| 1. |
- Kjellsson Lindblom, Emely, et al.
(författare)
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Hypoxia Induced by Vascular Damage at High Doses Could Compromise the Outcome of Radiotherapy
- 2019
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Ingår i: Anticancer Research. - : Anticancer Research USA Inc.. - 0250-7005 .- 1791-7530. ; 39:5, s. 2337-2340
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Tidskriftsartikel (refereegranskat)abstract
- Background/Aim: This study investigated the impact of temporary vascular collapse on tumour control probability (TCP) in stereotactic body radiotherapy (SBRT), taking into account different radiosensitivities of chronically and acutely hypoxic cells. Materials and Methods: Three-dimensional tumours with heterogeneous oxygenation were simulated assuming different fractions of collapsed vessels at every treatment fraction. The modelled tumours contained a chronically hypoxic subvolume of 30-60% of the tumour diameter, and a hypoxic fraction ≤5 mm Hg of 30-50%. The rest of the tumours were well-oxygenated at the start of the simulated treatment. Results: For all simulated cases, the largest reduction in TCP from 97% to 2% was found in a tumour with a small chronically hypoxic core treated with 60 Gy in eight fractions and assuming a treatment-induced vascular collapse of 35% in the well-oxygenated region. Conclusion: The timing of SBRT fractions should be considered together with the tumour oxygenation to avoid loss of TCP in SBRT.
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| 2. |
- Kjellsson Lindblom, Emely, et al.
(författare)
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Impact of SBRT fractionation in hypoxia dose painting - accounting for heterogeneous and dynamic tumour oxygenation
- 2019
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Ingår i: Medical physics (Lancaster). - : Wiley. - 0094-2405 .- 2473-4209. ; 46:5, s. 2512-2521
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Tidskriftsartikel (refereegranskat)abstract
- PurposeTumor hypoxia, often found in nonsmall cell lung cancer (NSCLC), implies an increased resistance to radiotherapy. Pretreatment assessment of tumor oxygenation is, therefore, warranted in these patients, as functional imaging of hypoxia could be used as a basis for dose painting. This study aimed at investigating the feasibility of using a method for calculating the dose required in hypoxic subvolumes segmented on 18F‐HX4 positron emission tomography (PET) imaging of NSCLC.MethodsPositron emission tomography imaging data based on the hypoxia tracer 18F‐HX4 of 19 NSCLC patients were included in the study. Normalized tracer uptake was converted to oxygen partial pressure (pO2) and hypoxic target volumes (HTVs) were segmented using a threshold of 10 mmHg. Uniform doses required to overcome the hypoxic resistance in the target volumes were calculated based on a previously proposed method taking into account the effect of interfraction reoxygenation, for fractionation schedules ranging from extremely hypofractionated stereotactic body radiotherapy (SBRT) to conventionally fractionated radiotherapy.ResultsGross target volumes ranged between 6.2 and 859.6 cm3, and the hypoxic fraction < 10 mmHg between 1.2% and 72.4%. The calculated doses for overcoming the resistance of cells in the HTVs were comparable to those currently prescribed in clinical practice as well as those previously tested in feasibility studies on dose escalation in NSCLC. Depending on the size of the HTV and the distribution of pO2, HTV doses were calculated as 43.6–48.4 Gy for a three‐fraction schedule, 51.7–57.6 Gy for five fractions, and 59.5–66.4 Gy for eight fractions. For patients in whom the HTV pO2 distribution was more favorable, a lower dose was required despite a bigger volume. Tumor control probability was lower for single‐fraction schedules, while higher levels of tumor control probability were found for schedules employing several fractions.ConclusionsThe method to account for heterogeneous and dynamic hypoxia in target volume segmentation and dose prescription based on 18F‐HX4‐PET imaging appears feasible in NSCLC patients. The distribution of oxygen partial pressure within HTV could impact the required prescribed dose more than the size of the volume.
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| 3. |
- Kjellsson Lindblom, Emely, et al.
(författare)
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Radiation-induced vascular damage and the impact on the treatment outcome of stereotactic body radiotherapy
- 2019
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Ingår i: Anticancer Research. - : Anticancer Research USA Inc.. - 0250-7005 .- 1791-7530. ; 39:6, s. 2721-2727
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Tidskriftsartikel (refereegranskat)abstract
- Background/Aim: The aim of this study was to investigate radiation-induced tumour vascular damage and its impact thereof on the outcome of stereotactic body radiotherapy (SBRT). Materials and Methods: Vessel densities in animal tumours before and after a single dose of 20 Gy were quantified and used as input for simulations of three-dimensional tumours with heterogeneous oxygenation. SBRT treatments of the modelled tumours in 1-8 fractions were simulated. The impact of vessel collapse on the outcome of SBRT was investigated by calculating tumour control probability (TCP) and the dose required to obtain a TCP of 50% (D50). Results: A radiation-induced increase of acute hypoxia in tumours during SBRT treatment could be simulated based on the experimental data. The D50 values for these tumours were higher than for the simulated tumours without vessel collapse. Conclusion: The vascular changes after high doses of radiation could compromise the outcome of SBRT by increasing tumour hypoxia.
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| 4. |
- Kjellsson Lindblom, Emely, 1988-
(författare)
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Time, dose and fractionation: accounting for hypoxia in the search for optimal radiotherapy treatment parameters
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The search for the optimal choice of treatment time, dose and fractionation regimen is one of the major challenges in radiation therapy. Several aspects of the radiation response of tumours and normal tissues give different indications of how the parameters defining a fractionation schedule should be altered relative to each other which often results in contradictory conclusions. For example, the increased sensitivity to fractionation in late-reacting as opposed to early-reacting tissues indicates that a large number of fractions is beneficial, while the issue of accelerated repopulation of tumour cells starting at about three weeks into a radiotherapy treatment would suggest as short overall treatment time as possible. Another tumour-to-normal tissue differential relevant to the sensitivity as well as the fractionation and overall treatment time is the issue of tumour hypoxia and reoxygenation.The tumour oxygenation is one of the most influential factors impacting on the outcome of many types of treatment modalities. Hypoxic cells are up to three times as resistant to radiation as well-oxygenated cells, presenting a significant obstacle to overcome in radiotherapy as solid tumours often contain hypoxic areas as a result of their poorly functioning vasculature. Furthermore, the oxygenation is highly dynamic, with changes being observed both from fraction to fraction and over a time period of weeks as a result of fast and slow reoxygenation of acute and chronic hypoxia. With an increasing number of patients treated with hypofractionated stereotactic body radiotherapy (SBRT), the clinical implications of a substantially reduced number of fractions and hence also treatment time thus have to be evaluated with respect to the oxygenation status of the tumour.One of the most promising tools available for the type of study aiming at determining the optimal radiotherapy approach with respect to fractionation is radiobiological modelling. With clinically validated in vitro-derived tissue-specific radiobiological parameters and well-established survival models, in silico modelling offers a wide range of opportunities to test various hypotheses with respect to time, dose, fractionation and details of the tumour microenvironment. Any type of radiobiological modelling study intended to provide a realistic representation of a clinical tumour should therefore take into account details of both the spatial and temporal tumour oxygenation.This thesis presents the results of three-dimensional radiobiological modelling of the response of tumours with heterogeneous oxygenation to various fractionation schemes, and oxygenation levels and dynamics using different survival models. The results of this work indicate that hypoxia and its dynamics play a major role in the outcome of radiotherapy, and that neglecting the oxygenation status of tumours treated with e.g. SBRT may compromise the treatment outcome substantially. Furthermore, the possibilities offered by incorporating modelling into the clinical routine are explored and demonstrated by the development of a new calibration function for converting the uptake of the hypoxia-PET tracer 18F-HX4 to oxygen partial pressure, and applying it for calculations of the doses needed to overcome hypoxia-induced radiation resistance. By hence demonstrating how the clinical impact of hypoxia on dose prescription and the choice of fractionation schedule can be investigated, this project will hopefully advance the evolution towards routinely incorporating functional imaging of hypoxia into treatment planning. This is ultimately expected to result in increased levels of local control with more patients being cured from their cancer.
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| 5. |
- Schiavo, Filippo, 1994-, et al.
(författare)
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Hypoxia dose painting in SBRT - the virtual clinical trial approach
- 2023
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Ingår i: Acta Oncologica. - 0284-186X .- 1651-226X. ; 62:10, s. 1239-1245
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Tidskriftsartikel (refereegranskat)abstract
- Background: Treating hypoxic tumours remains a challenge in radiotherapy as hypoxia leads to enhanced tumour aggressiveness and resistance to radiation. As escalating the doses is rarely feasible within the healthy tissue constraints, dose-painting strategies have been explored. Consensus about the best of care for hypoxic tumours has however not been reached because, among other reasons, the limits of current functional in-vivo imaging systems in resolving the details and dynamics of oxygen transport in tissue. Computational modelling of the tumour microenvironment enables the design and conduction of virtual clinical trials by providing relationships between biological features and treatment outcomes. This study presents a framework for assessing the therapeutic influence of the individual characteristics of the vasculature and the resulting oxygenation of hypoxic tumours in a virtual clinical trial on dose painting in stereotactic body radiotherapy (SBRT) circumventing the limitations of the imaging systems.Material and methods: The homogeneous doses required to overcome hypoxia in simulated SBRT treatments of 1, 3 or 5 fractions were calculated for tumours with heterogeneous oxygenation derived from virtual vascular networks. The tumour control probability (TCP) was calculated for different scenarios for oxygenation dynamics resulting on cellular reoxygenation.Results: A three-fractions SBRT treatment delivering 41.9 Gy (SD 2.8) and 26.5 Gy (SD 0.1) achieved only 21% (SD 12) and 48% (SD 17) control in the hypoxic and normoxic subvolumes, respectively whereas fast reoxygenation improved the control by 30% to 50%. TCP values for the individual tumours with similar characteristics, however, might differ substantially, highlighting the crucial role of the magnitude and time evolution of hypoxia at the microscale.Conclusion: The results show that local microvascular heterogeneities may affect the predicted outcome in the hypoxic core despite escalated doses, emphasizing the role of theoretical modelling in understanding of and accounting for the dominant factors of the tumour microenvironment.
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| 6. |
- Schiavo, Filippo, 1994-, et al.
(författare)
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Perfusion-Limited Hypoxia Determines the Outcome of Radiation Therapy of Hypoxic Tumours
- 2022
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Ingår i: Oxygen Transport to Tissue XLIII. - Cham : Springer. - 9783031141898 - 9783031141904 ; 1395, s. 249-254
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Konferensbidrag (refereegranskat)abstract
- Despite advancements in functional imaging, the resolution of modern techniques is still limited with respect to the tumour microenvironment. Radiotherapy strategies to counteract e.g., tumour hypoxia based on functional imaging therefore carry an inherent uncertainty that could compromise the outcome of the treatment. It was the aim of this study to investigate the impact of variations in the radiosensitivity of hypoxic tumours in small regions in comparison to the resolution of current imaging techniques on the probability of obtaining tumour control. A novel in silico model of three-dimensional tumour vasculature and oxygenation was used to model three tumours with different combinations of diffusion-limited, perfusion-limited and anaemic hypoxia. Specifically, cells in the transition region from a tumour core with diffusion-limited hypoxia to the well-oxygenated tumour rim were considered with respect to their differential radiosensitivity depending on the character of the hypoxia. The results showed that if the cells in the transition region were under perfusion-limited hypoxia, the tumour control probability was substantially lower in comparison to the case when the cells were anaemic (or under diffusion-limited hypoxia). This study therefore demonstrates the importance of differentiating between different forms of hypoxia on a scale currently unattainable to functional imaging techniques, lending support to the use and importance of radiobiological modelling of the cellular radiosensitivity and response at microscale.
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| 7. |
- Schiavo, Filippo, 1994-, et al.
(författare)
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The Impact of Heterogeneous Cell Density in Hypoxic Tumors Treated with Radiotherapy
- 2023
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Ingår i: Advances in Experimental Medicine and Biology. - 0065-2598 .- 2214-8019. ; 1438, s. 121-126
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Tidskriftsartikel (refereegranskat)abstract
- Hypoxia is frequently found in solid tumors and is known to increase the resistance to several kinds of treatment modalities including radiation therapy. Besides, the treatment response is also largely determined by the total number of clonogenic cells, i.e., cells with unlimited proliferative capacity. Depending on the duration of hypoxia, the rate of proliferation and hence also the clonogen density could be expected to differ in hypoxic compartments. The combination at the microscale between heterogeneous tumor oxygenation and clonogen density could therefore be crucial with respect to the outcome of a radiotherapy treatment. In this study it was investigated the impact of heterogeneous clonogen density on the outcome of stereotactic radiotherapy treatments of hypoxic tumors. A recently developed three-dimensional model for tissue vasculature and oxygenation was used to create realistic in silico tumors with heterogeneous oxygenation. Stereotactic radiotherapy treatments were simulated, and cell survival was calculated on a voxel-level accounting for the oxygenation. For a tumor with a diameter of 1 cm and a baseline clonogenic density of 107/cm3 for the normoxic subvolume, when the relative density for the hypoxic cells drops by a factor of 10 the tumor control probability (TCP) decreases by about 10% when relatively small hypoxic volumes and few fractions are considered; longer treatments tend to level out the results. With increasing size of the hypoxic subvolume, the TCP decreased overall as expected, and the difference in TCP between a homogeneous and a heterogeneous distribution of cells increased. The results demonstrate a delicate interplay between the heterogeneous distribution of tumor oxygenation and clonogenic cells that could significantly impact on the treatment outcome of radiotherapy.
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| 8. |
- Schiavo, Filippo, 1994-
(författare)
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The virtual tumour - in silico modelling of tumour vasculature, oxygenation and treatment outcome
- 2022
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Poor tumour oxygenation, namely hypoxia, is one of the major challenges that has been recognised in radiotherapy, yet it is not being accounted for in standard treatments. Hypoxia, resulting from a heterogeneous distribution of vessels (chronic hypoxia) or of a loss in vascular perfusion (acute hypoxia), affects all kinds of solid tumours to different extents. Although over-sustained angiogenesis with vascular remodelling is one of the key hallmarks of cancer, the resulting tumour vasculature is often frail and lacking a clear hierarchical structure, hence incapable of maintaining the same nutrients and oxygen supply standards of healthy vascular networks.It is ascertained that hypoxic cells require an up to three times higher radiation dose than normoxic tissues to achieve the same biological effect. Tumour hypoxia correlates to worse disease prognoses when compared to normoxic tumours. However, many of its biological aspects remain only partially understood. Although from a clinical perspective most of the countermeasures that have been devised to oxygenate or kill hypoxic cells can be evaluated in terms of short- and long-term effects, a clear and pristine understanding of the mechanisms involved in the curative process of hypoxic tumours has not been provided. From this perspective, in silico modelling of the tumour key radiobiological features could instead represent a new frontier: unprecedented computational power and numerical optimisation routines permit to expand virtually the set of possible microenvironmental situations, with simulations of real treatments and concurrent intercomparison of hypothetical scenarios. The fact that the real vascular anatomy of a deep-seated tumour is not fully accessible – and hence not precisely modellable – could be compensated by a large casuistry of heterogeneous oxygenation patterns provided by the model, with inherent best- and worst- case studies. At the same time, in silico modelling would not replace in vivo functional imaging, but would rather act in synergy with that as an additional layer of study: based on the underlying macroscopic information that for instance positron emission tomography (PET) or magnetic resonance imaging (MRI) could offer, the microscopic radiobiological nature of the tumour could be simulated.This thesis consists of papers I-II and an introductory overview of the topics, which provide the background needed for their basic understanding. Starting with an account of tumour hypoxia, its radiobiology and the solutions that have been explored so far to counteract its negative effects are also discussed. Paper I is concerned with the presentation of the novel three-dimensional radiobiological model developed, which is the core of a comprehensive project developed during the PhD work; therefore, it will be introduced in the framework of previously designed models that dealt within this subject in the context of radiotherapy. Since this is probably the first model of its kind designed to be implemented into a treatment planning system (TPS), the subsequent natural steps will consist of the integration of the model in a research version of a TPS and study of the efficacy of various treatment scenarios in terms of underlying tumour oxygenation and treatment choices regarding beam quality, fractionation, and total dose.
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| 9. |
- Schiavo, Filippo, 1994-, et al.
(författare)
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Towards the virtual tumor for optimizing radiotherapy treatments of hypoxic tumors : A novel model of heterogeneous tissue vasculature and oxygenation
- 2022
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Ingår i: Journal of Theoretical Biology. - : Elsevier BV. - 0022-5193 .- 1095-8541. ; 547
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Tumor oxygenation is one of the key features influencing the response of cells to radiation and chemo therapies. This study presents a novel in silico tumor model simulating realistic 3D microvascular structures and related oxygenation maps, featuring regions with different levels and typologies of hypoxia (chronic, acute and anemic). Such model, if integrated into a treatment planning system, could allow evaluations and comparisons of various scenarios when deciding the therapy to administer. Methods and Materials: Spherical tumors between 0.6 and 1.5 cm in diameter encompassed uniformly by vascular trees generated starting from pseudo-fractal principles were simulated with a voxel resolution of 10 µm. The approach ensures a continuous transition from a well-perfused rim to a core with poor vascularization. The oxygen diffusion equation in the tumor is solved by a finite difference method. Several quantities, such as the fractal dimension (FD), the microvascular density (MVD) and the hypoxic fraction (HF) were assessed and compared. Results: Different tumors with various degrees of chronic hypoxia were simulated by varying the tumor size and the number of bifurcations in the vascular networks. The simulations showed that for the case of chronically hypoxic tumors, in well-oxygenated volumes FD = 2.53 ± 0.07, MVD = 3460 ± 2180 vessels/mm3 and HF = 4.0 ± 3.4%, while in hypoxic volumes FD = 2.34 ± 0.09, MVD = 365 ± 156 vessels/mm3, HF = 49.8 ± 18.3%. The superimposition of acute or anemic hypoxia accentuated the oxygen deprivation in the core of the volumes. Conclusions: Tumors varying in diameter and extension of their vasculature were simulated, showing features that define two distinctive subvolumes in terms of oxygenation. The model could be regarded as a testbed for simulations of key radiobiological features governing the tumor response to radio- and chemotherapy and thus for treatment outcome simulations.
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| 10. |
- Toma-Dasu, Iuliana, et al.
(författare)
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Risk of second cancer following radiotherapy
- 2017
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Ingår i: Physica medica (Testo stampato). - : Elsevier BV. - 1120-1797 .- 1724-191X. ; 42, s. 211-212
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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