Proton therapy for selected low grade glioma patients in the Netherlands

Weide, H. L. van der; Kramer, Miranda C.A.; Scandurra, D.; Eekers, Daniëlle; Klaver, Y.L.B.; Wiggenraad, Ruud; Romero, Alejandra Méndez; Coremans, I.; Boersma, Liesbeth; Vulpen, Marco van; Langendijk, Johannes A.

doi:10.1016/j.radonc.2020.11.004

Cited by 25 publications

(13 citation statements)

References 98 publications

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“…Besides lower DNA damage in 3D cell microenvironments compared to 2D ones, the GBM/HUVECs co‐culture 3D models also featured lower DNA damage when compared to the U251 monoculture models. This shows that the integration of biochemical cues, induced by the presence of endothelial cells, affects the response to proton radiation of GBM cells, and paves the way for a series of studies involving other cell types (e.g., microglia, pericytes), [ 44 ] patient‐derived GB [ 11 ] and alternative proton treatments such as FLASH [ 45 ] (based on ultra‐fast dose rates) in presence of the developed 3D biomimetic design.…”

Section: Introductionmentioning

confidence: 99%

Micro‐Vessels‐Like 3D Scaffolds for Studying the Proton Radiobiology of Glioblastoma‐Endothelial Cells Co‐Culture Models

Akolawala,

Keuning,

Rovituso

et al. 2023

Adv Healthcare Materials

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Glioblastoma (GBM) is a devastating cancer of the brain with an extremely poor prognosis. While X‐ray radiotherapy and chemotherapy remain the current standard, proton beam therapy is an appealing alternative as protons can damage cancer cells while sparing the surrounding healthy tissue. However, the effects of protons on in vitro GBM models at the cellular level, especially when co‐cultured with endothelial cells, the building blocks of brain micro‐vessels, are still unexplored. In this work, novel 3D‐engineered scaffolds inspired by the geometry of brain microvasculature are designed, where GBM cells cluster and proliferate. The architectures are fabricated by two‐photon polymerization (2PP), pre‐cultured with endothelial cells (HUVECs), and then cultured with a human GBM cell line (U251). The micro‐vessel structures enable GBM in vivo‐like morphologies, and the results show a higher DNA double‐strand breakage in GBM monoculture samples when compared to the U251/HUVECs co‐culture, with cells in 2D featuring a larger number of DNA damage foci when compared to cells in 3D. The discrepancy in terms of proton radiation response indicates a difference in the radioresistance of the GBM cells mediated by the presence of HUVECs and the possible induction of stemness features that contribute to radioresistance and improved DNA repair.

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Section: Introductionmentioning

confidence: 99%

Micro‐Vessels‐Like 3D Scaffolds for Studying the Proton Radiobiology of Glioblastoma‐Endothelial Cells Co‐Culture Models

Akolawala,

Keuning,

Rovituso

et al. 2023

Adv Healthcare Materials

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“…Another emerging RT option is proton therapy, which enables sparing of larger volumes of brain [20] , [21] , [22] . However, utilisation of technical possibilities to the full extent is hampered by the lack of knowledge on RT dose–effect relationships in the brain and the subsequent clinical relevance [23] . Radiation dose to the hippocampus has been associated with NCF decline [24] and hippocampal sparing RT can result in superior cognitive outcome in patients with multiple brain metastases [25] .…”

Section: Introductionmentioning

confidence: 99%

“…Beside the focus on various brain subregions by using anatomical imaging, it would be very valuable to gain more insight into neuronal networks by using functional imaging techniques [36] . Ultimately, the goal is the development of high-quality NTCP models for RIBD endpoints that can be used to select the most optimal RT treatment plan, for example proton therapy [23] or other technical innovations in the future such as ultra-high dose rate (FLASH) RT [37] for patients with LGG and other brain tumours.…”

Section: Introductionmentioning

confidence: 99%

Clinical relevance of the radiation dose bath in lower grade glioma, a cross-sectional pilot study on neurocognitive and radiological outcome

Weide

Langendijk

et al. 2022

Clinical and Translational Radiation Oncology

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To investigate the clinical relevance of the radiotherapy (RT) dose bath in patients treated for lower grade glioma (LGG). Methods: Patients (n = 17) treated with RT for LGG were assessed with neurocognitive function (NCF) tests and structural Magnetic Resonance Imaging (MRI) and categorized in subgroups based on tumour lateralisation. RT dose, volumetric results and cerebral microbleed (CMB) number were extracted for contralateral cerebrum, contralateral hippocampus, and cerebellum. The RT clinical target volume (CTV) was included in the analysis as a surrogate for focal tumour and other treatment effects. The relationships between RT dose, CTV, NCF and radiological outcome were analysed per subgroup. Results: The subgroup with left-sided tumours (n = 10) performed significantly lower on verbal tests. The RT dose to the right cerebrum, as well as CTV, were related to poorer performance on tests for processing speed, attention, and visuospatial abilities, and more CMB. In the subgroup with right-sided tumours (n = 7), RT dose in the left cerebrum was related to lower verbal memory performance, (immediate and delayed recall, r = − 0.821, p = 0.023 and r = − 0.937, p = 0.002, respectively), and RT dose to the left hippocampus was related to hippocampal volume (r = − 0.857, p = 0.014), without correlation between CTV and NCF. Conclusion: By using a novel approach, we were able to investigate the clinical relevance of the RT dose bath in patients with LGG more specifically. We used combined MRI-derived and NCF outcome measures to assess radiation-induced brain damage, and observed potential RT effects on the left-sided brain resulting in lower verbal memory performance and hippocampus volume.

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“…While some validation on sex-specific NTCP has been conducted for adult clinical data, there is still a gap in pediatric patients. 23,24 This present study aims to extend current NTCP modeling to assess pediatric cranial irradiation for a range of simulated clinical scenarios (medulloblastoma and ependymoma). Sensitivity analyses will investigate the potential impact of sex and intrinsic radiosensitivity (α/β ratio) on side-effects for brainstem, optical structures, pituitary gland, and cochlea.…”

Section: Introductionmentioning

confidence: 99%

Normal tissue complication probability modeling to guide individual treatment planning in pediatric cranial proton and photon radiotherapy

et al. 2021

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Proton therapy (PT) is broadly accepted as the gold standard of care for pediatric patients with cranial cancer. The superior dose distribution of PT compared to photon radiotherapy reduces normal tissue complication probability (NTCP) for organs at risk. As NTCPs for pediatric organs are not well understood, clinics generally base radiation response on adult data. However, there is evidence that radiation response strongly depends on the age and even sex of a patient. Furthermore, questions surround the influence of individual intrinsic radiosensitivity (α/β ratio) on pediatric NTCP. While the clinical pediatric NTCP data is scarce, radiobiological modeling and sensitivity analyses can be used to investigate the NTCP trends and its dependence on individual modeling parameters. The purpose of this study was to perform sensitivity analyses of NTCP models to ascertain the dependence of radiosensitivity, sex, and age of a child and predict cranial side-effects following intensity-modulated proton therapy (IMPT) and intensity-modulated radiotherapy (IMRT). Methods: Previously, six sex-matched pediatric cranial datasets (5, 9, and 13 years old) were planned in Varian Eclipse treatment planning system (13.7). Up to 108 scanning beam IMPT plans and 108 IMRT plans were retrospectively optimized for a range of simulated target volumes and locations. In this work, dose-volume histograms were extracted and imported into BioSuite Software for radiobiological modeling. Relative-Seriality and Lyman-Kutcher-Burman models were used to calculate NTCP values for toxicity endpoints, where TD50, (based on reported adult clinical data) was varied to simulate sex dependence of NTCP. Plausible parameter ranges, based on published literature for adults, were used in modeling. In addition to sensitivity analyses, a 20% difference in TD50 was used to represent the radiosensitivity between the sexes (with females considered more radiosensitive) for ease of data comparison as a function of parameters such as α/β ratio. Results: IMPT plans resulted in lower NTCP compared to IMRT across all models (p < 0.0001). For medulloblastoma treatment, the risk of brainstem necrosis (> 10%) and cochlea tinnitus (> 20%) among females could potentially be underestimated considering a lower TD50 value for females. Sensitivity analyses show that the difference in NTCP between sexes was significant (p < 0.0001). Similarly, both brainstem necrosis and cochlea tinnitus NTCP varied significantly (p < 0.0001) across tested α/β as a function of TD50 values (assumption being that TD50 values are 20% lower in females). If the true α/β of these pediatric tissues is higher than expected (α/β ∼ 3), the risk of tinnitus for IMRT can significantly increase (p < 0.0001).

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Proton therapy for selected low grade glioma patients in the Netherlands

Cited by 25 publications

References 98 publications

Micro‐Vessels‐Like 3D Scaffolds for Studying the Proton Radiobiology of Glioblastoma‐Endothelial Cells Co‐Culture Models

Micro‐Vessels‐Like 3D Scaffolds for Studying the Proton Radiobiology of Glioblastoma‐Endothelial Cells Co‐Culture Models

Clinical relevance of the radiation dose bath in lower grade glioma, a cross-sectional pilot study on neurocognitive and radiological outcome

Normal tissue complication probability modeling to guide individual treatment planning in pediatric cranial proton and photon radiotherapy

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