arXiv subjects

Juan Pardo-Montero

Publications and source records attributed to Juan Pardo-Montero.

12 recordsLinked to original sources

arXiv2026

Effect of the dose distribution and organ architecture on the toxicity in FLASH radiotherapy: a modeling study

Objective: This study aims to investigate the influence of organ architecture (specifically the distinction between serial and parallel tissue) on the protective FLASH effect when organs are irradiated with inhomogeneous dose distributions. Approach: An in silico modeling framework was developed using two distinct methods to calculate the effective FLASH dose: the first method utilized a biophysical model of radiolytic oxygen depletion (ROD); the second employed a phenomenological logistic function where the effective FLASH dose is a function of local dose and dose rate. Both models assume that the underlying mechanism behind the FLASH effect is local. Normal Tissue Complication Probability (NTCP) for heterogeneous dose distributions was calculated using the Lyman-Kutcher-Burman (LKB) model and the generalized equivalent uniform dose, varying the volume effect parameter n from 1.0 (parallel) to below 0.01 (serial) to explore different architectures. Results: Both the ROD and phenomenological models showed FLASH sparing compared to conventional radiotherapy. Also, the sparing increased with decreasing $n$ (the sparing is more important for serial organs). For example, for a specific calculation, when the NTCP for conventional radiotherapy was 0.2 (set value) the corresponding NTCP for FLASH delivery ranged from 0.14 for n=1 to 0.11 for n=0.1. Significance: Our results indicate that if the underlying mechanism/s behind the FLASH effect is/are local, the toxicity sparing associated to FLASH-RT can be dependent on the architecture of the irradiated organ/tissue, being more important for serial organs, which are more sensitive to large local doses than to average doses.

physics.med-ph↗

arXiv2026

Charge collection efficiency of thimble ionization chambers exposed to ultra-high dose per pulse

Background: Commercially available ionization chambers (ICs) exposed to ultra-high dose per pulse (UHDP) exhibit deviations from a linear dose response due to volume recombination. Simulation models have been developed to describe the charge collection efficiency (CCE) but focused on parallel-plate ICs. This study aims to measure and simulate the CCE and polarity effect of thimble ICs in UHDP. Methods: The response of two PinPoint3D T31022 (PP3D) and two PinPoint T31023 (PP) ICs was investigated experimentally at the national metrology institute of Germany (PTB). The ICs were irradiated using the UHDP reference electron beam with dose per pulse up to 9.3 Gy for different voltages. A novel finite element code capable of simulating 1D and 2D geometries was developed. Results: Thimble ICs exhibit a pronounced polarization effect when irradiated with UHDP. When the sign of the collected charge is negative, the CCE is larger than when it is positive. The major contribution to the polarity effect can be attributed to the polarity-dependent charge transport and recombination. Experimental and simulated CCE (polarity effect correction factor) agrees within 1.4 % (7.0 %) and 1.6 % (3.2 %) for the PP3D and PP ICs, respectively. The CCE of parallel-plate and thimble ICs is related through a geometrical rule. Conclusions: The PP IC shows greater CCE due to its smaller external radius. The numerical model is able to satisfactory reproduce the actual CCE and polarity effect for these two chambers. At UHDP, thimble ICs should be used with caution due to their large polarity effect.

physics.med-ph↗

arXiv2026

On the calculation of the radiobiological effect of radiolytic oxygen depletion in FLASH radiotherapy

Objective: Radiolytic oxygen depletion (ROD) may play a role in the sparing of cells irradiated with ultra-high dose rates. Different methods have been used to quantify the effect of ROD during FLASH irradiation on cell survival, typically involving some kind of averaging of the oxygen effect and the LQ model. In this work, we compare the results obtained with several of these methods and introduce a novel method based on the non-linear differential form of the LQ model. Approach: We present a novel method to account for a varying oxygen concentration on the dose-response based on the non-linear differential form of the LQ model, and we compare the results obtained with this method with those obtained with other methods that linearize the averaging of the oxygen effect during irradiation. Main results: We found differences in the surviving fractions obtained with the method introduced in this work and other methods that introduce different linearizations (averaging) of the non-linear dependence on the oxygen concentration, especially for oxygenations and doses that lead to important changes in the OERs during the delivery of the dose (initial oxygenations $\approx$5--10 mmHg and doses $>30$~Gy). On the other hand, we showed that the method presented by Zhu \emph{et al.} is equivalent to a first-order Euler numerical method of the differential LQ model. Significance: The method introduced in this work and the method of Zhu \emph{et al.} may allow a more precise quantification of the effect of ROD on dose-response, both for tumors and normal tissues. While all the reviewed methods show an oxygen-dependent sparing effect of FLASH radiotherapy driven by ROD and qualitatively similar results, the method introduced in this work and that of Zhu \emph{et al.} may be more suitable to quantitatively analyze new preclinical (and future clinical) data coming from experimental studies.

physics.med-ph↗

arXiv2025

Evaluation of the two-voltage method for parallel-plate ionization chambers irradiated with pulsed beams

Air-vented ionization chambers exposed to clinical radiation beams may suffer from recombination during the drift of the charge carriers towards the electrodes. Thus, dosimetry protocols recommend the use of a correction factor, usually denominated saturation factor ($k_{\rm sat}$), to correct the ionization chamber readout for the incomplete collection of charge. The two-voltage method is the recommended methodology for the calculation of the saturation factor, however, it is based on the early Boag model, which only takes into account the presence of positive and negative ions in the ionization chamber and does not account for the electric field screening or the free electron contribution to the signal. The numerical simulation shows a better agreement with the experimental data than the current analytical theories in terms of charge collection efficiency. The classical two-voltage method, systematically overestimates the saturation factor, with differences increasing with dose per pulse also present at low dose per pulse. These results may have implications for the dosimetry with ionization chambers in therapy modalities that use a dose per pulse higher than conventional radiotherapy such as intraoperative radiotherapy but also in conventional dose per pulse for ionization chambers that suffer from significant charge recombination.

physics.med-ph↗

arXiv2025

Analysis of the sensitivity of tumor control probability in molecular radiotherapy to uncertainties in the dose rate curves

In this work, we have investigated the sensitivity of the effectiveness (TCP) of molecular radiotherapy (MRT) treatment to uncertainties of the dose rate curves that may appear when reconstructing those curves. We generated different dose rate curves from experimental data, imposing the constraint of equal dose for each of them. Then, we computed TCPs and looked for correlations between metrics measuring the differences between the dose rate curves and differences in TCP. Finally, according to these results, we estimated the range of tolerable uncertainties in the dose rate curves. The study was performed for different radiopharmaceuticals and different radiosensitive parameters that can affect the dose rate response ($α/β$, sub-lethal repair rate). The best correlation between differences in the dose rate curves and TCP was found for a metric that computes averaged linear differences between the curves. With this metric, we quantified differences in dose rate curves that would lead to differences in TCP of 0.02, a parameter denoted $m_{1,\: 0.02}$ that is a surrogate of the dependence of the TCP on the dose rate profile. The results showed that the sensitivity of the TCP to dose rate variations decreases (i.e. larger values of $m_{1,\: 0.02}$) with increasing $α/β$ and sub-lethal damage repair rate of the tumor cells, and increasing biological half-life of the dose rate curves. The radiobiological effect of a MRT treatment on a tumor depends on the absorbed dose and the dose rate profile. Ideally, both magnitudes should be measured with accuracy in order to progress towards the optimization of individualized MRT treatments. Our study suggests that this would be more important for tumors with low $α/β$ and moderately slow sub-lethal damage repair treated with fast-decaying radiopharmaceuticals.

physics.med-ph↗

arXiv2023

Variation of the relative biological effectiveness with fractionation in proton therapy: analysis of prostate cancer response

Purpose: To present a methodology to analyze the variation of RBE with fractionation from clinical data of tumor control probability (TCP) and to apply it to study the response of prostate cancer to proton therapy. M&M: We analyzed the dependence of the RBE on the dose per fraction by using the LQ model and the Poisson TCP formalism. Clinical TCPs for prostate cancer treated with photon and proton therapy for conventional fractionation (2 Gy(RBE)x37 fractions), moderate hypofractionation (3 Gy(RBE)x20 fractions) and hypofractionation (7.25 Gy(RBE)x5 fractions) were obtained from the literature and analyzed. Results: The theoretical analysis showed three distinct regions with RBE monotonically decreasing, increasing or staying constant with the dose per fraction, depending on the change of (α, \{beta}) values between photon and proton irradiation (the equilibrium point being at(α_p/\{beta}_p)=(α_X/\{beta}_X)(α_X/α_p)). An analysis of the clinical data showed RBE values that decline with increasing dose per fraction: for low risk RBE=1.124, 1.119, and 1.102 for 1.82 Gy, 2.73 Gy and 6.59 Gy per fraction (physical proton doses), respectively; for intermediate risk RBE=1.119, and 1.102 for 1.82 Gy, and 6.59 Gy per fraction (physical proton doses), respectively. These values are nonetheless very close to the nominal 1.1 value. Conclusions: We presented a methodology to analyze the RBE for different fractionations, and we used it to study clinical data for prostate cancer. The analysis shows a monotonically decreasing RBE with increasing dose per fraction, which is expected from the LQ formalism and the changes in (α, \{beta}) between photon and proton irradiation. However, the calculations in this study have to be considered with care as they may be biased by limitations in the modeling and/or by the clinical data set used for the analysis.

physics.med-ph↗

arXiv2023

An in-silico study of conventional and FLASH radiotherapy iso-effectiveness: Radiolytic oxygen depletion and its potential impact on tumor control probability

FLASH radiotherapy (FLASH-RT) has shown the potential to spare normal tissue while seemingly maintaining the effectiveness of conventional radiotherapy (CONV-RT). It has been suggested that the protective effect arises from the radiolytic oxygen depletion (ROD) caused by FLASH-RT, but it is not entirely clear why this protective effect is not observed in tumors. Iso-effectiveness has been experimentally observed in time-volume curves of preclinical tumors irradiated with FLASH and conventional radiotherapy, but it may not translate to clinical trials, where tumor control probability (TCP) is typically the investigated endpoint. In this work, we used mathematical models to investigate the iso-effectiveness of FLASH-RT/CONV-RT on tumors, focusing on the role of ROD. We used a spatiotemporal reaction-diffusion model, including ROD, to simulate tumor oxygenation. From those oxygen distributions we obtained surviving fractions (SFs), using the linear-quadratic model with oxygen enhancement ratios (OER). We then used the calculated SFs to describe the evolution of preclinical tumor volumes through a mathematical model of tumor response. We also calculated TCPs using the Poisson-LQ approach. Our study suggests that ROD causes differences in SF between FLASH-RT and CONV-RT, especially in low $α$/$β$ and poorly oxygenated cells. These changes do not lead to significant differences in the evolution of preclinical tumors. However, when extrapolating this effect to TCP curves, we observed important differences between both techniques (TCP is lower in FLASH-RT). Nonetheless, it cannot be discarded that other effects not modeled in this work could contribute to tumor control and maintain the iso-effectiveness of FLASH-RT.

physics.med-ph↗

arXiv2022

A biomathematical model of tumor response to radioimmunotherapy with $α$PDL1 and $α$CTLA4

There is evidence of synergy between radiotherapy and immunotherapy. Radiotherapy can increase liberation of tumor antigens, causing activation of antitumor T-cells. This effect can be boosted with immunotherapy. Radioimmunotherapy has potential to increase tumor control rates. Biomathematical models of response to radioimmunotherapy may help on understanding of the mechanisms affecting response, and assist clinicians on the design of optimal treatment strategies. In this work we present a biomathematical model of tumor response to radioimmunotherapy. The model uses the linear-quadratic response of tumor cells to radiation (or variation of it), and builds on previous developments to include the radiation-induced immune effect. We have focused this study on the combined effect of radiotherapy and $α$PDL1/$α$CTLA4 therapies. The model can fit preclinical data of volume dynamics and control obtained with different dose fractionations and $α$PDL1/$α$CTLA4. A biomathematical study of optimal combination strategies suggests that a good understanding of the involved biological delays, the biokinetics of the immunotherapy drug, and the interplay between them, may be of paramount importance to design optimal radioimmunotherapy schedules. Biomathematical models like the one we present can help to interpret experimental data on the synergy between radiotherapy and immunotherapy, and to assist in the design of more effective treatments.

physics.med-ph↗

arXiv2022

Evaluation of indirect damage and damage saturation effects in dose-response curves of hypofractionated radiotherapy of early-stage NSCLC and brain metastases

Background and purpose: To investigate the possible contribution of indirect damage and damage saturation to tumour control obtained with SBRT/SRS treatments for early-stage NSCLC and brain metastases. Methods and Materials: We have constructed a dataset of early-stage NSCLC and brain metastases dose-response. These data were fitted to models based on the linear-quadratic (LQ), the linear-quadratic-linear (LQL), and phenomenological modifications of the LQ-model to account for indirect cell damage. We use the Akaike-Information-Criterion formalism to compare performance, and studied the stability of the results with changes in fitting parameters and perturbations on dose/TCP values. Results: In NSCLC, a modified LQ-model with a beta-term increasing with dose yields the best-fits for $α$/$β$=10 Gy. Only the inclusion of very fast accelerated proliferation or low $α$/$β$ values can eliminate such superiority. In brain, the LQL model yields the best-fits, and the ranking is not affected by variations of fitting parameters or dose/TCP perturbations. Conclusions: For $α$/$β$=10 Gy, a modified LQ-model with a beta-term increasing with dose provides better fits to NSCLC dose-response curves. For brain metastases, the LQL provides the best fit. This might be interpreted as a hint of indirect damage in NSCLC, and damage saturation in brain metastases. The results for NSCLC are strongly dependent on the value of $α$/$β$ and may require further investigation, while those for brain seem to be clearly significant. Our results can assist in the design of improved radiotherapy for NSCLC and brain metastases, aiming at avoiding over/under-treatment.

physics.med-ph↗

arXiv2022

Quantification of internal dosimetry in PET patients II: Individualized Monte Carlo-based dosimetry for [18F]Fluorocholine PET

Purpose: To obtain individualized internal doses with a Monte Carlo method in patients undergoing diagnostic FCH-PET studies and to compare such doses with the MIRD method calculations. Methods: A patient cohort of 17 males were imaged after intravenous administration of a mean FCH activity of 244.3 MBq. The resulting PET/CT images were processed in order to generate individualized input source and geometry files for dose computation with the MC tool GATE. The resulting dose estimates were studied and compared to the MIRD method with two different computational phantoms. Mass correction of the S-factors was applied when possible. Potential sources of uncertainty were closely examined: the effect of partial body images, urinary bladder emptying, and biokinetic modeling. Results: Large differences in doses between our methodology and the MIRD method were found, generally in the range of $\pm$25%, and up to $\pm$120% for some cases. The mass scaling showed improvements, especially for non-walled and high-uptake tissues. Simulations of the urinary bladder emptying showed negligible effects on doses to other organs, with the exception of the prostate. Dosimetry based on partial PET/CT images (excluding the legs) resulted in an over-estimation of mean doses to bone, skin, and remaining tissues, and minor differences in other organs/tissues. Estimated uncertainties associated with the biokinetics of FCH introduce variations of cumulated activities in the range of $\pm$10% in the high-uptake organs. Conclusions: The MC methodology allows for a higher degree of dosimetry individualization than the MIRD methodology, which in some cases leads to important differences in dose values. Dosimetry of FCH-PET based on a single partial PET study seems viable due to the particular biokinetics of FCH, even though some correction factors may need to be applied to estimate mean skin/bone doses.

physics.med-ph↗

arXiv2021

A Mathematical Model of Thyroid Disease Response to Radiotherapy

We present a mechanistic biomathematical model of molecular radiotherapy of thyroid disease. The general model consists of a set of differential equations describing the dynamics of different populations of thyroid cells with varying degrees of damage caused by radiotherapy (undamaged cells, sub-lethally damaged cells, doomed cells, and dead cells), as well as the dynamics of thyroglobulin and antithyroglobulin autoantibodies, which are important surrogates of treatment response. The model is presented in two flavours: on the one hand, as a deterministic continuous model, which is useful to fit populational data, and on the other hand, as a stochastic Markov model, which is particularly useful to investigate tumor control probabilities and treatment individualization. The model was used to fit the response dynamics (tumor/thyroid volumes, thyroglobulin and antithyroglobulin autoantibodies) observed in experimental studies of thyroid cancer and Graves' disease treated with I-131-radiotherapy. A qualitative adequate fitting of the model to the experimental data was achieved. We also used the model to investigate treatment individualization strategies for differentiated thyroid cancer, aiming to improve the tumor control probability. We found that simple individualization strategies based on the absorbed dose in the tumor and tumor radiosensitivity (which are both magnitudes that can potentially be individually determined for every patient) can lead to an important raise of tumor control probabilities.

physics.med-ph↗

arXiv2021

A kinetic model of continuous radiation damage to populations of cells: Comparison to the LQ model and application to molecular radiotherapy

The linear-quadratic (LQ) model to describe the survival of irradiated cells may be the most frequently used biomathematical model in radiotherapy. There has been an intense debate on the mechanistic origin of the LQ model. An interesting approach is that of obtaining LQ-like behavior from kinetic models, systems of differential equations that model the induction and repair of damage. Development of such kinetic models is particularly interesting for application to continuous dose rate therapies, such as molecular radiotherapy or brachytherapy. In this work, we present a simple kinetic model that describes the kinetics of populations of tumor cells, rather than lethal/sub-lethal lesions, which may be especially useful for application to continuous dose rate therapies, as in molecular radiotherapy. The multi-compartment model consists of a set of three differential equations. The model incorporates in an easy way different cross-interacting compartments of cells forming a tumor, and may be of especial interest for studying dynamics of treated tumors. In the fast dose delivery limit, the model can be analytically solved, obtaining a simple closed-form expression. Fitting of several surviving curves with both this solution and the LQ model shows that they produce similar fits, despite being functionally different. We have also investigated the operation of the model in the continuous dose rate scenario, firstly by fitting pre-clinical data of tumor response to 131I-CLR1404 therapy, and secondly by showing how damage repair and proliferation rates can cause a treatment to achieve control or not. Kinetic models like the one presented in this work may be of special interest when modeling response to molecular radiotherapy.

physics.med-ph↗