBH). Additionally, incidental dose distribution to the cIMN based on the field design in the MA20, EORTC22922/10925 and AMAROS trials was assessed. Results: The incidental dose (Dmean +/- SD) to the cIMN-CTV was 13.0 (+/- 4.7) +/- 4.7) Gy with a maximum dose of < 30 Gy in 113/120 cases. If IMNI was included (n = 80), the Dmean to the cIMN-CTV was significantly higher compared to no IMNI, but still comparably low (n = 40; 14.3 Gy vs. 9.6 Gy; p = 0.0001). Furthermore, the dose in the cIMN during free breathing (n = 80) was higher compared to DIBH (n = 40; 13.9 Gy vs. 11.2 Gy; p = 0.002). Simulated treatment plans based on the randomized RNI trials revealed neglectable dose coverage of the cIMN (Dmean 1.0-1.8 Gy) for all protocols. Conclusion: Neither in the randomized RNI trials nor during contemporary treatment techniques clinically relevant dose distribution to the cIMN was observed. Further studies are warranted to assess the potential impact of intended irradiation of cIMN in high-risk patients.

Background Post-Therapy-Pneumonitis (PTP) is a critical side effect of both, thoracic radio(chemo)therapy (R(C)T) and immune checkpoint inhibition (ICI). However, disease characteristics and patient-specific risk factors of PTP after combined R(C)T + ICI are less understood. Given that RT-triggered PTP is strongly dependent on the volume and dose of RT, driven by inflammatory mechanisms, we hypothesize that combination therapy of R(C)T with ICI influences the dose-volume-effect correlation for PTP. This study focuses on the development of a method for evaluation of alterations in the dose-volume-effect correlation of PTP after R(C)T with and without ICI. Methods and materials PTP volumes were delineated on the follow-up diagnostic Computed Tomography (CT) and deformably matched to the planning CT. Dose data was converted to 2-Gy equivalent doses (EQD2) and dosimetrically analyzed. The method was exemplarily tested on an internal patient cohort including 90 patients having received thoracic R(C)T + ICI (39) and R(C)T (51). Additionally, data on previous chemotherapy and RT, smoking status and pulmonary co-morbidity was conducted. An exploratory analysis has been performed and a matched pair analysis with regard to planning target volumes (PTV) was conducted for curative intended (definitive) and palliative patient cohorts individually. Results The presented method was able to demonstrate differences in the dose-volume-effect-correlation of PTP for the different therapies. The dosimetric analysis revealed large volumetric fractions (55%) of the PTP volumes to be located outside of high dose (EQD2 < 40 Gy) regions for R(C)T + ICI. There was a non-significant trend towards increased AUC values for R(C)T + ICI compared to R(C)T only (3743.6 Gy∙% vs. 2848.8 Gy∙%; p -value = 0.171). In contrast to the data for the palliative intended treatment group, for definitive R(C)T + ICI, data tended towards increased volumes with higher doses. Conclusions The proposed method was capable to demonstrate dosimetric differences in the dose-volume-effect relationship of PTP for patients with R(C)T + ICI and patients with R(C)T only. In this exploratory analysis, the patient cohorts were too small and inhomogeneous to reveal statistically significant dosimetric differences within PTP volumes for the different groups. However, our observations suggest, that for safe application of thoracic R(C)T + ICI, further careful investigation of dosimetric prescription and analysis concepts with larger and conformer study groups is recommendable.