Browsing by Author "Gago-Arias, Araceli"

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    A kinetic model of continuous radiation damage to populations of cells: comparison to the LQ model and application to molecular radiotherapy
    (2020) Neira, Sara; Gago-Arias, Araceli; Guiu-Souto, Jacobo; Pardo-Montero, Juan
    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 I-131-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.
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    A Mathematical Model of Thyroid Disease Response to Radiotherapy
    (2021) Gago-Arias, Araceli; Neira, Sara; Terragni, Filippo; Pardo-Montero, Juan
    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.
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    Development of a Compartmental Pharmacokinetic Model for Molecular Radiotherapy with 131I-CLR1404
    (2021) Neira, Sara; Gago-Arias, Araceli; Gonzalez-Crespo, Isabel; Guiu-Souto, Jacobo; Pardo-Montero, Juan
    Pharmacokinetic modeling of the radiopharmaceuticals used in molecular radiotherapy is an important step towards accurate radiation dosimetry of such therapies. In this paper, we present a pharmacokinetic model for CLR1404, a phospholipid ether analog that, labeled with I-124/I-131, has emerged as a promising theranostic agent. We follow a systematic approach for the model construction based on a decoupling process applied to previously published experimental data, and using the goodness-of-fit, Sobol's sensitivity analysis, and the Akaike Information Criterion to construct the optimal form of the model, investigate potential simplifications, and study factor prioritization. This methodology was applied to previously published experimental human time-activity curves for 9 organs. The resulting model consists of 17 compartments involved in the CLR1404 metabolism. Activity dynamics in most tissues are well described by a blood contribution plus a two-compartment system, describing fast and slow uptakes. The model can fit both clinical and pre-clinical kinetic data of I-124/I-131. In addition, we have investigated how simple fits (exponential and biexponential) differ from the complete model. Such fits, despite providing a less accurate description of time-activity curves, may be a viable alternative when limited data is available in a practical case.
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    Dosimetric Evaluation of Cardiac Structures on Left Breast Cancer Radiotherapy: Impact of Movement, Dose Calculation Algorithm and Treatment Technique
    (2023) Wittwer, Esteban Barnafi; Rippker, Carolin; Caprile, Paola; Torres, Demetrio Elias; El Far, Rodrigo; Gago-Arias, Araceli; Merino, Tomas
    Background: Breast cancer is the most frequently diagnosed and leading cause of cancer-related deaths among females. The treatment of breast cancer with radiotherapy, albeit effective, has been shown to be toxic to the heart, resulting in an elevated risk of cardiovascular disease and associated fatalities. Methods: In this study, we evaluated the impact of respiratory move-ment, treatment plans and dose calculation algorithm on the dose de-livered to the heart and its substructures during left breast radiothera-py over a cohort of 10 patients. We did this through three image sets, four different treatment plans and the employment of three algorithms on the same treatment plan. The dose parameters were then employed to estimate the impact on the 9-year excess cumulative risk for acute cardiac events by applying the model proposed by Darby. Results: The left ventricle was the structure most irradiated. Due to the lack of four-dimensional computed tomography (4DCT), we used a set of images called phase-average CT that correspond to the average of the images from the respiratory cycle (exhale, exhale 50%, inhale, inhale 50%). When considering these images, nearly 10% of the heart received more than 5 Gy and doses were on av-erage 27% higher when compared to free breathing images. Deep inspiration breath-hold plans reduced cardiac dose for nine out of 10 patients and reduced mean heart dose in about 50% when com-pared to reference plans. We also found that the implementation of deep inspiration breath-hold would reduce the relative lifetime risk of ischemic heart disease to 10%, in comparison to 21% from the reference plan. Conclusion: Our findings illustrate the importance of a more accu-rate determination of the dose and its consideration in cardiologists' consultation, a factor often overlooked during clinical examination. They also motivate the evaluation of the dose to the heart substruc-tures to derive new heart dose constraints, and a more mindful and individualized clinical practice depending on the treatment employed.
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    Evaluation of indirect damage and damage saturation effects in dose- response curves of hypofractionated radiotherapy of early-stage NSCLC and brain metastases
    (2021) Gago-Arias, Araceli; Neira, Sara; Pombar, Miguel; Gomez-Caamano, Antonio; Pardo-Montero, Juan
    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 oc/ fi = 10 Gy. Only the inclusion of very fast accelerated proliferation or low oc/fi 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 oc/fi = 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 oc/fi 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. (c) 2021 The Author(s). Published by Elsevier B.V. Radiotherapy and Oncology 101 (2021) 1-8 This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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    Quantification of internal dosimetry in PET patients II: Individualized Monte Carlo-based dosimetry for [18F]fluorocholine PET
    (2021) Neira, Sara; Guiu-Souto, Jacobo; Pais, Paulino; Martinez de Llano, Sofia Rodriguez; Fernandez, Carlos; Pubul, Virginia; Ruibal, Alvaro; Pombar, Miguel; Gago-Arias, Araceli; Pardo-Montero, Juan
    Purpose To obtain individualized internal doses with a Monte Carlo (MC) method in patients undergoing diagnostic [18F]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 [18F]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 +/- 25%, and up to +/- 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 overestimation 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 +/- 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.
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    Quantification of internal dosimetry in PET patients: individualized Monte Carlo vs generic phantom-based calculations
    (2020) Neira, Sara; Guiu-Souto, Jacobo; Diaz-Botana, Pablo; Pais, Paulino; Fernandez, Carlos; Pubul, Virginia; Ruibal, Alvaro; Candela-Juan, Cristian; Gago-Arias, Araceli; Pombar, Miguel; Pardo-Montero, Juan
    Purpose The purpose of this work is to calculate individualized dose distributions in patients undergoing(18)F-FDG PET/CT studies through a methodology based on full Monte Carlo (MC) simulations and PET/CT patient images, and to compare such values with those obtained by employing nonindividualized phantom-based methods. Methods We developed a MC-based methodology for individualized internal dose calculations, which relies on CT images (for organ segmentation and dose deposition), PET images (for organ segmentation and distributions of activities), and a biokinetic model (which works with information provided by PET and CT images) to obtain cumulated activities. The software vGATE version 8.1. was employed to carry out the Monte Carlo calculations. We also calculated deposited doses with nonindividualized phantom-based methods (Cristy-Eckerman, Stabin, and ICRP-133). Results Median MC-calculated dose/activity values are within 0.01-0.03 mGy/MBq for most organs, with higher doses delivered especially to the bladder wall, major vessels, and brain (medians of 0.058, 0.060, 0.066 mGy/MBq, respectively). Comparison with values obtained with nonindividualized phantom-based methods has shown important differences in many cases (ranging from -80% to + 260%). These differences are significant (p < 0.05) for several organs/tissues, namely, remaining tissues, adrenals, bladder wall, bones, upper large intestine, heart, pancreas, skin, and stomach wall. Conclusions The methodology presented in this work is a viable and useful method to calculate internal dose distributions in patients undergoing medical procedures involving radiopharmaceuticals, individually, with higher accuracy than phantom-based methods, fulfilling the guidelines provided by the European Council directive 2013/59/Euratom.
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    Radiobiological Meta-Analysis of the Response of Prostate Cancer to Different Fractionations: Evaluation of the Linear-Quadratic Response at Large Doses and the Effect of Risk and ADT
    (2023) Pardo-Montero, Juan; Gonzalez-Crespo, Isabel; Gomez-Caamano, Antonio; Gago-Arias, Araceli
    Prostate cancer is currently treated with different radiotherapy fractionations, including extreme hypofractionation. Some studies suggest that the response to large radiation doses per fraction may depart from the response predicted by the widely used linear-quadratic (LQ) model. In this study, we analysed a large dataset of dose-response data to evaluate departures from the LQ behaviour at large doses. In general, the response of prostate cancer to large doses of radiotherapy is best described by the LQ model, even though we observed some discrepancies at large doses for intermediate-risk patients, which merit further investigation. In addition, we characterised the radiobiological response of prostate cancer according to risk (low, intermediate, or high) and the addition or not of ADT to treatment.