Heterogeneous Dose Distribution Research Articles

A preliminary study of linear accelerator-based spatially fractionated radiotherapy

PurposeThis study aimed to provide quantitative information for implementing Lattice radiotherapy (LRT) using a medical linear accelerator equipped with the Millennium 120 multi-leaf collimator (MLC). The research systematically evaluated the impact of varying vertex diameters and separations on dose distribution, peak-to-valley dose ratio (PVDR), and normal tissue dose.MethodsA cylindrical Virtual Water™ phantom was used to create LRT treatments using the Eclipse version 16.0 treatment planning system (Varian, Palo Alto, USA). The plans were optimized employing a 3 × 3 × 3 lattice structure with vertex diameters ranging from 0.5 to 2.0 cm and separations from 1.0 to 5.0 cm. The prescribed dose was 20.0 Gy to 50% of the vertex volume in a single fraction. Peak-to-valley dose ratio (PVDR) was calculated along three orthogonal axes, and normal tissue dose and monitor units (MU) were analyzed. Additionally, the modulation complexity score (MCS) was calculated for each plan to quantitatively assess treatment plan complexity.ResultsThe PVDR analysis demonstrated heterogeneous dose distribution, with optimal values below 30% in all directions for 5.0 cm separation. PVDR in the superior-inferior direction was consistently lower than in other directions. Normal tissue dose analysis revealed increasing mean dose with larger diameters and separations, while the volume receiving high doses decreased. MU analysis showed significant contributions from collimator angles of 315.0° and 45.0°. MCS values ranged from 0.02 to 0.17 for 0.5 cm vertex diameter and 0.08 to 0.20 for larger diameters (1.0-2.0 cm) across different separations, respectively.ConclusionsThis study demonstrates the technical feasibility of implementing LRT using a medical linear accelerator with Millennium 120 MLC. The findings provide insights into optimizing LRT treatment plans, offering a comprehensive quantitative reference for achieving desired dose heterogeneity while maintaining normal tissue protection.

Highs and Lows of Spatially Fractionated Radiation Therapy: Dosimetry and Clinical Outcomes.

Spatially fractionated radiation therapy (SFRT) intentionally delivers a heterogeneous dose distribution characterized by alternating regions of high and low doses throughout a tumor. This modality may enhance response to subsequent whole tumor radiation in bulky and radioresistant lesions that are historically less responsive to conventional radiation doses alone. The current study presents a single institution experience with modern era SFRT using predominantly a volumetric modulated arc therapy (VMAT) lattice technique. Patients treated with SFRT between 10/2019 and 6/2022 were included for analysis. Patient characteristics, tumor characteristics, and dosimetric parameters were collected retrospectively as part of an institutional review board approved registry and protocol. Descriptive statistics were used to collate patient data and Kaplan Meier analysis were generated for overall survival and local control. Univariate analyses were used to investigate factors associated with outcomes. A total of 176 patients with 186 sites treated were included. Median age was 64 and the most commonly treated histologies were non-small cell lung cancer and sarcoma. The most common SFRT dose was 20 Gy in 1 fraction with 88% of patients receiving follow-up whole tumor radiotherapy to a median EQD2 dose of 32.5 Gy (α/β=10). Median gross tumor volume (GTV) was 480.5 cc (7.8-10,897.8). Median follow-up was 322 days with 1 year overall survival 37% and 1 year local control 81%. Local control was available in 138 treated sites (131 patients. SFRT factors including dose to 10% (D10%), dose to 90% (D90%), equivalent uniform dose, and mean dose were highly predictive of local control. Grade 3 toxicity occurred in 9 patients. All of these patients received follow-up whole tumor radiation and at least two of these were attributable to unexpected rapid regression of tumor. SFRT is a promising technique that appears to confer good local control across a disparate group of patients with bulky and radioresistant tumors. Dosimetric parameters of SFRT treatment plans may be independent predictors of local control. Further investigation is warranted as are prospective trials to evaluate the role of SFRT in both the palliative and definitive setting.

Dosimetric impact of intrafraction patient motion on MLC-based 3D-conformal spatially fractionated radiation therapy treatment of large and bulky tumors.

To evaluate the dosimetric impact on spatially fractionated radiation therapy (SFRT) plan quality due to intrafraction patient motion via multi-field MLC-based method for treating large and bulky (≥8cm) unresectable tumors. For large tumors, a cone beam CT-guided 3D conformal MLC-based SFRT method was utilized with 15Gy prescription. An MLC GTV-fitting algorithm provided 1cm diameter apertures with a 2cm center-to-center distance at the isocenter. This generated a highly heterogeneous sieve-like dose distribution within an hour, enabling same-day SFRT treatment. Fifteen previously treated SFRT patients were analyzed (5 head & neck [H&N], 5 chest and lungs, and 5 abdominal and pelvis masses). For each plan, intrafraction motion errors were simulated by incrementally shifting original isocenters of each field in different x-, y-, and z-directions from 1 to 5mm. The dosimetric metrics analyzed were: peak-to-valley-dose-ratio (PVDR), percentage of GTV receiving 7.5Gy, GTV mean dose, and maximum dose to organs-at-risk (OARs). For±1,±2,±3,±4, and±5mm isocenter shifts: PVDR dropped by 3.9%, 3.8%, 4.0%, 4.1%, and 5.5% on average respectively. The GTV(V7.5) remained within 0.2%, and the GTV mean dose remained within 3.3% on average, compared to the original plans. The average PVDR drop for 5mm shifts was 4.2% for H&N cases, 10% for chest and lung, and 2.2% for abdominal and pelvis cases. OAR doses also increased. The maximum dose to the spinal cord increased by up to 17 cGy in H&N plans, mean lung dose (MLD) changed was small for chest/lung, but the bowel dose varied up to 100 cGy for abdominal and pelvis cases. Due to tumor size, location, and characteristics of MLC-based SFRT, isocenter shifts of up to±5mm in different directions had moderate effects on PVDR for H&N and pelvic tumors and a larger effect on chest tumors. The dosimetric impact on OAR doses depended on the treatment site. Site-specific patient masks, Vac-Lok bags, and proper immobilization devices similar to SBRT/SRT setups should be used to minimize these effects.

Prognostic Factors of Mandibular Osteoradionecrosis Including Accurate Colocalization of Avulsions and Dosimetric Dental Mapping Software, a Case-control Study

IntroductionOsteoradionecrosis of the mandible (ORN) remains a significant complication in the intensity modulated radiotherapy (IMRT) era. Dental dose cannot be predicted from heterogeneous IMRT dose distributions; mandibular dose metrics cannot guide dentist avulsion decisions in high risk ORN situations. Using a mapping tool to report dental root dose, avulsions and ORN sites, we reexamined ORN risk factors in a case-control study. MethodsFrom 2008 to 2019, 897 consecutive patients with oral cavity/oropharynx (OC/OR) or unknown primary cancer (CUP) and undergoing IMRT were analyzed to identify ORN cases. These were matched (1 ORN/2 controls) retrospectively for tumor, surgery, tobacco in a monocentric case-control study. Univariate and multivariate analyses integrated ORN factors and accurate dental dose data (grouped into 4 mandibular sectors). Generalizability was investigated in a simulated population database. Results171 patients were included. Median follow-up was 5.2 and 4.5 years in the ORN and control groups, respectively. Median time to ORN was 12 months. In univariate analysis, post-IMRT avulsions at the ORN site (Hazard ratio (HR) = 3.6; 95% confidence interval (CI) = 1.5-8.9; p=0.005), tumor laterality (HR =4.4; 95% CI = 1.4-14, p = 0.01), mean mandibular dose (HR = 1.1; 95% CI = 1.01-1.1; p = 0.018) and mean dose to the ORN site (HR = 1.1; 95% CI = 1.1-1.2; p < 0.001) correlated with higher ORN risk. In multivariate analysis, mean dose to the ORN site (HR = 1.1; 95% CI = 1.1-1.2; p < 0.001) and post-IMRT avulsions at the ORN site (HR = 4.6; 95% CI = 1.5-14.7; p = 0.009) were associated with ORN. For each increase in Gray in dental dose, the ORN risk increased by 12%. Simulations confirmed study observations. ConclusionDental dose and avulsions are associated with ORN with a 12% increase in risk with each additional Gray. Accurate dose information can help dentists in their decisions after IMRT.

Use of dose-volume histograms for metabolic response prediction in hepatocellular carcinoma patients undergoing transarterial radioembolization with Y-90 resin microspheres.

Voxel-based dosimetry offers improved outcomes in the treatment of hepatocellular carcinoma (HCC) with transarterial radioembolization (TARE) using glass microspheres. However, the adaptation of voxel-based dosimetry to resin-based microspheres has been poorly studied, and the prognostic relevance of heterogeneous dose distribution remains unclear. This study aims to explore the use of dose-volume histograms for resin microspheres and to determine thresholds for objective metabolic response in HCC patients treated with resin-based TARE. We retrospectively reviewed HCC patients who underwent TARE with Y-90-loaded resin microspheres in our institution between January 2021 and December 2022. Voxel-based dosimetry was performed on post-treatment Y-90 PET/CT images to extract parameters including mean dose absorbed by the tumor (mTD), the percentage of the targeted tumor volume (pTV), and the minimum doses absorbed by consecutive percentages within the tumor volume (D10, D25, D50, D75, D90). Assessment of metabolic response was done according to PERCIST criteria with F-18 FDG PET/CT imaging at 8-12weeks after the treatment. This study included 35 lesions targeted with 22 TARE sessions in 19 patients (15 males, 4 females, mean age 60 ± 13years). Objective metabolic response was achieved in 43% of the lesions (n = 15). Responsive lesions had significantly higher mTD, pTV, and D25-D90 values (all p < 0.05). Optimal cut-off values for mTD, pTV, and D50 were 94.6Gy (sensitivity 73%, specificity 70%, AUC 0.72), 94% (sensitivity 73%, specificity 55%, AUC 0.64), and 91Gy (sensitivity 80%, specificity 80%, AUC 0.80), respectively. Parameters derived from dose-volume histograms could offer valuable insights for predicting objective metabolic response in HCC patients treated with resin-based TARE. If verified with larger prospective cohorts, these parameters could enhance the precision of dose distribution and potentially optimize treatment outcomes.

Development of an automated treatment planning approach for lattice radiation therapy.

Lattice radiation therapy (LRT) alternates regions of high and low doses within the target. The heterogeneous dose distribution is delivered to a geometrical structure of vertices segmented inside the tumor. LRT is typically used to treat patients with large tumor volumes with cytoreduction intent. Due to the geometric complexity of the target volume and the required dose distribution, LRT treatment planning demands additional resources, which may limit clinical integration. We introduce a fully automated method to (1) generate an ordered lattice of vertices with various sizes and center-to-center distances and (2) perform dose optimization and calculation. We aim to report the dosimetry associated with these lattices to help clinical decision-making. Sarcoma cancer patients with tumor volume between 100 cm3 and 1500 cm3 who received radiotherapy treatment between 2010 and 2018 at our institution were considered for inclusion. Automated segmentation and dose optimization/calculation were performed by using the Eclipse Scripting Application Programming Interface (ESAPI, v16, Varian Medical Systems, Palo Alto, USA). Vertices were modeled by spheres segmented within the gross tumor volume (GTV) with 1cm/1.5cm/2cm diameters (LRT-1cm/1.5cm/2cm) and 2 to 5cm center-to-center distance on square lattices alternating along the superior-inferior direction. Organs at risk were modeled by subtracting the GTV from the body structure (body-GTV). The prescription dose was that 50% of the vertice volume should receive at least 20Gy in one fraction. The automated dose optimization included three stages. The vertices optimization objectives were refined during optimization according to their values at the end of the first and second stages. Lattices were classified according to a score based on the minimization of body-GTV max dose and the maximization of GTV dose uniformity (measured with the equivalent uniform dose [EUD]), GTV dose heterogeneity (measured with the GTV D90%/D10% ratio), and the number of patients with more than one vertex inserted in the GTV. Plan complexity was measured with the modulation complexity score (MCS). Correlations were assessed with the Spearman correlation coefficient (r) and its associated p-value. Thirty-three patients with GTV volumes between 150 and 1350 cm3 (median GTV volume=494 cm3 , IQR=272-779 cm3 were included. The median time required for segmentation/planning was 1min/21min. The number of vertices was strongly correlated with GTV volume in each LRT lattice for each center-to-center distance (r>0.85, p-values<0.001 in each case). Lattices with center-to-center distance=2.5cm/3cm/3.5cm in LRT-1.5cm and center-to-center distance=4cm in LRT-1cm had the best scores. These lattices were characterized by high heterogeneity (median GTV D90%/D10% between 0.06 and 0.19). The generated plans were moderately complex (median MCS ranged between 0.19 and 0.40). The automated LRT planning method allows for the efficacious generation of vertices arranged in an ordered lattice and the refinement of planning objectives during dose optimization, enabling the systematic evaluation of LRT dosimetry from various lattice geometries.

Radio-Immune Response Model for Radiotherapy Plans with Heterogeneous Dose Distribution

In order to model the immune response in tumor of the patients under radiotherapy for cancer. Characteristics of the numerical model and preliminary application are presented. Immune response was modelled by 4 set of ordinary difference equations (ODE) as a function of biomedical variables including the amount of tumor antigen naturally released by tumor, the activation of cytotoxic T-lymphocytes (CTL) by radiation, immune suppression by tumor volume and the use of immunotherapy drugs. The effect of heterogeneous radiation dose distribution is also considered by hyperbolic tangent function to account for the immunogenic response of tissue under highly heterogeneous dose distribution intentionally modulated in spatially fractionated radiotherapy. Boundary behaviors of the model were investigated for tumors with different biomedical characteristics and under different treatment conditions. The developed model was applied to the tumor volume change in a mouse with 67NR tumors after radiation of 10 Gy to full or half volume of tumor and a clinical patient treated for sarcoma three times over 4 years. Tumor growth is exponential at early phase, slow down over time with increasing immune response and eventually reaches an equilibrium condition (known as terminal tumor volume) for tumors with little to no immune suppression capability (ISC) even in the lack of radiation treatment. Breaking-through the equilibrium for tumor to grow exponentially happens when ISC is larger than the bifurcation threshold, analytically calculated from the proposed model. Tumor with ISC close to the bifurcation threshold can show complex growth behavior depending on the treatment condition and it should be carefully considered for the optimal treatment. Tumor volume change over 30 days period on mouse was modeled well with this model. Full dose irradiation reduced the tumor volume faster in the first 10 days but half volume irradiation reduced the tumor volume faster at later stage due to the improved immune response which cannot be modelled with traditional linear quadratic model. Tumor volume on a patient retreated three times over 4 years was also accurately estimated. The proposed immune response model is capable to estimate tumor volume response under full or partial volume irradiation considering the complex immune characteristics of the tissue.

Accounting for fractionation and heterogeneous dose distributions in the modelling of osteoradionecrosis in oropharyngeal carcinoma treatment

Background and purposeOsteoradionecrosis (ORN) of the mandible is a severe complication following radiotherapy (RT). With a renewed interest in hypofractionation for head and neck radiotherapy, more information concerning ORN development after high fraction doses is important. The aim of this explorative study was to develop a model for ORN risk prediction applicable across different fractionation schemes using Equivalent Uniform Doses (EUD). Material and methodsWe performed a retrospective cohort study in 334 oropharyngeal squamous cell carcinoma (OPSCC) patients treated with either a hypofractionated Stereotactic Body Radiation Therapy (HF-SBRT) boost or conventional Intensity Modulated Radiation Therapy (IMRT). ORN was scored with the CTCAE v5.0. HF-SBRT and IMRT dose distributions were converted into equivalent dose in 2 Gy fractions (α/β = 0.85 Gy) and analyzed using EUD. The parameter a that led to an EUD that best discriminated patients with and without grade ≥ 2 ORN was selected. Patient and treatment-related risk factors of ORN were analyzed with uni- and multivariable regression analysis. ResultsA total of 32 patients (9.6%) developed ORN grade ≥ 2. An EUD(a = 8) best discriminated between ORN and non-ORN (AUC = 0.71). In multivariable regression, pre-RT extractions (SHR = 2.34; p = 0.012), mandibular volume (SHR = 1.04; p = 0.003), and the EUD(a = 8) (SHR = 1.14; p < 0.001) were significantly associated with ORN. ConclusionRisk models for ORN based on conventional DVH parameters cannot be directly applied to HF-SBRT fractionation schemes and dose distributions. However, after correcting for fractionation and non-uniform dose distributions using EUD, a single model can distinguish between ORN and non-ORN after conventionally fractionated radiotherapy and hypofractionated boost treatments.

Radio-immune response modelling for spatially fractionated radiotherapy.

Radiation-induced cell death is a complex process influenced by physical, chemical and biological phenomena. Although consensus on the nature and the mechanism of the bystander effect were not yet made, the immune process presumably plays an important role in many aspects of the radiotherapy including the bystander effect. A mathematical model of immune response during and after radiation therapy is presented. Immune response of host body and immune suppression of tumor cells are modelled with four compartments in this study; viable tumor cells, T cell lymphocytes, immune triggering cells, and doomed cells.&#xD;The growth of tumor was analyzed in two distinctive modes of tumor status (immune limited and immune escape) and its bifurcation condition. Tumors in the immune limited mode can grow only up to a finite size, named as terminal tumor volume analytically calculated from the model. The dynamics of the tumor growth in the immune escape mode is much more complex than the tumors in the immune limited mode especially when the status of tumor is close to the bifurcation condition. Radiation can kill tumor cells not only by radiation damage but also by boosting immune reaction. The model demonstrated that the highly heterogeneous dose distribution in spatially fractionated radiotherapy (SFRT) can make a drastic difference in tumor cell killing compared to the homogeneous dose distribution. SFRT can not only enhance but also moderate the cell killing depending on the immune response triggered by many factors such as dose prescription parameters, tumor volume at the time of treatment and tumor characteristics. The model was applied to the lifted data of 67NR tumors on mice and a sarcoma patient treated multiple times over 1200 days for the treatment of tumor recurrence as a demonstration.&#xD.

Clinical aspects of spatially fractionated radiation therapy treatments

PurposeTo provide clinical guidance for centers wishing to implement photon spatially fractionated radiation therapy (SFRT) treatments using either a brass grid or volumetric modulated arc therapy (VMAT) lattice approach. MethodsWe describe in detail processes which have been developed over the course of a 3-year period during which our institution treated over 240 SFRT cases. The importance of patient selection, along with aspects of simulation, treatment planning, quality assurance, and treatment delivery are discussed. Illustrative examples involving clinical cases are shown, and we discuss safety implications relevant to the heterogeneous dose distributions. ResultsSFRT can be an effective modality for tumors which are otherwise challenging to manage with conventional radiation therapy techniques or for patients who have limited treatment options. However, SFRT has several aspects which differ drastically from conventional radiation therapy treatments. Therefore, the successful implementation of an SFRT treatment program requires the multidisciplinary expertise and collaboration of physicians, physicists, dosimetrists, and radiation therapists. ConclusionsWe have described methods for patient selection, simulation, treatment planning, quality assurance and delivery of clinical SFRT treatments which were built upon our experience treating a large patient population with both a brass grid and VMAT lattice approach. Preclinical research and patient trials aimed at understanding the mechanism of action are needed to elucidate which patients may benefit most from SFRT, and ultimately expand its use.

Dosiomics-Based Prediction of Radiation-Induced Valvulopathy after Childhood Cancer.

Valvular Heart Disease (VHD) is a known late complication of radiotherapy for childhood cancer (CC), and identifying high-risk survivors correctly remains a challenge. This paper focuses on the distribution of the radiation dose absorbed by heart tissues. We propose that a dosiomics signature could provide insight into the spatial characteristics of the heart dose associated with a VHD, beyond the already-established risk induced by high doses. We analyzed data from the 7670 survivors of the French Childhood Cancer Survivors' Study (FCCSS), 3902 of whom were treated with radiotherapy. In all, 63 (1.6%) survivors that had been treated with radiotherapy experienced a VHD, and 57 of them had heterogeneous heart doses. From the heart-dose distribution of each survivor, we extracted 93 first-order and spatial dosiomics features. We trained random forest algorithms adapted for imbalanced classification and evaluated their predictive performance compared to the performance of standard mean heart dose (MHD)-based models. Sensitivity analyses were also conducted for sub-populations of survivors with spatially heterogeneous heart doses. Our results suggest that MHD and dosiomics-based models performed equally well globally in our cohort and that, when considering the sub-population having received a spatially heterogeneous dose distribution, the predictive capability of the models is significantly improved by the use of the dosiomics features. If these findings are further validated, the dosiomics signature may be incorporated into machine learning algorithms for radiation-induced VHD risk assessment and, in turn, into the personalized refinement of follow-up guidelines.

Monte Carlo study of the free radical yields in minibeam radiation therapy.

Minibeam radiation therapy (MBRT) is a novel technique which has been shown to widen the therapeutic window through significant normal tissue sparing. Despite the heterogeneous dose distributions, tumor control is still ensured. Nevertheless the exact radiobiological mechanisms responsible for MBRT efficacy are not fullyunderstood. Reactive oxygen species (ROS) resulting from water radiolysis were investigated given their implications not only on targeted DNA damage, but also for their role in the immune response and non-targeted cell signalling effects: two potential drivers of MBRTefficacy. Monte Carlo simulations were performed using TOPAS-nBio to carry out the irradiation of a water phantom with beams of protons (pMBRT), photons (xMBRT), 4 He ions (HeMBRT), and 12 C ions (CMBRT). Primary yields at the end of the chemical stage were calculated in spheres of 20 μm diameter, located in the peaks and valleys at various depths up to the Bragg peak. The chemical stage was limited to 1 ns to approximate biological scavenging, and the yield of · OH, H2 O2 , and wasrecorded. Beyond 10 mm, there were no substantial differences in the primary yields between peaks and valleys of the pMBRT and HeMBRT modalities. For xMBRT, there was a lower primary yield of the radical species · OHand at all depths in the valleys compared to the peaks, and a higher primary yield of H2 O2 . Compared to the peaks, the valleys of the CMBRT modality were subject to a higher · OHand yield, and lower H2 O2 yield. This difference between peaks and valleys became more severe in depth. Near the Bragg peak, the increase in the primary yield of the valleys over the peaks was 6% and 4% for · OH and respectively, while there was a decrease in the yield of H2 O2 by 16%. Given the similar ROS primary yields in the peaks and valleys of pMBRT and HeMBRT, the level of indirect DNA damage is expected to be directly proportional to the peak to valley dose ratio (PVDR). The difference in the primary yields implicates a lower level of indirect DNA damage in the valleys compared to the peaks than what would be suggested by the PVDR for xMBRT, and a higher level for CMBRT. These results highlight the notion that depending on the particle chosen, one can expect different levels of ROS in the peaks and valley that goes beyond what would be expected by the macroscopic PVDR. The combination of MBRT with heavier ions is shown to be particularly interesting as the primary yield in the valleys progressively diverges from the level observed in the peaks as the LET increases. While differences in the reported · OH yields of this work implicated the indirect DNA damage, H2 O2 yields particularly implicate non-targeted cell signalling effects, and therefore this work provides a point of reference for future simulations in which the distribution of this species at more biologically relevant timescales could beinvestigated.

Experimental Setups for In Vitro Studies on Radon Exposure in Mammalian Cells-A Critical Overview.

Naturally occurring radon and its short lived progeny are the second leading cause of lung cancer after smoking, and the main risk factor for non-smokers. The radon progeny, mainly Polonium-218 (218Po) and Polonium-214 (214Po), are responsible for the highest dose deposition in the bronchial epithelium via alpha-decay. These alpha-particles release a large amount of energy over a short penetration range, which results in severe and complex DNA damage. In order to unravel the underlying biological mechanisms which are triggered by this complex DNA damage and eventually give rise to carcinogenesis, in vitro radiobiology experiments on mammalian cells have been performed using radon exposure setups, or radon analogues, which mimic alpha-particle exposure. This review provides an overview of the different experimental setups, which have been developed and used over the past decades for in vitro radon experiments. In order to guarantee reliable results, the design and dosimetry of these setups require careful consideration, which will be emphasized in this work. Results of these in vitro experiments, particularly on bronchial epithelial cells, can provide valuable information on biomarkers, which can assist to identify exposures, as well as to study the effects of localized high dose depositions and the heterogeneous dose distribution of radon.

Increasing to Accuracy Reductions Heterogeneous Dose Distribution to All-Out Volume of the Irradiation at Models Modified Weibull Distribution

Purpose: To development of the methods of the estimation quality, systematized clinical information, which is described in the manner of probability of the arising the NTCP (complications in tissues) depending on volume of the irradiation and sharing the dose their uniform and heterogeneous irradiation.&#x0D; Material and methods: Used designed mathematical models for calculation of NTCP and mathematical models, which allow to calculate reduction values of the identical doses of the uniform irradiation tissues equivalent on probability of the arising the beam complication to heterogeneous sharing the doses.&#x0D; Results: Method of increasing to precision of the estimation to consensus systematized clinical information, founded on its presentation in the manner of differential histogram dose-volume, and on reductions heterogeneous doses distribution in identical dose all-out and uniform irradiation tissue.&#x0D; Conclusion: It is shown that designed method of the estimation of the heterogeneous sharing the dose by way of his adduction to equivalent, on probability of the arising the beam complications in tissues, all-out irradiations tissues, allows to raise accuracy of the calculation of the identical dose of the source lumpy distribution tolerants doses. She allows to raise precision of the estimation to consensus systematized clinical values of tolerant doses, received of specialist.

Cell Type-Specific Patterns in the Accumulation of DNA Damage Following Multifractional Radiation Exposure.

Predicting the risk of second malignant neoplasms is complicated by uncertainties regarding the shape of the dose-response relationship at high doses. Limited understanding of the competitive relationship between cell killing and the accumulation of DNA lesions at high doses, as well as the effects of other modulatory factors unique to radiation exposure during radiotherapy, such as dose heterogeneity across normal tissue and dose fractionation, contribute to these uncertainties. The aim of this study was to analyze the impact of fractionated irradiations on two cell systems, focusing on the endpoints relevant for cancer induction. To simulate the heterogeneous dose distribution across normal tissue during radiotherapy, exponentially growing VH10 fibroblasts and AHH-1 lymphoblasts were irradiated with 9 and 12 fractions (VH10) and 10 fractions (AHH-1) at 0.25, 0.5, 1, or 2 Gy per fraction. The effects on cell growth, cell survival, radiosensitivity and the accumulation of residual DNA damage lesions were analyzed as functions of dose per fraction and the total absorbed dose. Residual γH2AX foci and other DNA damage markers (micronuclei, nuclear buds, and giant nuclei) were accumulated at high doses in both cell types, but in a cell type-dependent manner. The competitive relationship between cell killing and the accumulation of carcinogenic DNA damage following multifractional radiation exposure is cell type-specific.

A Review on Tumor Control Probability (TCP) and Preclinical Dosimetry in Targeted Radionuclide Therapy (TRT).

Targeted radionuclide therapy (TRT) uses radiopharmaceuticals to specifically irradiate tumor cells while sparing healthy tissue. Response to this treatment highly depends on the absorbed dose. Tumor control probability (TCP) models aim to predict the tumor response based on the absorbed dose by taking into account the different characteristics of TRT. For instance, TRT employs radiation with a high linear energy transfer (LET), which results in an increased effectiveness. Furthermore, a heterogeneous radiopharmaceutical distribution could result in a heterogeneous dose distribution at a tissue, cellular as well as subcellular level, which will generally reduce the tumor response. Finally, the dose rate in TRT is protracted, relatively low, and variable over time. This allows cells to repair more DNA damage, which may reduce the effectiveness of TRT. Within this review, an overview is given on how these characteristics can be included in TCP models, while some experimental findings are also discussed. Many parameters in TCP models are preclinically determined and TCP models also play a role in the preclinical stage of radiopharmaceutical development; however, this all depends critically on the calculated absorbed dose. Accordingly, an overview of the existing preclinical dosimetry methods is given, together with their limitation and applications. It can be concluded that although the theoretical extension of TCP models from external beam radiotherapy towards TRT has been established quite well, the experimental confirmation is lacking. Thus, requiring additional comprehensive studies at the sub-cellular, cellular, and organ level, which should be provided with accurate preclinical dosimetry.

Cluster model incorporating heterogeneous dose distribution of partial parotid irradiation for radiotherapy induced xerostomia prediction with machine learning methods

Purpose A cluster model incorporating heterogeneous dose distribution within the parotid gland was developed and validated retrospectively for radiotherapy (RT) induced xerostomia prediction with machine learning (ML) techniques. Methods Sixty clusters were obtained at 1 Gy step size with threshold doses ranging from 1 to 60 Gy, for each of the enrolled 155 patients with HNC from three institutions. Feature clusters were selected with the neighborhood component analysis (NCA) and subsequently fed into four supervised ML models for xerostomia prediction comparison: support vector machines (SVM), k-nearest neighbor (kNN), naïve Bayes (NB), and random forest (RF). The predictive performance of each model was evaluated using cross validation resampling with the area-under-the-curves (AUC) of the receiver-operating-characteristic (ROC). The xerostomia predicting capacity using testing data was assessed with accuracy, sensitivity, and specificity for these models and three cluster connectivity choices. Mean dose based logistic regression served as the benchmark for evaluation. Results Feature clusters identified by NCA fell in three threshold dose ranges: 5–15Gy, 25–35Gy, and 45–50Gy. Mean dose predictive power was 15% lower than that of the cluster model using the logistic regression classifier. Model validation demonstrated that kNN model outperformed slightly other three models but no substantial difference was observed. Applying the fine-tuned models to testing data yielded that the mean accuracy from SVM, kNN and NB models were between 0.68 and 0.7 while that of RF was ∼0.6. SVM model yielded the best sensitivity (0.76) and kNN model delivered consistent sensitivity and specificity. This is consistent with cross validation. Clusters calculated with three connectivity choices exhibited minimally different predictions. Conclusion Compared to mean dose, the proposed cluster model has shown its improvement as the xerostomia predictor. When combining with ML techniques, it could provide a clinically useful tool for xerostomia prediction and facilitate decision making during radiotherapy planning for patients with HNC.

OC-0450 Model-based selection of NSCLC patients for proton therapy with heterogeneous dose distributions

OC-0450 Model-based selection of NSCLC patients for proton therapy with heterogeneous dose distributions

Including Volume Effects in Biological Treatment Plan Optimization for Carbon Ion Therapy: Generalized Equivalent Uniform Dose-Based Objective in TRiP98.

We describe a way to include biologically based objectives in plan optimization specific for carbon ion therapy, beyond the standard voxel-dose-based criteria already implemented in TRiP98, research planning software for ion beams. The aim is to account for volume effects—tissue architecture-dependent response to damage—in the optimization procedure, using the concept of generalized equivalent uniform dose (gEUD), which is an expression to convert a heterogeneous dose distribution (e.g., in an organ at risk (OAR)) into a uniform dose associated with the same biological effect. Moreover, gEUD is closely related to normal tissue complication probability (NTCP). The multi-field optimization problem here takes also into account the relative biological effectiveness (RBE), which in the case of ion beams is not factorizable and introduces strong non-linearity. We implemented the gEUD-based optimization in TRiP98, allowing us to control the whole dose–volume histogram (DVH) shape of OAR with a single objective by adjusting the prescribed gEUD 0 and the volume effect parameter a, reducing the volume receiving dose levels close to mean dose when a = 1 (large volume effect) while close to maximum dose for a >> 1 (small volume effect), depending on the organ type considered. We studied the role of gEUD 0 and a in the optimization, and we compared voxel-dose-based and gEUD-based optimization in chordoma cases with different anatomies. In particular, for a plan containing multiple OARs, we obtained the same target coverage and similar DVHs for OARs with a small volume effect while decreasing the mean dose received by the proximal parotid, thus reducing its NTCP by a factor of 2.5. Further investigations are done for this plan, considering also the distal parotid gland, obtaining a NTCP reduction by a factor of 1.9 for the proximal and 2.9 for the distal one. In conclusion, this novel optimization method can be applied to different OARs, but it achieves the largest improvement for organs whose volume effect is larger. This allows TRiP98 to perform a double level of biologically driven optimization for ion beams, including at the same time RBE-weighted dose and volume effects in inverse planning. An outlook is presented on the possible extension of this method to the target.

Spatiotemporal optimisation of prostate intensity modulated proton therapy (IMPT) treatments

Objective. In intensity modulated particle therapy (IMPT), the adoption of spatially and temporally heterogeneous dose distributions allows to decouple the fractionation scheme from the patient anatomy, so that an hypofractionated schedule can be selectively created inside the tumour, while simultaneously exploiting the fractionation effect in the healthy tissues. In this paper, the authors show the reproducibility of the method on a set of prostate patients, quantifying the dependencies of the achievable benefit with respect to conventional and hypofractionated schemes and the sensitivity of the method to setup errors and range uncertainty. Approach. On a cohort of 9 patients, non-uniform IMPT plans were optimised and compared to conventional and hypofractionated schedules. For each patient, the comparison of the three strategies has been based on the output of the cost function used to optimise the treatments. The analysis has been repeated considering different α/β ratios for the tumour, namely 1.5, 3 and 4.5 Gy. For a single patient, setup errors and beam range uncertainty have been analysed: the plans, for each optimisation strategy, have been iteratively forward planned 500 times with randomly varying the patient position in each fraction, and 200 times for systematic range shift. Main results. An average 10% benefit has been shown for the lowest α/β ratio considered for the tumour, where the non-uniform schedule generally converges to hypofractionation; the benefit decreases to 5%–7% for higher α/β ratios, for which the non-uniform schedule always showed better outcomes with respect to the other fractionation schedules. An increased sensitivity to uncertainty, especially for setup errors, has been shown, which can be associated to the spatial non-uniformity of the dose distributions peculiar of the spatiotemporal plans. Significance. This work represents the first investigation of spatiotemporal fractionation for prostate cancer and the beginning of further investigations before clinical implementation can be considered.