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Introduction: Re-irradiation is frequently performed in the era of precision oncology, but previous doses to organs-at-risk (OAR) must be assessed to avoid cumulative overdoses. Stereotactic magnetic resonance-guided online adaptive radiotherapy (SMART) enables highly precise ablation of tumors close to OAR. However, OAR doses may change considerably during adaptive treatment, which complicates potential re-irradiation. We aimed to compare the baseline plan with different dose accumulation techniques to inform re-irradiation., Patients & Methods: We analyzed 18 patients who received SMART to lung or liver tumors inside prospective databases. Cumulative doses were calculated inside the planning target volumes (PTV) and OAR for the adapted plans and theoretical non-adapted plans via (1) cumulative dose volume histograms (DVH sum plan) and (2) deformable image registration (DIR)-based dose accumulation to planning images (DIR sum plan). We compared cumulative dose parameters between the baseline plan, DVH sum plan and DIR sum plan using equivalent doses in 2 Gy fractions (EQD2)., Results: Individual patients presented relevant increases of near-maximum doses inside the proximal bronchial tree, spinal cord, heart and gastrointestinal OAR when comparing adaptive treatment to the baseline plans. The spinal cord near-maximum doses were significantly increased in the liver patients (D2% median: baseline 6.1 Gy, DIR sum 8.1 Gy, DVH sum 8.4 Gy, p = 0.04; D0.1 cm³ median: baseline 6.1 Gy, DIR sum 8.1 Gy, DVH sum 8.5 Gy, p = 0.04). Three OAR overdoses occurred during adaptive treatment (DIR sum: 1, DVH sum: 2), and four more intense OAR overdoses would have occurred during non-adaptive treatment (DIR sum: 4, DVH sum: 3). Adaptive treatment maintained similar PTV coverages to the baseline plans, while non-adaptive treatment yielded significantly worse PTV coverages in the lung (D95% median: baseline 86.4 Gy, DIR sum 82.4 Gy, DVH sum 82.2 Gy, p = 0.006) and liver patients (D95% median: baseline 87.4 Gy, DIR sum 82.1 Gy, DVH sum 81.1 Gy, p = 0.04)., Conclusion: OAR doses can increase during SMART, so that re-irradiation should be planned based on dose accumulations of the adapted plans instead of the baseline plan. Cumulative dose volume histograms represent a simple and conservative dose accumulation strategy., (© 2023. The Author(s).)

Introduction: Approximately 40% of non-small-cell lung cancer (NSCLC) patients develop brain metastases (BM). Stereotactic radiosurgery (SRS) instead of whole-brain radiotherapy (WBRT) is increasingly administered as an upfront treatment to patients with a limited number of BM. We present outcomes and validation of prognostic scores for these patients treated with upfront SRS., Methods: We retrospectively analyzed 199 patients with a total of 268 SRS courses for 539 brain metastases. Median patient age was 63 years. For larger BM, dose reduction to 18 Gy or hypofractionated SRS in 6 fractions was applied. We analyzed the BMV-, the RPA-, the GPA- and the lung-mol GPA score. Cox proportional hazards models with univariate and multivariate analyses were fitted for overall survival (OS) and intracranial progression-free survival (icPFS)., Results: Sixty-four patients died, 7 of them of neurological causes. Thirty eight patients (19,3%) required a salvage WBRT. Median OS was 38, 8 months (IQR: 6-NA). In univariate analysis as well as multivariate analysis, the Karnofsky performance scale index (KPI) ≥90% (P = 0, 012 and P = 0, 041) remained as independent prognostic factor for longer OS. All 4 prognostic scoring indices could be validated for OS assessment (BMV P = 0, 007; RPA P = 0, 026; GPA P = 0, 003; lung-mol GPA P = 0, 05)., Conclusion: In this large cohort of NSCLC patients with BM treated with upfront and repeated SRS, OS was markedly favourable, in comparison to literature. Upfront SRS is an effective treatment approach in those patients and can decidedly reduce the impact of BM on overall prognosis. Furthermore, the analysed scores are useful prognostic tools for OS prediction., Competing Interests: Disclosure Dr. Adeberg reports Grants from Novocure GmbH, Accuray International Sàrl, Merck Serono GmbH and outside the submitted work. Consulting fees from Accuray International Sàrl, Sanofi Genzyme, AstraZeneca and honoraria for lectures / presentations from Accuray International Sàrl and MSD outside the submitted work. Travel reimbursements from AstraZeneca outside the submitted work. Advisory boards for Sanofi Genzyme and Novartis outside the submitted work. Dr. König reports personal fees from speaker fees from the company Optune, outside the submitted work. Prof. Dr. Christopoulos reports grants and personal fees from Roche, grants and personal fees from Takeda, grants from Amgen, grants from Merck, grants and personal fees from AstraZeneca, grants and personal fees from Novartis, personal fees from Gilead, personal fees from Janssen, personal fees from Daiichi Sankyo, personal fees from Eli Lilly, personal fees from Pfizer, personal fees from Chugai, personal fees from Boehringer Ingelheim, outside the submitted work. Dr. Eichkorn reports and Travel reimbursement from Bristol-Myers Squibb outside the submitted work. Prof. Dr. Rieken reports personal fees from Accuray Inc., personal fees from AstraZeneca GmbH, personal fees from Bristol Myers Squibb GmbH & Co., personal fees from Novocure GmbH, personal fees from Merck KGaA, grants from Accuray Inc., outside the submitted work. Prof. Dr. Debus reports grants from Viewray Inc, grants from Accuray International Sari, grants from RaySearch Laboratories AB, grants from Vision RT Limited, grants from Merck Serono GmbH, grants from Astellas Pharma GmbH, grants from Astra Zeneca GmbH, grants from Siemens Healthcare GmbH, grants from Solution Akademie GmbH, grants from Egomed PLC Surrey Reserach Park, grants from Quintiles GmbH, grants from Pharmaceutical Research Associates GmbH, grants from Boehringer Ingelheim Pharma GmbH&CoKG, grants from PTW-Freiburg Dr. Pychlau GmbH, grants from Nanobiotix S.A., grants from Accuray Incorporated, outside the submitted work. PD Dr. El Shafie reports grants from Ruprecht-Karls Universität Heidelberg, during the conduct of the study; personal fees from Accuray Inc., personal fees from AstraZeneca GmbH, personal fees from Bristol Myers Squibb GmbH & Co., personal fees from Novocure GmbH, personal fees from Merck KGaA, personal fees from Takeda GmbH, grants from Accuray Inc., outside the submitted work. The remaining authors declare no conflict of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Stereotactic radiotherapy of ultracentral lung tumors (ULT) is challenging as it may cause overdoses to sensitive mediastinal organs with severe complications. We aimed to describe long-term outcomes after stereotactic magnetic resonance (MR)-guided online adaptive radiotherapy (SMART) as an innovative treatment of ULT., Patients & Methods: We analyzed 36 patients that received SMART to 40 tumors between 02/2020 - 08/2021 inside prospective databases. ULT were defined by planning target volume (PTV) overlap with the proximal bronchial tree or esophagus. We calculated Kaplan Meier estimates for overall survival (OS) and progression-free survival (PFS), and competing risk estimates for the incidence of tumor progression and treatment-related toxicities. ULT patients (N = 16) were compared to non-ULT patients (N = 20)., Results: Baseline characteristics were similar between ULT and non-ULT, but ULT were larger (median PTV: ULT 54.7 cm 3 , non-ULT 19.2 cm 3 ). Median follow-up was 23.6 months. ULT and non-ULT showed a similar OS (2-years: ULT 67%, non-ULT 60%, p = 0.7) and PFS (2-years: ULT 37%, non-ULT 34%, p = 0.73). Progressions occurred mainly at distant sites (2-year incidence of distant progression: ULT 63%, non-ULT 61%, p = 0.77), while local tumor control was favorable (2-year incidence of local progression: ULT 7%, non-ULT 0%, p = 0.22). Treatment of ULT led to significantly more toxicities ≥ grade (G) 2 (ULT: 9 (56%), non-ULT: 1 (5%), p = 0.002). Most toxicities were moderate (G2). Two ULT patients developed high-grade toxicities: 1) esophagitis G3 and bronchial bleeding G4 after VEGF treatment, 2) bronchial bleeding G3. Estimated incidence of high-grade toxicities was 19% (3-48%) in ULT, and no treatment-related death occurred., Conclusion: Our small series supports SMART as potentially effective treatment of ULT. SMART with careful fractionation could reduce severe complications, but treatment of ULT remains a high-risk procedure and needs careful benefit-risk-assessment., Competing Interests: Disclosures J. H.-R. and S. K. received speaker fees from ViewRay Inc. J. H.-R. received speaker fees from Pfizer Inc., travel reimbursement from ViewRay Inc., IntraOP Medical and Elekta Instrument AB as well as grants from IntraOP Medical and Varian Medical Systems outside the submitted work. S.A. and J.D. received grants from Accuray International Sàrl and Merck Serono GmbH outside the submitted work. J.D. received grants from CRI – The Clinical Research Institute GmbH, View Ray Inc., Accuray Incorporated, RaySearch Laboratories AB, Vision RT limited, Astellas Pharma GmbH, Astra Zeneca GmbH, Solution Akademie GmbH, Ergomed PLC Surrey Research Park, Siemens Healthcare GmbH, Quintiles GmbH, Pharmaceutecal Research Associates GmbH, Boehringer Ingelheim Pharma GmbH Co, PTW-Freiburg Dr. Pychlau GmbH, Nanobiotix A.A. and IntraOP Medical outside the submitted work. M.T. received speaker fees, advisory board honoraria and travel reimbursements from Abbvie, Bristol-Myers Squibb, MSD, Astrazeneca, Novartis, Roche, Takeda, Lilly, Chugai, Celgene, Boehringer and Pfizer as well as speaker fees and advisory board honoraria from Janssen outside the submitted work. M.T. received research grants from Bristol-Myers Squibb, Astrazeneca, Roche and Takeda outside the submitted work. T.E. received grants from Ruprecht-Karls Universität Heidelberg, Herbert Kienzle Foundation and Else Kröner-Fresenius Foundation and received travel reimbursement from Bristol-Myers Squibb outside the submitted work. The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Metastatic non-small cell lung cancer (NSCLC) often requires a multimodal treatment including chemotherapy, targeted therapy and radiotherapy. In addition to this, many patients take supportive drugs. Since only scarce data on possible interactions between radiotherapy and pharmaceutical or herbal drugs exist, description of clinical cases is of special interest., Case Report: A patient with stage IV NSCLC was treated with docetaxel/ramucirumab followed by radiotherapy for brain and bone metastases while taking several other over-the-counter drugs (OTCs) including topical St. John's wort skin oil., Results: A 63-year-old female patient with stage IV NSCLC presented with 11 asymptomatic brain metastases and a painful osteolytic bone metastasis in the 12th thoracic vertebral body (T12). Four weeks before the start of palliative whole-brain radiotherapy and bone irradiation of T12, she was administered a combination of docetaxel and ramucirumab. At an administered dose of 24 Gy, the patient presented with severe folliculitis capitis, while skin examination over the thoracolumbar spine was unremarkable although skin dose was similar. After thorough questioning, the patient reported using a herbal skin oil that contained St. John's wort for scalp care only, but not for skin care of her back during radiotherapy. After stopping the topical application of the skin oil, folliculitis improved with a course of systemic and topical antibiotics within 10 days, though the healing process was prolonged and included desquamation and hyperpigmentation., Conclusion: St. John's wort seems to be a significant radiosensitizer for photon radiotherapy and can cause severe skin toxicity even though the literature lacks data on this interaction. As an OTC, it is easily accessible and often used by oncological patients due to antidepressant and local antimicrobial and pain-relieving effects.

Background: Delivery of stereotactic body radiotherapy (SBRT) to ultracentral lung tumors remains a major challenge, with potentially excessive SBRT-related toxicity. This study investigates a risk-optimized approach to ultracentral SBRT in an elderly and comorbid patient cohort., Patients and Methods: Analysis encompassed 129 patients (mean age: 70 ± 11 years, median Charlson comorbidity index: 4 [range, 3-5]) following risk-adapted SBRT to central or ultracentral primary and secondary lung tumors between 2012 and 2019 (78 central, 51 ultracentral). Ultracentral tumors were defined by planning target volume overlap with the proximal bronchial tree. Whereas ultracentral tumors were treated with a risk-optimized fractionation scheme of 50 Gy in 10 fractions, central tumors received higher-fractionated 60 Gy in 8 fractions. Outcome parameters and toxicity for ultracentral and central tumors were assessed using Kaplan-Meier and competing risk analyses., Results: Local failure rate was not significantly increased in ultracentral tumors compared with central tumors (2-year local failure rate ultracentral, 26.9%; 95% confidence interval [CI], 12.2%-44.2%; central, 14.6%; 95% CI, 6.6%-25.5%; P = .17). Overall survival was similar in both groups (2-year overall survival central, 55.4%; 95% CI, 44.5%-68.9%; ultracentral, 54.9%; 95% CI, 40.8%-73.9%; P = .6). Toxicity was moderate, with toxicity ≥ grade 3 rates of 15.3% (95% CI, 5.9%-28.9%) for ultracentral and 7.3% (95% CI, 2.7%-15.0%) for central tumors after 2 years (P = .27). No grade 4 toxicity and only 1 potential grade 5 toxicity were observed in the ultracentral cohort., Conclusion: Risk-optimized SBRT to ultracentral lung tumors is a reasonably effective and safe treatment alternative in frail patients., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: The improved efficacy of tyrosine kinase inhibitors (TKI) mandates reappraisal of local therapy (LT) for brain metastases (BM) of oncogene-driven non-small-cell lung cancer (NSCLC)., Patients and Methods: This study included all epidermal growth factor receptor-mutated (EGFR + , n = 108) and anaplastic lymphoma kinase-rearranged (ALK + , n = 33) TKI-naive NSCLC patients diagnosed with BM in the Thoraxklinik Heidelberg between 2009 and 2019. Eighty-seven patients (62%) received early LT, while 54 (38%) received delayed (n = 34; 24%) or no LT (n = 20; 14%). LT comprised stereotactic (SRT; n = 40; 34%) or whole-brain radiotherapy (WBRT; n = 77; 66%), while neurosurgical resection was carried out in 19 cases., Results: Median overall survival (OS) was 49.1 months for ALK + and 19.5 months for EGFR + patients (P = 0.001), with similar median intracranial progression-free survival (icPFS) (15.7 versus 14.0 months, respectively; P = 0.80). Despite the larger and more symptomatic BM (P < 0.001) of patients undergoing early LT, these experienced longer icPFS [hazard ratio (HR) 0.52; P = 0.024], but not OS (HR 1.63; P = 0.12), regardless of the radiotherapy technique (SRT versus WBRT) and number of lesions. High-risk oncogene variants, i.e. non-del19 EGFR mutations and 'short' EML4-ALK fusions (mainly variant 3, E6:A20), were associated with earlier intracranial progression (HR 2.97; P = 0.001). The longer icPFS with early LT was also evident in separate analyses of the EGFR + and ALK + subsets., Conclusions: Despite preferential use for cases with poor prognostic factors, early LT prolongs the icPFS, but not OS, in TKI-treated EGFR + /ALK + NSCLC. Considering the lack of survival benefit, and the neurocognitive effects of WBRT, patients presenting with polytopic BM may benefit from delaying radiotherapy, or from radiosurgery of multiple or selected lesions. For SRT candidates, the improved tumor control with earlier radiotherapy should be weighed against the potential toxicity and the enhanced intracranial activity of newer TKI. High-risk EGFR/ALK variants are associated with earlier intracranial failure and identify patients who could benefit from more aggressive management., Competing Interests: Disclosure RAE: Personal fees from Accuray, AstraZeneca, BMS, Novocure, Merck, Takeda, and grants from Accuray outside the submitted work. FB: Research funding from BMS and travel grants from BMS and MSD outside the submitted work. DK: Personal fees from AstraZeneca, Bristol-Myers Squibb, and Pfizer outside the submitted work. MT: Advisory board honoraria from Novartis, Lilly, BMS, MSD, Roche, Celgene, Takeda, AbbVie, Boehringer; speaker's honoraria from Lilly, MSD, Takeda; research funding from AstraZeneca, BMS, Celgene, Novartis, Roche; and travel grants from BMS, MSD, Novartis, Boehringer outside the submitted work. CPH: Consultation, lecture, and other fees from Novartis, Basilea, Bayer, Grifols, Boehringer, Pierre Fabre, Covidien, Siemens, Chiesi, InterMune, MEDA Pharma, Bracco, Pfizer, MSD, Roche, Lilly, AstraZeneca, Schering-Plough, Essex, Gilead, MeVis, Fresenius, Astellas as well as ownership of GSK stocks outside the submitted work. FJH: Advisory board fees and honoraria from Lilly, Roche, AstraZeneca, Novartis, Boehringer, Chiesi, Teva, Pulmonx BTG, and Olympus, as well as research funding from Lilly, Roche, AstraZeneca, Novartis, Boehringer, Chiesi, and Teva outside the submitted work. AS: Grants and personal fees from Bayer, BMS, grants from Chugai, as well as personal fees from AstraZeneca, MSD, Takeda, Seattle Genetics, Novartis, Illumina, Thermo Fisher, Eli Lily, Takeda, outside the submitted work. PC: Research funding from AstraZeneca, Novartis, Roche, Takeda, and advisory board/lecture fees from AstraZeneca, Boehringer Ingelheim, Chugai, Novartis, Pfizer, Roche, Takeda outside the submitted work. All other authors have declared no conflicts of interest. Data sharing The datasets generated for this study are available upon reasonable request., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)