Tumor Control Probability Research Articles

Proton versus photon therapy for high-risk prostate cancer with dose escalation of dominant intraprostatic lesions: a preliminary planning study.

This study aimed to investigate the feasibility of safe-dose escalation to dominant intraprostatic lesions (DILs) and assess the clinical impact using dose-volume (DV) and biological metrics in photon and proton therapy. Biological parameters defined as late grade ≥ 2 gastrointestinal (GI) and genitourinary (GU) derived from planned (D P) and accumulated dose (D A) were utilized. In total, 10 patients with high-risk prostate cancer with multiparametric MRI-defined DILs were investigated. Each patient had two plans with a focal boost to the DILs using intensity-modulated proton therapy (IMPT) and volumetric-modulated arc therapy (VMAT). Plans were optimized to obtain DIL coverage while respecting the mandatory organ-at-risk constraints. For the planning evaluation, DV metrics, tumor control probability (TCP) for the DILs and whole prostate excluding the DILs (prostate-DILs), and normal tissue complication probability (NTCP) for the rectum and bladder were calculated. Wilcoxon signed-rank test was used for analyzing TCP and NTCP data. IMPT achieved a higher Dmean for the DILs compared to VMAT (IMPT: 68.1 GyRBE vs. VMAT: 66.6 Gy, p < 0.05). Intermediate-high rectal and bladder doses were lower for IMPT (p < 0.05), while the high-dose region (V60 Gy) remained comparable. IMPT-TCP for prostate-DIL were higher compared to VMAT (IMPT: 86%; α/β = 3, 94.3%; α/β = 1.5 vs. VMAT: 84.7%; α/β = 3, 93.9%; α/β = 1.5, p < 0.05). Likewise, IMPT obtained a moderately higher DIL TCP (IMPT: 97%; α/β = 3, 99.3%; α/β = 1.5 vs. VMAT: 95.9%; α/β = 3, 98.9%; α/β = 1.5, p < 0.05). Rectal D A-NTCP displayed the highest GI toxicity risk at 5.6%, and IMPT has a lower GI toxicity risk compared to VMAT-predicted Quantec-NTCP (p < 0.05). Bladder D P-NTCP projected a higher GU toxicity than D A-NTCP, with VMAT having the highest risk (p < 0.05). Dose escalation using IMPT is able to achieve a high TCP for the DILs, with the lowest rectal and bladder DV doses at the intermediate-high-dose range. The reduction in physical dose was translated into a lower NTCP (p < 0.05) for the bladder, although rectal toxicity remained equivalent.

Absolute oxygen-guided radiation therapy improves tumor control in three preclinical tumor models.

Clinical attempts to find benefit from specifically targeting and boosting resistant hypoxic tumor subvolumes have been promising but inconclusive. While a first preclinical murine tumor type showed significant improved control with hypoxic tumor boosts, a more thorough investigation of efficacy from boosting hypoxic subvolumes defined by electron paramagnetic resonance oxygen imaging (EPROI) is necessary. The present study confirms improved hypoxic tumor control results in three different tumor types using a clonogenic assay and explores potential confounding experimental conditions. Three murine tumor models were used for multi-modal imaging and radiotherapy: MCa-4 mammary adenocarcinomas, SCC7 squamous cell carcinomas, and FSa fibrosarcomas. Registered T2-weighted MRI tumor boundaries, hypoxia defined by EPROI as pO2 ≤ 10 mmHg, and X-RAD 225Cx CT boost boundaries were obtained for all animals. 13 Gy boosts were directed to hypoxic or equal-integral-volume oxygenated tumor regions and monitored for regrowth. Kaplan-Meier survival analysis was used to assess local tumor control probability (LTCP). The Cox proportional hazards model was used to assess the hazard ratio of tumor progression of Hypoxic Boost vs. Oxygenated Boost for each tumor type controlling for experimental confounding variables such as EPROI radiofrequency, tumor volume, hypoxic fraction, and delay between imaging and radiation treatment. An overall significant increase in LTCP from Hypoxia Boost vs. Oxygenated Boost treatments was observed in the full group of three tumor types (p < 0.0001). The effects of tumor volume and hypoxic fraction on LTCP were dependent on tumor type. The delay between imaging and boost treatments did not have a significant effect on LTCP for all tumor types. This study confirms that EPROI locates resistant tumor hypoxic regions for radiation boost, increasing clonogenic LTCP, with potential enhanced therapeutic index in three tumor types. Preclinical absolute EPROI may provide correction for clinical hypoxia images using additional clinical physiologic MRI.

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

In treatment planning for proton therapy a constant Relative Biological Effectiveness (RBE) of 1.1 is used, disregarding variations with linear energy transfer, clinical endpoint, or fractionation. 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. We analyzed the dependence of the RBE on the dose per fraction by using the LQ model and the Poisson TCP formalism. Clinical tumor control probabilities for prostate cancer (low and intermediate risk) treated with photon and proton therapy for conventional fractionation (2Gy(RBE)×37 fractions), moderate hypofractionation (3Gy(RBE)×20 fractions) and hypofractionation (7.25Gy(RBE)×5 fractions) were obtained from the literature and analyzed aiming at obtaining the RBE and its dependence on the dose per fraction. The theoretical analysis of the dependence of the RBE on the dose per fraction showed three distinct regions with RBE monotonically decreasing, increasing or staying constant with the dose per fraction, depending on the change of (α, β) values between photon and proton irradiation (the equilibrium point being at (αp /βp )=(αX /βX )(αX /αp )). 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 1.82Gy, 2.73Gy and 6.59Gy per fraction (physical proton doses), respectively; for intermediate risk RBE≈1.119 and 1.102 for 1.82Gy and 6.59Gy per fraction (physical proton doses), respectively. These values are nonetheless very close to the nominal 1.1 value. In this study, we have presented a methodology to analyze the RBE for different fractionations, and we used it to study clinical data for prostate cancer and evaluate the RBE versus dose per fraction. The analysis shows a monotonically decreasing RBE with increasing dose per fraction, which is expected from the LQ formalism and the changes in (α, β) values 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 assumptions and/or by the clinical data set used for the analysis.

Model development of dose and volume predictors for esophagitis induced during chemoradiotherapy for lung cancer as a step towards radiobiological treatment planning

BackgroundCurrently, radiation therapy treatment planning system intends biological optimization that relies heavily upon plan metrics from tumor control probability (TCP) and normal tissue complication probability (NTCP) modeling. Implementation and expansion of TCP and NTCP models with alternative data is an important step towards reliable radiobiological treatment planning. In this retrospective single institution study, the treatment charts of 139 lung cancer patients treated with chemo-radiotherapy were reviewed and correlated dosimetric predictors with the incidence of esophagitis and established NTCP model of esophagitis grade 1 and 2 for lung cancer patients.MethodsEsophagus is an organ at risk (OAR) in lung cancer radiotherapy (RT). Esophagitis is a common toxicity induced by RT. In this study, dose volume parameters Vx (Vx: percentage esophageal volume receiving ≥ x Gy) and mean esophagus dose (MED) as quantitative dose-volume metrics, the esophagitis grade 1 and 2 as endpoints, were reviewed and derived from the treatment planning system and the electronic medical record system. Statistical analysis of binary logistic regression and probit were performed to have correlated the probability of grade 1 and 2 esophagitis to MED and Vx. IBM SPSS software version 24 at 5% significant level (α = 0.05) was used in the statistical analysis.ResultsThe probabilities of incidence of grade 1 and 2 esophagitis proportionally increased with increasing the values of Vx and MED. V20, V30, V40, V50 and MED are statistically significant good dosimetric predictors of esophagitis grade 1. 50% incidence probability (TD50) of MED for grade 1 and 2 esophagitis were determined. Lyman Kutcher Burman model parameters, such as, n, m and TD50, were fitted and compared with other published findings. Furthermore, the sigmoid shaped dose responding curve between probability of esophagitis grade 1 and MED were generated respecting to races, gender, age and smoking status.ConclusionsV20, V30, V40 and V50 were added onto Quantitative Analysis of Normal Tissue Effects in the clinic, or QUANTEC group’s dose constrains of V35, V50, V70 and MED. Our findings may be useful as both validation of 3-Dimensional planning era models and also additional clinical guidelines in treatment planning and plan evaluation using radiobiology optimization.

Influence of Dose Distribution in the Target on the Values of Integral Radiobiological Criteria Based on Synthetic Dose-Volume Histograms

Purpose: To investigate the influence of absorbed dose distribution in the tumor volume on the values of&#x0D; integral radiobiological criteria, such as the probability of local tumor control (Tumor Control Probability, TCP) and normal tissue complication probability (NTCP), based on synthetic dose-volume histograms (DVH), which enables to assess the treatment effectiveness and probability of complications&#x0D; from healthy organs and tissues.&#x0D; Material and methods: Synthetic dose-volume histograms were considered theoretically possible to analyze the dependence of equivalent uniform dose (EUD) on values of Nimirko model parameters and absorbed dose distribution for both tumor and critical organs. The calculation was carried out in Wolfram&#x0D; Mathematica program based on the algorithm, where an array of absorbed dose values per fraction of&#x0D; irradiation volume with step by absorbed dose was calculated for the given values of absorbed dose and&#x0D; the parameter determining the width of distribution. The resulting array was differentiated to obtain&#x0D; the differential DVH. The EUD values were obtained from the normalized differential DVHs.&#x0D; Results: During analysis of EUD value dependence on parameter a values determining degree of nonlinearity of absorbed dose summation in sub-volumes of irradiation and on absorbed dose distribution&#x0D; the following was revealed: for critical organs at high values of parameter a the essential role belongs to&#x0D; high and average values of absorbed dose, and for tumors at low values of parameter a the main role belongs to the minimum value of absorbed dose. Thus, the value of parameter a should be negative for a&#x0D; tumor, and positive for critical organs, and should be specifically defined for specific structures.&#x0D; Conclusion: To improve the predictive value (prediction) of the effect of radiotherapy using the&#x0D; TCP/NTCP Nimirko model, an adequate definition of the parameter a, the value of which can only be determined from absorbed dose distributions over the volume of anatomical structures within clinical trials, is necessary.

The Microvascular Network Density and Morphology Affect the Radiotherapy Outcome at the Microscale Level: A Computational Analysis.

Half of the cancer patients are treated with radiotherapy to obtain tumor control while minimizing radiation toxicity. In this context, hypoxia is known to determine treatment resistance, driving tumor relapse after treatment. Therefore, we investigated the role of microvasculature density and morphology in shaping the tissue oxygen distribution and consequently affecting the treatment outcome. We developed an advanced computational model to describe oxygen delivery in the vascular network and the surrounding tissue. A peculiar aspect of the model is its mesoscale mixed-dimensional approach, which allows the explicit inclusion of vascular network geometry and the description of the red blood cells' effect. The oxygen delivery is modeled considering both diffusive and convective phenomena. A 30 × 2GyRBE treatment is delivered in silico simulating photons, protons, and carbon ions. First, we estimated the surviving fraction by the classical linear quadratic model modified to account for the oxygen effect. Then, leveraging the 3D description of the surviving fraction at the microenvironment scale, we compute the local tumor control probability (LTCP) in different oxygenation states (reference, acute hypoxia, high oxygen consumption). We report correlations between the LTCP and the hypoxic volume fractions (with pO2 lower than 1 mmHg) starting with photons. These hypoxic regions are present locally, even in highly vascularized tissue, if the network is not uniformly distributed, as it might be in cancer. They are also present in tissue with low microvascular density, even with regular morphology. Interestingly, the domain considered is comparable to or smaller than the clinical imaging standard voxel dimension, and the average oxygen partial pressure in the tissue region fails to spot treatments with low LTCP, questioning whether these hypoxia areas are visible clinically via imaging. Protons have a similar effect, highlighting a similar behavior across the oxygenation levels at the microscale level. Finally, carbon ions seem more effective than photons and protons in the presence of hypoxia due to the lower oxygen effect at high LET. For this reason, the treatment with carbon ions results in high LTCPs, whatever vascular network is considered (density and morphology differences). These results show the effect of microvascular density and regularity on the radiotherapy outcome and they help us understand how the microvascular network morphology affects tumor oxygenation and the radiotherapy outcome.

Estimating Potential Benefits of Online Adaptive Proton Therapy for Head-and-Neck Cancer: A Retrospective Study

Proton therapy is highly sensitive to anatomical changes and setup variations in head-and-neck (HN) treatments. To address this issue, proton centers often acquire patient CT images weekly to monitor patient anatomical changes during the treatment course and perform offline plan adaptation when needed. However, offline adaptation cannot fully account for daily setup variations or the anatomical changes occurring with high frequency. There are a few groups endeavoring to develop advanced technologies to enable online adaptive proton therapy (APT). However, the necessity of online APT remains controversial, as it is unknown that whether online APT will significantly improve treatment quality and outcomes compared to offline APT. The purpose of this study is to estimate the clinical potential of online APT in the management of HN cancers in relation to the current offline APT. Our retrospective study was conducted with four HN patients (35 fractions per patient), who had been treated with intensity modulated proton therapy and had offline adaptation once or twice during their treatment courses. Synthetic CT (sCT) images were generated from 140 daily CBCT images for us to recalculate the dose of the treatment plan in patient's actual treatment anatomy for each treatment fraction and adapt the plan when warranted. These adaptations were assumed to be performed online before treatment delivery to mimic an online APT course. Accumulative doses were calculated for both courses using the CBCT-based sCT images of every fraction for us to compare the target coverage, organ at risk (OAR) sparing, tumor control probability (TCP) and normal tissue complication probability (NTCP). An in-house script was developed to semi-automate this process in a commercial treatment planning system to facilitate our study. All patients would benefit from online APT to different extents. For the first patient, with OAR doses comparable to the actual offline course, the retrospective online APT course improved dose coverages of the three CTVs from 95.2%, 98.64% and 89.53% to 98.88%, 99.81%, 98.97%, which would lead to a 4.52% improvement in TCP. Similarly, online APT would yield a 2.66% improvement in TCP for the second patient. For the third patient, with comparable CTV dose coverages, the mean doses of right parotid and oral cavity were decreased from 29.52 Gy relative biological effectiveness (RBE) and 41.89 Gy RBE to 22.16 Gy RBE and 34.61 Gy RBE, leading to a reduce of 1.67% and 3.40% in NTCP. The mean dose of right parotid was decreased from 21.71 Gy RBE to 19.37 Gy RBE for the last patient, leading to a reduce of 0.73% in NTCP. Our results showed that online APT could better maintain the treatment plan quality than offline APT for all the four patients, despite their significant anatomical changes. Future investigation will focus on collecting more patient data to obtain statistically significant results and help identify the patients to whom the online APT will be of most benefit.

Feasibility of Using Pseudo-CT for Dosimetry, Radiomics, and Efficacy Assessment in IMRT/VMAT of Brain Tumors: A Multi-Omics Analysis

Pseudo-CT generated by convolutional neural networks (CNN) and planning MRI has facilitated the promotion of MRI-Only. The technology not only reduces the time and money spent on CT scans, but also eliminates the cumbersome CT-MR registration. The feasibility in Stereotactic Brain Radiotherapy has been analyzed in previous studies by our team. However, when the prescribed requirements are not met, IMRT/VMAT are still selected. The study aims to evaluate the feasibility of pseudo-CT in IMRT/VMAT for brain cancer via the following 5 aspects: (1) image difference, (2) dose accuracy, (3) radiomics feature, (4) efficacy assessment, and (5) correlation analysis. Brain tumor patients who had received radiotherapy at our institution and had planning MRI and CT were included in the study. Redesign of IMRT and VMAT radiotherapy plans according to 3 × 15Gy for each patient. Hounsfield unit (HU) values for PTV and OARs were used to assess image differences. And dose accuracy analysis contained a 2D dose volume histogram (DVH) metrics (Dmax, Dmean, D2%, D50%, D98%, HI, CI) and 3D gamma metrics (criteria: 1-3%/2mm, 1%/1mm, 10% threshold). Then 107 original image features of PTV and OARs were extracted for radiometry analysis. And tumor control probability (TCP) of PTV (Poisson model) and normal tissue complication probability (NTCP) of OARs (Lyman-Kutcher-Burman model) were used for the variance analysis of efficacy assessment. Wilcox-test was used for significance of differences test (0.05), and spearman correlation analysis was used to explore the key features of the dose bias. A total of 42 patients were included, with 42 planning CTs and pseudo-CTs (mDixon-T1), and 38 pseudo-CTs (mDixon-T1-CE). The median volume of PTV was 4.1 cc (range 0.5-27.3), with no significant differences in HU, DVH, 3D gamma, and NTCP/TCP metrics. The median local gamma passing rates (1%/1mm) between planning CTs and pseudo-CTs (mDixon-T1) were 93.1% (range 65.5%-99.7%, IMRT) and 93.3% (range 63.9%-99.6%, VMAT). And more than 85% original radiomics features have significant difference. Further, the feature HU-Min was found to be more correlated with dose metrics in the correlation analysis. We speculate that it may be caused by the smoothing of the low frequency signal before outputting image. And since Shape_MeshVolume, Shape_VoxelVolume and PTV volume difference are highly correlated with dose deviation, it indicates that dose deviation affected by CT-MR registration. This study has the potential to provide guidance for the clinical application of pseudo-CT in the MRI-Only workflow with IMRT/VMAT for brain tumors. These quantitative results strongly indicate pseudo-CT can be used as a substitute for the initial CT in IMRT/VMAT for small brain lesions (size <5 cm, numbers <5), but not for radiomics analysis. Additionally, the impact of inter-image differences on dose accuracy is less significant compared to the deviation caused by image registration.

Prioritizing Toxicities in Automated Outcome-Directed Treatment Plan Optimization

We recently reported on quality of life (QOL)-guided radiotherapy including NTCP-based treatment plan optimization. This method employs NTCP objective functions, prioritized based on their impact on QOL, instead of conventional dose-based objective functions for individual organs at risk (OAR). We recently expanded this method to include simple models for tumor control probability (TCP) and general plan quality (e.g., hotspot reduction, target dose homogeneity), allowing for fully automated planning. The aim of this study was to test the feasibility of this method and to study predicted toxicity profiles of various plans by prioritizing toxicities differently during treatment plan optimization. Thirty patients, representative of our population receiving definitive (chemo)radiotherapy for head and neck cancer, were selected for this study. Fully automated VMAT treatment plans were created using a mix of NTCP and TCP objective functions. TCP objective functions were based on a PTV D98 ≥ 95% of the prescribed dose. Automated plans were created for each patient using different priorities for 20 toxicities including salivary, swallowing and speech problems, pain and general symptoms. Toxicities were prioritized in different ways: 1) minimizing the impact on QOL; 2) minimizing salivary toxicity; 3) minimizing swallowing related toxicity; 4) equal weights for each toxicity. Manually created clinical VMAT plans were used as reference. Toxicity priorities were easily selected prior to optimization and resulting plans did not need any manual post-processing. Fully automated NTCP-TCP-based optimization consistently resulted in superior plans when compared to the clinical reference plans and always in lower NTCPs for swallowing, speech, pain and general toxicities. Dose reductions in OARs depended on which toxicities were prioritized during plan optimization, e.g., the mean dose in the parotid glands was on average 13 Gy lower in salivary sparing plans compared with plans focused on swallowing sparing, and the average NTCP of salivary toxicities in those plans was 7% lower. However, these reductions were at the cost of higher NTCPs for dysphagia and moderate-to-severe general symptoms such as fatigue. Plans optimized based on the QOL model had the highest QOL scores. Automated outcome-directed treatment plan optimization is feasible and consistently outperforms manually generated VMAT plans in terms of NTCP and QOL scores. Predicted toxicity profiles depend on toxicity priority settings prior to planning. The highest QOL score was obtained when toxicities were prioritized according to relative impact on QOL.

RBE Model Based Proton Planning of Stereotactic Body Radiotherapy for Spine Metastasis: A Dosimetric Analysis

Study of proton stereotactic body radiotherapy (SBRT) for spine metastasis is limited, largely due to theorized increased risk of spinal cord injury with higher end of range RBE. Though the 1.1 RBE constant for proton beam is clinically used, data indicate that proton RBE is variable and dependent on technical-, tissue-, and patient-factors. To better understand safety of proton SBRT for spine metastasis, we performed a dosimetric analysis comparing plans delivered by photon robotic technique versus intensity modulated proton therapy (IMPT) and accounting for RBE weighted dose. A total of 9 patients with spine metastasis (3 cervical, 3 thoracic, 3 lumbar) previously treated with a frameless robotic radiosurgery system (Sunnyvale, CA) were identified. Each level contained a case with paraspinal extension, a reirradiation case, and a case with epidural extension (Bilsky grade ≥1c) as such cases in current practice often require planning target volume (PTV) under-coverage in order to meet organ at risk (OAR) dose constraints. Given these challenges, selected cases were clinically treated with 30 Gy in 5 fractions despite an institutional preference of further dose escalation. Comparative IMPT plans were generated using 30 GyE in 5 fractions and 1.1 RBE constant. IMPT plans were then made using 1.1 RBE and 45 GyE in 5 fractions: a prescription dose associated with a 2-yr local control rate of 95% on prior tumor control probability modelling. A treatment planning system was used to separately generate and optimize RBE weighted plans based on Carabe-, McNamara-, or Wedenberg models for prescription doses of 30 GyE and 45 GyE. IMPT plans used robust optimization parameters of ± 3.5% range and 2-mm setup uncertainties. PTV coverage and OAR sparing were compared using Wilcoxon signed-rank tests. PTV coverage (PTV volume receiving prescription dose) was significantly improved with IMPT at 30 GyE / 1.1 RBE (median PTV V30: 93%) compared to CK at 30 Gy (median: 88.5%, p = .02). PTV coverage was similar when comparing CK at 30 Gy with IMPT at 45 GyE / 1.1 RBE (median PTV V45: 90%, p = .23). When comparing maximum spinal cord dose (cord Dmax), there was improved OAR sparing with IMPT at 30 GyE / 1.1 RBE (median: 17.6 GyE, p = .04) and IMPT at 45 GyE / 1.1 RBE (median: 16.1 GyE, p = .04) when respectively compared to CK at 30 Gy (median: 18 Gy). No difference was seen in cord Dmax when comparing CK at 30 Gy to RBE weighted plans at 30 GyE using Carabe- (median: 17.3 GyE, p = .22), McNamara- (median: 17.4 GyE, p = .22), or Wedenberg (median: 17.0 GyE, p = .08) model. Median cord Dmax values for RBE weighted plans at 45 GyE were numerically equivalent. The average increase in variable RBE plans' maximum dose compared to fixed RBE plans was 105.3% +/- 3.5%. We report the first dosimetric analysis of proton SBRT for spine metastasis using variable RBE dose models. IMPT may provide improved target coverage and better sparing of adjacent OARs compared to CK though fixed RBE computation may underestimate maximum dose to adjacent OARs.

Low Tesla MR Imaging for Spine with Hardware

Acquiring MR images with minimized susceptibility artifacts is essential for spines with medical hardware to delineate clinical target volumes (CTVs) in radiation therapy for chordomas, chondrosarcomas, and other sarcomas. Since it can be more challenging to visualize the primary structures in high-tesla MR images due to metal-induced artifacts, we optimized imaging parameters to acquire high-quality, low-tesla MR images for clinical use. OptimalMR imaging parameters were investigated under general guidelines for artifact reduction techniques by testing several 3D spin echo and gradient echo sequences in a 0.23-T MR scanner. A customized spine phantom was developed to acquire MR images for bony materials which included, 4-6 industrial titanium screws, an aluminum plate, and a superflab bolus. While the 3D b-FFE sequence was used to acquire MR images with a high signal-to-noise ratio, the other 3D T1-FFE, THRIVE, and DTSE sequences were applied to reduce susceptible artifacts to the medical hardware. The optimized parameters determined in the phantom test were applied to the 15 clinical cases, including patients with residual spinal tumors and fusion hardware. The low-tesla MR imaging technique was also used to scan sarcomas of the extremities and re-irradiation cases of spinal metastases. The optimized low-tesla MR images in the spine were noticeably useful to guide CTV delineations for patients with medical hardware, especially for residual or recurrent tumors. The imaging technique to minimize susceptibility artifacts enabled a more defined separation of each hardware component from the spinal cord and CTVs. In spine metastasis cases, pre-irradiated target volumes were determined, reflecting property changes in the bone marrow. The MR images acquired using the optimized parameters showed minimal artifacts to scan spine patients with hardware. By using the low-tesla MR images, spinal chordoma and chondrosarcoma patients could be treated to improve tumor control probabilities with minimized complications.

Results From a Multi-Institutional Pilot Study of iContour, an Interactive Online Platform with Real-Time Feedback to Improve Contouring Education for Radiation Oncology Residents

Numerous studies have shown that variability in contouring by radiation oncologists is common and associated with poor clinical outcomes. Contouring is taught via an apprenticeship model during residency with inconsistent results. Currently, there is no standardized contouring curriculum. We hypothesized that an interactive online educational platform for learners to practice contouring and receive real-time visual feedback would be a useful curricular tool. The iContour platform displays anonymized DICOM data and allows for input and analysis of user contours in a web-based interface. Nine cases are available from the Head/Neck (H+N), Gynecologic (Gyn), and Gastrointestinal (GI) disease sites. The system presents users with a case and asks them to contour representative slices from 2-3 target volumes or OARs. Upon submission, users are shown several forms of feedback. These include immediate visual comparison with expert contours on the same dataset (all cases), customized feedback based on overlap with prespecified "avoidance" and "inclusion" structures that highlight common mistakes (Gyn cases), and tumor control probability models to estimate the clinical impact of a user's contour variations on patient outcomes (H+N cases). Some cases include short videos outlining anatomy and contouring principles which are shown before the user contours. A pilot study was performed to evaluate technical performance and educational utility. Pre- and post-surveys with Likert-type questions (1-5 scale from strongly disagree to strongly agree) were used to assess user satisfaction and preferences regarding feedback. A total of 9 residents participated (median PGY3, range PGY2-5) from 5 institutions in 2 countries. Each participant completed 2 cases from a single disease site (n = 3 each for H+N, Gyn and GI), one with educational videos and one without. 67% of users had completed a prior clinical rotation in their disease site. Overall, residents felt the system was a useful educational tool (mean Likert score 4.67 +/- 0.47) and were interested in using it during clinical rotations (4.89 +/- 0.31). Most participants (7/9) felt iContour was more useful than existing resources for contouring education. Residents unanimously (9/9) found direct visual comparison with expert contours the most useful type of feedback, and that cases with videos before contouring were more educational. The iContour platform is a useful educational tool for radiation oncology residents. Participants felt receiving immediate visual feedback on contours was a valuable learning experience. Short instructional videos before contouring can be utilized to provide "just in time" teaching. A randomized study to formally assess the platform's impact on contouring skills is planned.

Dosimetric and radiobiological comparison between conventional and hypofractionated breast treatment plans using the Halcyon system.

The objective of this research is to compare the efficacy of conventional and hypofractionated radiotherapy treatment plans for breast cancer patients, with a specific focus on the unique features of the Halcyon system. The study collected and analyzed dose volume histogram (DVH) data for two groups of treatment plans implemented using the Halcyon system. The first group consisted of 19 patients who received conventional fractionated (CF) treatment with a total dose of 50 Gy in 25 fractions, while the second group comprised 9 patients who received hypofractionated (HF) treatment with a total dose of 42.56 Gy in 16 fractions. The DVH data was used to calculate various parameters, including tumor control probability (TCP), normal tissue complication probability (NTCP), and equivalent uniform dose (EUD), using radiobiological models. The results indicated that the CF plan resulted in higher TCP but lower NTCP for the lungs compared to the HF plan. The EUD for the HF plan was approximately 49 Gy (114% of its total dose) while that for the CF plan was around 53 Gy (107% of its total dose). The analysis suggests that while the CF plan is better at controlling tumors, it is not as effective as the HF plan in minimizing side effects. Additionally, it is suggested that there may be an optimal configuration for the HF plan that can provide the same or higher EUD than the CF plan.

HU-based material conversion for BNCT accurate dose estimation

NeuMANTA is a new generation boron neutron capture therapy (BNCT)-specific treatment planning system developed by the Neuboron Medical Group and upgraded to an important feature, a Hounsfield unit (HU)-based material conversion algorithm. The range of HU values was refined to 96 specific groups and established corresponding to tissue information. The elemental compositions and mass densities have an important effect on the calculated dose distribution. The region of interest defined in the treatment plan can be converted into multiple material compositions based on HU values or assigned specified single material composition in NeuMANTA. Different material compositions may cause normal tissue maximum dose rates to differ by more than 10% in biologically equivalent doses and to differ by up to 6% in physically absorbed doses. Although the tumor has a lower proportion of BNCT background dose, the material composition difference may affect the minimum dose of biologically equivalent dose and physically absorbed dose by more than 3%. In addition, the difference in material composition could lead to a change in neutron moderation as well as scattering. Therefore, the material composition has a significant impact on the assessment of normal tissue side effects and tumor control probability. It is essential for accurate dose estimation in BNCT.

Optimal Radiation Therapy Fractionation Regimens for Early-Stage Non-Small Cell Lung Cancer

A series of radiobiological models were developed to study tumor control probability (TCP) for stereotactic body radiation therapy (SBRT) of early-stage non-small cell lung cancer (NSCLC) per the Hypofractionated Treatment Effects in the Clinic (HyTEC) working group. This study was conducted to further validate 3 representative models with the recent clinical TCP data ranging from conventional radiation therapy to SBRT of early-stage NSCLC and to determine systematic optimal fractionation regimens in 1 to 30 fractions for radiation therapy of early-stage NSCLC that were found to be model-independent. Recent clinical 1-, 2-, 3-, and 5-year actuarial or Kaplan-Meier TCP data of 9808 patients from 56 published papers were collected for radiation therapy of 2 to 4 Gy per fraction and SBRT of early-stage NSCLC. This data set nearly triples the original HyTEC sample, which was used to further validate the HyTEC model parameters determined from a fit to the clinical TCP data. TCP data from the expanded data set are well described by the HyTEC models with α/β ratios of about 20 Gy. TCP increases sharply with biologically effective dose and reaches an asymptotic maximal plateau, which allows us to determine optimal fractionation schemes for radiation therapy of early-stage NSCLC. The HyTEC radiobiological models with α/β ratios of about 20 Gy determined from the fits to the clinical TCP data for SBRT of early-stage NSCLC describe the recent TCP data well for both radiation therapy of 2 to 4 Gy per fraction and SBRT dose and fractionation schemes of early-stage NSCLC. A steep dose response exists between TCP and biologically effective dose, and TCP reaches an asymptotic maximum. This feature results in model-independent optimal fractionation regimens determined whenever safe for SBRT and hypofractionated radiation therapy of early-stage NSCLC in 1 to 30 fractions to achieve asymptotic maximal tumor control, and T2 tumors require slightly higher optimal doses than T1 tumors. The proposed optimal fractionation schemes are consistent with clinical practice for SBRT of early-stage NSCLC.

Hypoxia dose painting in SBRT – the virtual clinical trial approach

Background Treating hypoxic tumours remains a challenge in radiotherapy as hypoxia leads to enhanced tumour aggressiveness and resistance to radiation. As escalating the doses is rarely feasible within the healthy tissue constraints, dose-painting strategies have been explored. Consensus about the best of care for hypoxic tumours has however not been reached because, among other reasons, the limits of current functional in-vivo imaging systems in resolving the details and dynamics of oxygen transport in tissue. Computational modelling of the tumour microenvironment enables the design and conduction of virtual clinical trials by providing relationships between biological features and treatment outcomes. This study presents a framework for assessing the therapeutic influence of the individual characteristics of the vasculature and the resulting oxygenation of hypoxic tumours in a virtual clinical trial on dose painting in stereotactic body radiotherapy (SBRT) circumventing the limitations of the imaging systems. Material and methods The homogeneous doses required to overcome hypoxia in simulated SBRT treatments of 1, 3 or 5 fractions were calculated for tumours with heterogeneous oxygenation derived from virtual vascular networks. The tumour control probability (TCP) was calculated for different scenarios for oxygenation dynamics resulting on cellular reoxygenation. Results A three-fractions SBRT treatment delivering 41.9 Gy (SD 2.8) and 26.5 Gy (SD 0.1) achieved only 21% (SD 12) and 48% (SD 17) control in the hypoxic and normoxic subvolumes, respectively whereas fast reoxygenation improved the control by 30% to 50%. TCP values for the individual tumours with similar characteristics, however, might differ substantially, highlighting the crucial role of the magnitude and time evolution of hypoxia at the microscale. Conclusion The results show that local microvascular heterogeneities may affect the predicted outcome in the hypoxic core despite escalated doses, emphasizing the role of theoretical modelling in understanding of and accounting for the dominant factors of the tumour microenvironment.

A novel TOX3-WDR5-ABCG2 signaling axis regulates the progression of colorectal cancer by accelerating stem-like traits and chemoresistance.

The eradication of cancer stem cells (CSCs) with drug resistance confers the probability of local tumor control after chemotherapy or targeted therapy. As the main drug resistance marker, ABCG2 is also critical for colorectal cancer (CRC) evolution, in particular cancer stem-like traits expansion. Hitherto, the knowledge about the expression regulation of ABCG2, in particular its upstream transcriptional regulatory mechanisms, remains limited in cancer, including CRC. Here, ABCG2 was found to be markedly up-regulated in CRC CSCs (cCSCs) expansion and chemo-resistant CRC tissues and closely associated with CRC recurrence. Mechanistically, TOX3 was identified as a specific transcriptional factor to drive ABCG2 expression and subsequent cCSCs expansion and chemoresistance by binding to -261 to -141 segments of the ABCG2 promoter region. Moreover, we found that TOX3 recruited WDR5 to promote tri-methylation of H3K4 at the ABCG2 promoter in cCSCs, which further confers stem-like traits and chemoresistance to CRC by co-regulating the transcription of ABCG2. In line with this observation, TOX3, WDR5, and ABCG2 showed abnormal activation in chemo-resistant tumor tissues of in situ CRC mouse model and clinical investigation further demonstrated the comprehensive assessment of TOX3, WDR5, and ABCG2 could be a more efficient strategy for survival prediction of CRC patients with recurrence or metastasis. Thus, our study found that TOX3-WDR5/ABCG2 signaling axis plays a critical role in regulating CRC stem-like traits and chemoresistance, and a combination of chemotherapy with WDR5 inhibitors may induce synthetic lethality in ABCG2-deregulated tumors.

Importance of tumor volume, overall treatment time and fractionation sensitivity for p16-positive and p16-negative oropharyngeal tumors

Background Analyses of clinical outcomes following radiotherapy (RT) have advanced our understanding of fundamental radiobiological characteristics in head and neck squamous cell carcinoma (HNSCC). Low fractionation sensitivity appears to be a common feature, as well as susceptibility to changes in overall treatment time (OTT). Large tumors should be harder to cure if a successful RT requires the sterilization of all clonogenic cells. Congruently, primary tumor volume has proven to be an important parameter. However, most findings come from an era when p16-negative HNSCC was the dominant tumor type. HPV-associated, p16-positive, oropharyngeal tumors (OPSCC) are more radiosensitive and have better outcome. The current study aims to investigate the role of primary tumor volume, OTT and estimate α-ratio for p16-positive OPSCC, and to quantify the differences in radiosensitivity depending on p16-status. Methods A cohort of 523 patients treated with RT was studied using a tumor control probability (TCP)-model that incorporates primary tumor volume (V) raised to an exponent c, OTT and α-estimation. The significance of V was also investigated in Cox-regression models. Results In the p16-positive cohort (n = 433), the volume exponent was 1.44 (95%CI 1.06–1.91), compared to 0.90 (0.54–1.32) for p16-negative tumors (n = 90). Hazard ratios per tumor volume doubling were 2.37 (1.72–3.28) and 1.83 (1.28–2.62) for p16-positive and p16-negative, respectively. The estimated α-ratio was 9.7 Gy (−2.3–21.6), and a non-significant daily loss of 0.30 Gy (−0.17–0.92) was found. An additional dose of 6.8 Gy (interquartile range 4.8-9.1) may theoretically counteract the more radioresistant behavior of p16-negative tumors. Conclusion Primary tumor volume plays a crucial role in predicting local tumor response, particularly in p16-positive OPSCC. The estimated α/β-ratio for p16-positive oropharyngeal tumors aligns with previous HNSCC studies, whereas the impact of prolonged OTT was slightly less than previously reported. The differences in radiosensitivity depending on p16-status were quantified. The findings should be validated in independent cohorts.

Assessment of residual geometrical errors of clinical target volumes and their impact on dose accumulation for head and neck radiotherapy

PurposeTo assess the residual geometrical errors (dr) and their impact on the clinical target volumes (CTV) dose coverage for head and neck cancer (HNC) proton therapy patients. MethodsWe analysed 28 HNC patients treated with 70 Gy (RBE) and 54.25 Gy (RBE) to the therapeutic CTV70 and prophylactic CTV54.25, respectively. Daily cone beam CTs were converted to high quality synthetic CTs (sCTs). The CTVs from the nominal CT were propagated to the corresponding sCTs using a hybrid deformable image registration (propagated CTVs) in RayStation 11B. For 11 patients, all propagated CTVs were reviewed by our HNC radiation oncologist (physician corrected CTVs).The residual geometrical error dr was quantified as a function of the daily CTVs volume overlap with the nominal plan CTV. The errors dr(propagated CTVs) and dr(physician corrected CTVs) and the difference in dice similarity coefficients (ΔDSC) were determined. Using clinical plans, dose coverage and the tumor control probability (TCP) for the nominal, accumulated and voxel-wise minimum scenarios were determined. ResultsThe difference in the residual geometrical error dr (propagated CTVs – physician corrected CTVs) and mean DSC (|ΔDSC|mean) were minor: Δdr(CTV70) = 0.16 mm, Δdr(CTV54.25) = 0.26 mm, |ΔDSC|mean < 0.9%. For all 28 patients, dr(CTV70) = 1.91 mm and dr(CTV54.25) = 1.90 mm. However, CTV54.25 above and below the cricoid cartilage differed substantially (1.00 mm c.f. 3.93 mm). The CTV54.25 coverage below the cricoid was then almost always lower, although the TCP of the accumulated dose was higher than the TCP of the voxel-wise minimum dose. ConclusionsSetup uncertainty setting of 2 mm is possible. The feasibility of using propagated CTVs for error determination is demonstrated.

The Use of 3D Printing Technology in Gynaecological Brachytherapy-A Narrative Review.

Radiation therapy, including image-guided adaptive brachytherapy based on magnetic resonance imaging, is the standard of care in locally advanced cervical and vaginal cancer and part of the treatment in other primary and recurrent gynaecological tumours. Tumour control probability increases with dose and brachytherapy is the optimal technique to increase the dose to the target volume while maintaining dose constraints to organs at risk. The use of interstitial needles is now one of the quality indicators for cervical cancer brachytherapy and needles should optimally be used in ≥60% of patients. Commercially available applicators sometimes cannot be used because of anatomical barriers or do not allow adequate target volume coverage due to tumour size or topography. Over the last five to ten years, 3D printing has been increasingly used for manufacturing of customised applicators in brachytherapy, with gynaecological tumours being the most common indication. We present the rationale, techniques and current clinical evidence for the use of 3D-printed applicators in gynaecological brachytherapy.