Purpose: The Ethos (Varian Medical Systems) radiotherapy device combines semi-automated anatomy detection and plan generation for cone beam computer tomography (CBCT)-based daily online adaptive radiotherapy (oART). However, CBCT offers less soft tissue contrast than magnetic resonance imaging (MRI). This work aims to present the clinical workflow of CBCT-based oART with shuttle-based offline MR guidance. Methods: From February to November 2023, 31 patients underwent radiotherapy on the Ethos (Varian, Palo Alto, CA, USA) system with machine learning (ML)-supported daily oART. Moreover, patients received weekly MRI in treatment position, which was utilized for daily plan adaptation, via a shuttle-based system. Initial and adapted treatment plans were generated using the Ethos treatment planning system. Patient clinical data, fractional session times (MRI + shuttle transport + positioning, adaptation, QA, RT delivery) and plan selection were assessed for all fractions in all patients. Results: In total, 737 oART fractions were applied and 118 MRIs for offline MR guidance were acquired. Primary sites of tumors were prostate (n = 16), lung (n = 7), cervix (n = 5), bladder (n = 1) and endometrium (n = 2). The treatment was completed in all patients. The median MRI acquisition time including shuttle transport and positioning to initiation of the Ethos adaptive session was 53.6 min (IQR 46.5–63.4). The median total treatment time without MRI was 30.7 min (IQR 24.7–39.2). Separately, median adaptation, plan QA and RT times were 24.3 min (IQR 18.6–32.2), 0.4 min (IQR 0.3–1,0) and 5.3 min (IQR 4.5–6.7), respectively. The adapted plan was chosen over the scheduled plan in 97.7% of cases. Conclusion: This study describes the first workflow to date of a CBCT-based oART combined with a shuttle-based offline approach for MR guidance. The oART duration times reported resemble the range shown by previous publications for first clinical experiences with the Ethos system.

Purpose: To provide the first report on proton radiotherapy (PRT) in the management of advanced nasopharyngeal angiofibroma (JNA) and evaluate potential benefits compared to conformal photon therapy (XRT). Methods: We retrospectively reviewed 10 consecutive patients undergoing PRT for advanced JNA in a definitive or postoperative setting with a relative biological effectiveness weighted dose of 45 Gy in 25 fractions between 2012 and 2022 at the Heidelberg Ion Beam Therapy Center. Furthermore, dosimetric comparisons and risk estimations for short- and long-term radiation-induced complications between PRT plans and helical XRT plans were conducted. Results: PRT was well tolerated, with only low-grade acute toxicities (CTCAE I–II) being reported. The local control rate was 100% after a median follow-up of 27.0 (interquartile range 13.3–58.0) months. PRT resulted in considerable tumor shrinkage, leading to complete remission in five patients and bearing the potential to provide partial or complete symptom relief. Favorable dosimetric outcomes in critical brain substructures by the use of PRT translated into reduced estimated risks for neurocognitive impairment and radiation-induced CNS malignancies compared to XRT. Conclusions: PRT is an effective treatment option for advanced JNA with minimal acute morbidity and the potential for reduced radiation-induced long-term complications.

(1) Background: External beam radiotherapy (EBRT) and concurrent chemotherapy, followed by brachytherapy (BT), offer a standard of care for patients with locally advanced cervical carcinoma. Conventionally, large safety margins are required to compensate for organ movement, potentially increasing toxicity. Lately, daily high-quality cone beam CT (CBCT)-guided adaptive radiotherapy, aided by artificial intelligence (AI), became clinically available. Thus, online treatment plans can be adapted to the current position of the tumor and the adjacent organs at risk (OAR), while the patient is lying on the treatment couch. We sought to evaluate the potential of this new technology, including a weekly shuttle-based 3T-MRI scan in various treatment positions for tumor evaluation and for decreasing treatment-related side effects. (2) Methods: This is a prospective one-armed phase-II trial consisting of 40 patients with cervical carcinoma (FIGO IB-IIIC1) with an age ≥ 18 years and a Karnofsky performance score ≥ 70%. EBRT (45–50.4 Gy in 25–28 fractions with 55.0–58.8 Gy simultaneous integrated boosts to lymph node metastases) will be accompanied by weekly shuttle-based MRIs. Concurrent platinum-based chemotherapy will be given, followed by 28 Gy of BT (four fractions). The primary endpoint will be the occurrence of overall early bowel and bladder toxicity CTCAE grade 2 or higher (CTCAE v5.0). Secondary outcomes include clinical feasibility, quality of life, and imaging-based response assessment.

Helium ion therapy (HRT) is a promising modality for the treatment of pediatric tumors and those located close to critical structures due to the favorable biophysical properties of helium ions. This in silico study aimed to explore the potential benefits of HRT in advanced juvenile nasopharyngeal angiofibroma (JNA) compared to proton therapy (PRT). We assessed 11 consecutive patients previously treated with PRT for JNA in a definitive or postoperative setting with a relative biological effectiveness (RBE) weighted dose of 45 Gy (RBE) in 25 fractions at the Heidelberg Ion-Beam Therapy Center. HRT plans were designed retrospectively for dosimetric comparisons and risk assessments of radiation-induced complications. HRT led to enhanced target coverage in all patients, along with sparing of critical organs at risk, including a reduction in the brain integral dose by approximately 27%. In terms of estimated risks of radiation-induced complications, HRT led to a reduction in ocular toxicity, cataract development, xerostomia, tinnitus, alopecia and delayed recall. Similarly, HRT led to reduced estimated risks of radiation-induced secondary neoplasms, with a mean excess absolute risk reduction of approximately 30% for secondary CNS malignancies. HRT is a promising modality for advanced JNA, with the potential for enhanced sparing of healthy tissue and thus reduced radiation-induced acute and long-term complications.

Purpose: This systematic literature review summarizes clinical studies and trials involving combined non-ablative hyperthermia and re-irradiation in locoregionally recurrent cancer except breast cancer. Methods: One database and one registry, MEDLINE and clinicaltrials.gov, respectively, were searched for studies on combined non-ablative hyperthermia and re-irradiation in non-breast cancer patients. Extracted study characteristics included treatment modalities and re-irradiation dose concepts. Outcomes of interest were tumor response, survival measures, toxicity data and palliation. Within-study bias assessment included the identification of conflict of interest (COI). The final search was performed on 29 August 2022. Results: Twenty-three articles were included in the final analysis, reporting on 603 patients with eight major tumor types. Twelve articles (52%) were retrospective studies. Only one randomized trial was identified. No COI statement was declared in 11 studies. Four of the remaining twelve studies exhibited significant COI. Low study and patient numbers, high heterogeneity in treatment modalities and endpoints, as well as significant within- and across-study bias impeded the synthesis of results. Conclusion: Outside of locoregionally recurrent breast cancer, the role of combined moderate hyperthermia and re-irradiation can so far not be established. This review underscores the necessity for more clinical trials to generate higher levels of clinical evidence for combined re-irradiation and hyperthermia.

Many cancer patients do not benefit from current immunotherapies. This lack of efficacy may be, in part, due to insufficient priming and activation of T cells. Here, we show that activation of liver-X-receptors (LXRs) promotes adaptive anti-tumor immunity by enhancing priming of T cells. Genetic LXR deletion in the host and depletion of dendritic and CD8+ T cells, but not of macrophages, abrogated anti-tumor effects of LXR-agonistic therapy. In cross-presentation assays, LXR agonism promoted T cell activation upon DC/T cell cross talk. Genetic deletion of LXRs in T cells, but not in dendritic cells, blunted this effect. Dissection of the temporal dynamics of LXR-enhanced T cell effector function showed that LXR agonism rendered T cells more receptive to adopting effector states upon stimulation. Consistently, LXR agonist therapy elicited T cell expansion in cancer patients enrolled in a phase I trial. Our findings establish LXR activation as an effective approach for enhancing T cell priming.