IS2aR, a computational tool to transform voxelized reference phantoms into patient-specific whole-body virtual CTs for peripheral dose estimation.

BACKGROUND: The risk of radiogenic cancer induction due to radiotherapy depends on the dose received by the patient's organs. Knowing the position of all organs is needed to assess this dose in a personalized way. However, radiotherapy planning computed tomography (pCT) scans contain truncated patient anatomy, limiting personalized dose evaluation. PURPOSE: To develop a simple and freely available computational tool that adapts an ICRP reference computational phantom to generate a patient-specific whole-body CT for peripheral dose computations. METHODS: Various bone-segmentation methods were explored onto fifteen pCTs, and the one with the highest Sørensen-Dice coefficient was implemented. The reference phantom is registered to the pCT, obtaining a registration transform matrix, which is then applied to create the whole-body virtual CT. Additional validation involved a comparison of absorbed doses to organs delineated on both the pCT and the virtual CT. RESULTS: A dedicated graphical user interface was designed and implemented to house the developed functions for i) selecting a registration region on which automatic bone segmentation and rigid registration will occur, ii) displaying the results of these processes under selectable views, and iii) exporting the final patient-specific whole-body CT. This software was termed IS2aR. The tested whole-body virtual CT generated by IS2aR fulfilled our requirements. CONCLUSIONS: IS2aR is a user-friendly computational software to create a personalized whole-body CT containing the original structures in the reference phantom. The personalized dose deposited in peripheral organs can be estimated further to assess second cancer induction risk in epidemiological studies.

A simple analytical model for a fast 3D assessment of peripheral photon dose during coplanar isocentric photon radiotherapy.

Considering that cancer survival rates have been growing and that nearly two-thirds of those survivors were exposed to clinical radiation during its treatment, the study of long-term radiation effects, especially secondary cancer induction, has become increasingly important. To correctly assess this risk, knowing the dose to out-of-field organs is essential. As it has been reported, commercial treatment planning systems do not accurately calculate the dose far away from the border of the field; analytical dose estimation models may help this purpose. In this work, the development and validation of a new three-dimensional (3D) analytical model to assess the photon peripheral dose during radiotherapy is presented. It needs only two treatment-specific input parameter values, plus information about the linac-specific leakage, when available. It is easy to use and generates 3D whole-body dose distributions and, particularly, the dose to out-of-field organs (as dose-volume histograms) outside the 5% isodose for any isocentric treatment using coplanar beams [including intensity modulated radiotherapy and volumetric modulated arc therapy (VMAT)]. The model was configured with the corresponding Monte Carlo simulation of the peripheral absorbed dose for a 6 MV abdomen treatment on the International Comission on Radiological Protection (ICRP) 110 computational phantom. It was then validated with experimental measurements using thermoluminescent dosimeters in the male ATOM anthropomorphic phantom irradiated with a VMAT treatment for prostate cancer. Additionally, its performance was challenged by applying it to a lung radiotherapy treatment very different from the one used for training. The model agreed well with measurements and simulated dose values. A graphical user interface was developed as a first step to making this work more approachable to a daily clinical application.

Peripheral Organ Equivalent Dose Estimation Procedure in Proton Therapy.

The aim of this work is to present a reproducible methodology for the evaluation of total equivalent doses in organs during proton therapy facilities. The methodology is based on measuring the dose equivalent in representative locations inside an anthropomorphic phantom where photon and neutron dosimeters were inserted. The Monte Carlo simulation was needed for obtaining neutron energy distribution inside the phantom. The methodology was implemented for a head irradiation case in the passive proton beam of iThemba Labs (South Africa). Thermoluminescent dosimeter (TLD)-600 and TLD-700 pairs were used as dosimeters inside the phantom and GEANT code for simulations. In addition, Bonner sphere spectrometry was performed inside the treatment room to obtain the neutron spectra, some relevant neutron dosimetric quantities per treatment Gy, and a percentual distribution of neutron fluence and ambient dose equivalent in four energy groups, at two locations. The neutron spectrum at one of those locations was also simulated so that a reasonable agreement between simulation and measurement allowed a validation of the simulation. Results showed that the total out-of-field dose equivalent inside the phantom ranged from 1.4 to 0.28 mSv/Gy, mainly due to the neutron contribution and with a small contribution from photons, 10% on average. The order of magnitude of the equivalent dose in organs was similar, displaying a slow reduction in values as the organ is farther from the target volume. These values were in agreement with those found by other authors in other passive beam facilities under similar irradiation and measurement conditions.

Low dose radiation therapy for COVID-19: Effective dose and estimation of cancer risk.

BACKGROUND AND PURPOSE: The objective of this work is to evaluate the risk of carcinogenesis of low dose ionizing radiation therapy (LDRT), for treatment of immune-related pneumonia following COVID-19 infection, through the estimation of effective dose and the lifetime attributable risk of cancer (LAR). MATERIAL AND METHODS: LDRT treatment was planned in male and female computational phantoms. Equivalent doses in organs were estimated using both treatment planning system calculations and a peripheral dose model (based on ionization chamber measurements). Skin dose was estimated using radiochromic films. Later, effective dose and LAR were calculated following radiation protection procedures. RESULTS: Equivalent doses to organs per unit of prescription dose range from 10 mSv/cGy to 0.0051 mSv/cGy. Effective doses range from 204 mSv to 426 mSv, for prescription doses ranging from 50 cGy to 100 cGy. Total LAR for a prescription dose of 50 cGy ranges from 1.7 to 0.29% for male and from 4.9 to 0.54% for female, for ages ranging from 20 to 80 years old. CONCLUSIONS: The organs that mainly contribute to risk are lung and breast. Risk for out-of-field organs is low, less than 0.06 cases per 10000. Female LAR is on average 2.2 times that of a male of the same age. Effective doses are of the same order of magnitude as the higher-dose interventional radiology techniques. For a 60 year-old male, LAR is 8 times that from a cardiac CT, when prescription dose is 50 cGy.

PERIPHERAL SURFACE DOSE FROM A LINEAR ACCELERATOR: RADIOCHROMIC FILM EXPERIMENTAL MEASUREMENTS OF FLATTENING FILTER FREE VERSUS FLATTENED BEAMS.

There is a growing interest in the use of flattening filter free (FFF) beams due to the shorter treatment times. The reduction of head scatter suggests a better radiation protection to radiotherapy patients, considering the expected decrease in peripheral surface dose (PSD). In this work, PSD of flattened (FF) and FFF-photon beams was compared. A radiochromic film calibration method to reduce energy dependence was used. PSD was measured at distances from 2 to 50 cm to the field border for different square field sizes, modifying relevant clinical parameters. Also, clinical breast and prostate stereotactic body radiotherapy (SBRT) plans were studied. For square beams, FFF PSD is lower compared with FF PSD (differences ranging from 3 to 64%) and 10 MV FFF yields to the lowest value, for distances greater than 5 cm. For SBRT plans, near and far away from the field border, there is a reduction of PSD for FFF-beams, but the behavior at intermediate distances should be checked depending on the case.

Incorporation of Dosimetric Gradients and Parotid Gland Migration Into Xerostomia Prediction.

Purpose: Due to the sharp gradients of intensity-modulated radiotherapy (IMRT) dose distributions, treatment uncertainties may induce substantial deviations from the planned dose during irradiation. Here, we investigate if the planned mean dose to parotid glands in combination with the dose gradient and information about anatomical changes during the treatment improves xerostomia prediction in head and neck cancer patients. Materials and methods: Eighty eight patients were retrospectively analyzed. Three features of the contralateral parotid gland were studied in terms of their association with the outcome, i.e., grade ≥ 2 (G2) xerostomia between 6 months and 2 years after radiotherapy (RT): planned mean dose (MD), average lateral dose gradient (GRADX), and parotid gland migration toward medial (PGM). PGM was estimated using daily megavoltage computed tomography (MVCT) images. Three logistic regression models where analyzed: based on (1) MD only, (2) MD and GRADX, and (3) MD, GRADX, and PGM. Additionally, the cohort was stratified based on the median value of GRADX, and a univariate analysis was performed to study the association of the MD with the outcome for patients in low- and high-GRADX domains. Results: The planned MD failed to recognize G2 xerostomia patients (AUC = 0.57). By adding the information of GRADX (second model), the model performance increased to AUC = 0.72. The addition of PGM (third model) led to further improvement in the recognition of the outcome (AUC = 0.79). Remarkably, xerostomia patients in the low-GRADX domain were successfully identified (AUC = 0.88) by the MD alone. Conclusions: Our results indicate that GRADX and PGM, which together serve as a proxy of dosimetric changes, provide valuable information for xerostomia prediction.

Intensity-modulated radiation therapy and volumetric modulated arc therapy versus conventional conformal techniques at high energy: Dose assessment and impact on second primary cancer in the out-of-field region.

The aim of this work was to estimate peripheral neutron and photon doses associated with the conventional 3D conformal radiotherapy techniques in comparison to modern ones such as Intensity modulated radiation therapy and volumetric modulated arc therapy. Assessment in terms of second cancer incidence ought to peripheral doses was also considered. For that, a dosimetric methodology proposed by the authors has been applied beyond the region where there is no CT information and, thus, treatment planning systems do not calculate and where, nonetheless, about one third of second primary cancers occurs.

Impact of different biologically-adapted radiotherapy strategies on tumor control evaluated with a tumor response model.

Motivated by the capabilities of modern radiotherapy techniques and by the recent developments of functional imaging techniques, dose painting by numbers (DPBN) was proposed to treat tumors with heterogeneous biological characteristics. This work studies different DPBN optimization techniques for virtual head and neck tumors assessing tumor response in terms of cell survival and tumor control probability with a previously published tumor response model (TRM). Uniform doses of 2 Gy are redistributed according to the microscopic oxygen distribution and the density distribution of tumor cells in four virtual tumors with different biological characteristics. In addition, two different optimization objective functions are investigated, which: i) minimize tumor cell survival (OFsurv) or; ii) maximize the homogeneity of the density of surviving tumor cells (OFstd). Several adaptive schemes, ranging from single to daily dose optimization, are studied and the treatment response is compared to that of the uniform dose. The results show that the benefit of DPBN treatments depends on the tumor reoxygenation capability, which strongly differed among the set of virtual tumors investigated. The difference between daily (fraction by fraction) and three weekly optimizations (at the beginning of weeks 1, 3 and 4) was found to be small, and higher benefit was observed for the treatments optimized using OFsurv. This in silico study corroborates the hypothesis that DPBN may be beneficial for treatments of tumors which show reoxygenation during treatment, and that a few optimizations may be sufficient to achieve this therapeutic benefit.

Uncomplicated and Cancer-Free Control Probability (UCFCP): A new integral approach to treatment plan optimization in photon radiation therapy.

PURPOSE: Biological treatment plan evaluation does not currently consider second cancer induction from peripheral doses associated to photon radiotherapy. The aim is to propose a methodology to characterize the therapeutic window by means of an integral radiobiological approach, which considers not only Tumour Control Probability (TCP) and Normal Tissue Complication Probability (NTCP) but also Secondary Cancer Probability (SCP). METHODS: Uncomplicated and Cancer-Free Control Probability (UCFCP) function has been proposed assuming a statistically uncorrelated response for tumour and normal tissues. The Poisson's and Lyman's models were chosen for TCP and NTCP calculations, respectively. SCP was modelled as the summation of risks associated to photon and neutron irradiation of radiosensitive organs. For the medium (>4Gy) and low dose regions, mechanistic and linear secondary cancer risks models were used, respectively. Two conformal and intensity-modulated prostate plans at 15MV (same prescription dose) were selected to illustrate the UCFCP features. RESULTS: UCFCP exhibits a bell-shaped behaviour with its maximum inside the therapeutic window. SCP values were not different for the plans analysed (∼2.4%) and agreed with published epidemiological results. Therefore, main differences in UCFCP came from differences in rectal NTCP (18% vs 9% for 3D-CRT and IMRT, respectively). According to UCFCP values, the evaluated IMRT plan ranked first. CONCLUSIONS: The level of SCP was found to be similar to that of NTCP complications which reinforces the importance of considering second cancer risks as part of the possible late sequelae due to treatment. Previous concerns about the effect of peripheral radiation, especially neutrons, in the induction of secondary cancers can be evaluated by quantifying the UCFCP.

Modelling radiation-induced cell death and tumour re-oxygenation: local versus global and instant versus delayed cell death.

The resistance of hypoxic cells to radiation, due to the oxygen dependence of radiosensitivity, is well known and must be taken into account to accurately calculate the radiation induced cell death. A proper modelling of the response of tumours to radiation requires deriving the distribution of oxygen at a microscopic scale. This usually involves solving the reaction-diffusion equation in tumour voxels using a vascularization distribution model. Moreover, re-oxygenation arises during the course of radiotherapy, one reason being the increase of available oxygen caused by cell killing, which can turn hypoxic tumours into oxic. In this work we study the effect of cell death kinetics in tumour oxygenation modelling, analysing how it affects the timing of re-oxygenation, surviving fraction and tumour control. Two models of cell death are compared, an instantaneous cell killing, mimicking early apoptosis, and a delayed cell death scenario in which cells can die shortly after being damaged, as well as long after irradiation. For each of these scenarios, the decrease in oxygen consumption due to cell death can be computed globally (macroscopic voxel average) or locally (microscopic). A re-oxygenation model already used in the literature, the so called full re-oxygenation, is also considered. The impact of cell death kinetics and re-oxygenation on tumour responses is illustrated for two radiotherapy fractionation schemes: a conventional schedule, and a hypofractionated treatment. The results show large differences in the doses needed to achieve 50% tumour control for the investigated cell death models. Moreover, the models affect the tumour responses differently depending on the treatment schedule. This corroborates the complex nature of re-oxygenation, showing the need to take into account the kinetics of cell death in radiation response models.

Dosimetric characterization and optimization of a customized Stanford total skin electron irradiation (TSEI) technique.

Total skin electron irradiation (TSEI) has been used as a treatment for mycosis fungoides. Our center has implemented a modified Stanford technique with six pairs of 6 MeV adjacent electron beams, incident perpendicularly on the patient who remains lying on a translational platform, at 200 cm from the source. The purpose of this study is to perform a dosimetric characterization of this technique and to investigate its optimization in terms of energy characteristics, extension, and uniformity of the treatment field. In order to improve the homogeneity of the distribution, a custom-made polyester filter of variable thickness and a uniform PMMA degrader plate were used. It was found that the characteristics of a 9 MeV beam with an 8 mm thick degrader were similar to those of the 6 MeV beam without filter, but with an increased surface dose. The combination of the degrader and the polyester filter improved the uniformity of the distribution along the dual field (180cm long), increasing the dose at the borders of field by 43%. The optimum angles for the pair of beams were ± 27°. This configuration avoided displacement of the patient, and reduced the treatment time and the positioning problems related to the abutting superior and inferior fields. Dose distributions in the transversal plane were measured for the six incidences of the Stanford technique with film dosimetry in an anthropomorphic pelvic phantom. This was performed for the optimized treatment and compared with the previously implemented technique. The comparison showed an increased superficial dose and improved uniformity of the 85% isodose curve coverage for the optimized technique.

Neutron contamination in radiotherapy: estimation of second cancers based on measurements in 1377 patients.

PURPOSE: Second cancer, as a consequence of a curative intent radiotherapy (RT), represents a growing concern nowadays. The unwanted neutron exposure is an important contributor to this risk in patients irradiated with high energy photon beams. The design and development by our group of a neutron digital detector, together with the methodology to estimate, from the detector readings, the neutron equivalent dose in organs, made possible the unprecedented clinical implementation of an online and systematic neutron dosimetry system. The aim of this study was to systematically estimate neutron equivalent dose in organs of a large patient group treated in different installations. PATIENTS AND METHODS: Neutron dosimetry was carried out in 1377 adult patients at more than 30 different institutions using the new neutron digital detector located inside the RT room. Second cancer risk estimates were performed applying ICRP risk coefficients. RESULTS: Averaged equivalent dose in organs ranges between 0.5 mSv and 129 mSv depending on the type of treatment (dose and beam-on time), the distance to isocenter and the linac model. The mean value of the second cancer risk for our patient group is 1.2%. Reference values are proposed for an overall estimation of the risks in 15 linac models (from 2.8 × 10(-5) to 62.7 × 10(-5)%/MU). CONCLUSIONS: The therapeutic benefit of RT must outweigh the second cancer risk. Thus, these results should be taken into account when taking clinical decisions regarding treatment strategy choice during RT planning.

Effects of heating rate and dose on trapping parameters of TLD-100 crystals.

The characteristics of the thermoluminescence glow curve and dosimetric peak of LiF:Mg,Ti (TLD-100) crystals are studied, with emphasis on the evaluation of the influence of the irradiation dose and heating rate on the dosimetric peak (peak 5) trapping parameters. These parameters were obtained using a computerized deconvolution routine that assumed first-order kinetics for each peak composing the glow curve. This routine was able to fit accurately (1.2% < FOM < 3.4%) all measured glow curves. It was found that for the evaluated range of photon doses (0.2 to 20 cGy) and heating rates (7 to 25 K/s), the behavior of the dosimetric peak was consistent with the predictions of the Randall-Wilkins first-order kinetic model. In particular, it was confirmed that the activation energy of the dosimetric peak is independent of the heating rate and irradiation dose, as expected from this model. The mean activation energy obtained for peak 5 was 2.27 ± 0.08 eV. The area under the experimental glow curves for the same dose remained stable regardless of the heating rate used, indicating that the thermal quenching effect did not have a significant influence within the studied range. By fixing the heating rate and varying the dose, it was found that the integral was proportional to the irradiation dose, as expected.

Predictive models for pulmonary function changes after radiotherapy for breast cancer and lymphoma.

PURPOSE: To propose multivariate predictive models for changes in pulmonary function tests (ΔPFTs) with respect to preradiotherapy (pre-RT) values in patients undergoing RT for breast cancer and lymphoma. METHODS AND MATERIALS: A prospective study was designed to measure ΔPFTs of patients undergoing RT. Sixty-six patients were included. Spirometry, lung capacity (measured by helium dilution), and diffusing capacity of carbon monoxide tests were used to measure lung function. Two lung definitions were considered: paired lung vs. irradiated lung (IL). Correlation analysis of dosimetric parameters (mean lung dose and the percentage of lung volume receiving more than a threshold dose) and ΔPFTs was carried out to find the best dosimetric predictor. Chemotherapy, age, smoking, and the selected dose-volume parameter were considered as single and interaction terms in a multivariate analysis. Stability of results was checked by bootstrapping. RESULTS: Both lung definitions proved to be similar. Modeling was carried out for IL. Acute and late damage showed the highest correlations with volumes irradiated above ~20 Gy (maximum R(2) = 0.28) and ~40 Gy (maximum R(2) = 0.21), respectively. RT alone induced a minor and transitory restrictive defect (p = 0.013). Doxorubicin-cyclophosphamide-paclitaxel (Taxol), when administered pre-RT, induced a late, large restrictive effect, independent of RT (p = 0.031). Bootstrap values confirmed the results. CONCLUSIONS: None of the dose-volume parameters was a perfect predictor of outcome. Thus, different predictor models for ΔPFTs were derived for the IL, which incorporated other nondosimetric parameters mainly through interaction terms. Late ΔPFTs seem to behave more serially than early ones. Large restrictive defects were demonstrated in patients pretreated with doxorubicin-cyclophosphamide-paclitaxel.

Dose-volume constraints to reduce rectal side effects from prostate radiotherapy: evidence from MRC RT01 Trial ISRCTN 47772397.

PURPOSE: Radical radiotherapy for prostate cancer is effective but dose limited because of the proximity of normal tissues. Comprehensive dose-volume analysis of the incidence of clinically relevant late rectal toxicities could indicate how the dose to the rectum should be constrained. Previous emphasis has been on constraining the mid-to-high dose range (>/=50 Gy). Evidence is emerging that lower doses could also be important. METHODS AND MATERIALS: Data from a large multicenter randomized trial were used to investigate the correlation between seven clinically relevant rectal toxicity endpoints (including patient- and clinician-reported outcomes) and an absolute 5% increase in the volume of rectum receiving the specified doses. The results were quantified using odds ratios. Rectal dose-volume constraints were applied retrospectively to investigate the association of constraints with the incidence of late rectal toxicity. RESULTS: A statistically significant dose-volume response was observed for six of the seven endpoints for at least one of the dose levels tested in the range of 30-70 Gy. Statistically significant reductions in the incidence of these late rectal toxicities were observed for the group of patients whose treatment plans met specific proposed dose-volume constraints. The incidence of moderate/severe toxicity (any endpoint) decreased incrementally for patients whose treatment plans met increasing numbers of dose-volume constraints from the set of V30