The Impact of Heterogeneous Cell Density in Hypoxic Tumors Treated with Radiotherapy.

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.

Hypoxia dose painting in SBRT - the virtual clinical trial approach.

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.

Towards the virtual tumor for optimizing radiotherapy treatments of hypoxic tumors: A novel model of heterogeneous tissue vasculature and oxygenation.

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.

Assessment of the Probability of Tumour Control for Prescribed Doses Based on Imaging of Oxygen Partial Pressure.

In radiotherapy, hypoxia is a known negative factor, occurring especially in solid malignant tumours. Nitroimidazole-based positron emission tomography (PET) tracers, due to their selective binding to hypoxic cells, could be used as surrogates to image and quantify the underlying oxygen distributions in tissues. The spatial resolution of a clinical PET image, however, is much larger than the cellular spatial scale where hypoxia occurs. A question therefore arises regarding the possibility of quantifying different hypoxia levels based on PET images, and the aim of the present study is the prescription of corresponding therapeutic doses and its exploration.A tumour oxygenation model was created consisting of two concentric spheres with different oxygen partial pressure (pO2) distributions. In order to mimic a PET image of the simulated tumour, given the relation between uptake and pO2, fundamental effects that limit spatial resolution in a PET imaging system were considered: the uptake distribution was processed with a Gaussian 3D filter, and a re-binning to reach a typical PET image voxel size was performed. Prescription doses to overcome tumour hypoxia and predicted tumour control probability (TCP) were calculated based on the processed images for several fractionation schemes. Knowing the underlying oxygenation at microscopic scale, the actual TCP expected after the delivery of the calculated prescription doses was evaluated. Results are presented for three different dose painting strategies: by numbers, by contours and by using a voxel grouping-based approach.The differences between predicted TCP and evaluated TCP indicate that careful consideration must be taken on the dose prescription strategy and the selection of the number of fractions, depending on the severity of hypoxia.

Impact of SBRT fractionation in hypoxia dose painting - Accounting for heterogeneous and dynamic tumor oxygenation.

PURPOSE: Tumor 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 18 F-HX4 positron emission tomography (PET) imaging of NSCLC. METHODS: Positron emission tomography imaging data based on the hypoxia tracer 18 F-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. RESULTS: Gross 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. CONCLUSIONS: The method to account for heterogeneous and dynamic hypoxia in target volume segmentation and dose prescription based on 18 F-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.