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Background: The limited availability of proton beam therapy (PBT) requires individual treatment selection strategies, such as the model-based approach. In this study, we assessed the dosimetric benefit of PBT compared to photon therapy (XRT), analysed the corresponding changes in normal tissue complication probability (NTCP) on a variety of available models, and illustrated model-based patient selection in an in-silico study for patients with brain tumours., Methods: For 92 patients treated at two PBT centres, volumetric modulated arc therapy treatment plans were retrospectively created for comparison with the clinically applied PBT plans. Several dosimetric parameters for the brain excluding tumour and margins, cerebellum, brain stem, frontal and temporal lobes, hippocampi, cochleae, chiasm, optic nerves, lacrimal glands, lenses, pituitary gland, and skin were compared between both modalities using Wilcoxon signed-rank tests. NTCP differences (ΔNTCP) were calculated for 11 models predicting brain necrosis, delayed recall, temporal lobe injury, hearing loss, tinnitus, blindness, ocular toxicity, cataract, endocrine dysfunction, alopecia, and erythema. A patient was assumed to be selected for PBT if ΔNTCP exceeded a threshold of 10 percentage points for at least one of the side-effects., Results: PBT substantially reduced the dose in almost all investigated OARs, especially in the low and intermediate dose ranges and for contralateral organs. In general, NTCP predictions were significantly lower for PBT compared to XRT, in particular in ipsilateral organs. Considering ΔNTCP of all models, 80 patients (87.0%) would have been selected for PBT in this in-silico study, mainly due to predictions of a model on delayed recall (51 patients)., Conclusion: In this study, substantial dose reductions for PBT were observed, mainly in contralateral organs. However, due to the sigmoidal dose response, NTCP was particularly reduced in ipsilateral organs. This underlines that physical dose-volume parameters alone may not be sufficient to describe the clinical relevance between different treatment techniques and highlights potential benefits of NTCP models. Further NTCP models for different modern treatment techniques are mandatory and existing models have to be externally validated in order to implement the model-based approach in clinical practice for cranial radiotherapy., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: The limited availability of proton beam therapy (PBT) requires individual treatment selection strategies that can be based on normal tissue complication probability (NTCP) models. We developed and externally validated NTCP models for common late side-effects following PBT in brain tumour patients to optimise patients' quality of life., Methods: Cohorts from three PBT centres (216 patients) were investigated for several physician-rated endpoints at 12 and 24 months after PBT: alopecia, dry eye syndrome, fatigue, headache, hearing and memory impairment, and optic neuropathy. Dose-volume parameters of associated normal tissues and clinical factors were used for logistic regression modelling in a development cohort. Statistically significant parameters showing high area under the receiver operating characteristic curve (AUC) values in internal cross-validation were externally validated. In addition, analyses of the pooled cohorts and of time-dependent generalised estimating equations including all patient data were performed., Results: In the validation study, mild alopecia was related to high dose parameters to the skin [e.g. the dose to 2% of the volume (D2%)] at 12 and 24 months after PBT. Mild hearing impairment at 24 months after PBT was associated with the mean dose to the ipsilateral cochlea. Additionally, the pooled analyses revealed dose-response relations between memory impairment and intermediate to high doses to the remaining brain as well as D2% of the hippocampi. Mild fatigue at 24 months after PBT was associated with D2% to the brainstem as well as with concurrent chemotherapy. Moreover, in generalised estimating equations analysis, dry eye syndrome was associated with the mean dose to the ipsilateral lacrimal gland., Conclusion: We developed and in part validated NTCP models for several common late side-effects following PBT in brain tumour patients. Validation studies are required for further confirmation., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Neurocognitive function of adult patients with brain tumours may deteriorate after radiotherapy. Proton beam therapy (PBT) reduces the volume of irradiated healthy brain tissue and could potentially preserve neurocognition and quality of life (QoL). As present data are still limited, the impact of clinical factors and dosimetric parameters on neurocognitive function and QoL during recurrence-free follow-up after PBT is investigated., Methods: The current study includes 62 brain tumour patients treated with PBT between 2015 and 2017. Neurocognition and QoL were assessed at baseline and every 3 months after PBT using the Montreal Cognitive Assessment (MoCA) test together with EORTC-QLQ-C30 and BN20 questionnaires, respectively. Objective and self-reported measures of neurocognitive functions were correlated. During two years of follow-up, the impact of clinical co-factors as well as dosimetric parameters of several brain structures were analysed using a mixed-model approach., Results: At baseline, mean MoCA total score was 24.8/30 and self-reported cognitive function was 68.9/100. Both remained stable over time. Patients with impaired neurocognition on the MoCA test reported significantly lower global health status, cognitive, physical and role function as well as more fatigue, pain, headache and communication deficits compared to normal performing patients. For most follow-up time points, the majority of MoCA subitems correlated significantly to QoL items regarding neurocognition. Slight deterioration of the MoCA score was associated with tumours located in the left hemisphere and with an increase in relative volume of the anterior cerebellum that received doses of 30-40 Gy(RBE)., Conclusion: Self-reported and objectively measured neurocognition and most other QoL domains remained largely stable over time during recurrence-free follow-up for brain tumour patients treated with PBT. The association between reduced cognitive function and irradiated volume of the anterior cerebellum requires validation in larger studies and comparison to patients treated with photon therapy., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Resistance of cancer stem-like and cancer tumor bulk cells to radiochemotherapy and destructive infiltration of the brain fundamentally influence the treatment efficiency to cure of patients suffering from Glioblastoma (GBM). The interplay of adhesion and stress-related signaling and activation of bypass cascades that counteract therapeutic approaches remain to be identified in GBM cells. We here show that combined inhibition of the adhesion receptor β1 integrin and the stress-mediator c-Jun N-terminal kinase (JNK) induces radiosensitization and blocks invasion in stem-like and patient-derived GBM cultures as well as in GBM cell lines. In vivo, this treatment approach not only significantly delays tumor growth but also increases median survival of orthotopic, radiochemotherapy-treated GBM mice. Both, in vitro and in vivo, effects seen with β1 integrin/JNK co-inhibition are superior to the monotherapy. Mechanistically, the in vitro radiosensitization provoked by β1 integrin/JNK targeting is caused by defective DNA repair associated with chromatin changes, enhanced ATM phosphorylation and prolonged G2/M cell cycle arrest. Our findings identify a β1 integrin/JNK co-dependent bypass signaling for GBM therapy resistance, which might be therapeutically exploitable.