Beltran, Chris J

BNCT is a high LET radiation therapy modality that allows for biologically targeted radiation delivery to tumors while reducing normal tissue impacts. Although the clinical use of BNCT has largely been limited to phase I/II trials and has primarily focused on difficult-to-treat malignancies such as recurrent head and neck cancer and recurrent gliomas, recently there has been a renewed interest in expanding the use of BNCT to other disease sites, including breast cancer. Given its high LET characteristics, its biologically targeted and tumor specific nature, as well as its potential for use in complex treatment settings including reirradiation and widespread metastatic disease, BNCT offers several unique advantages over traditional external beam radiation therapy. The two main boron compounds investigated to date in BNCT clinical trials are BSH and BPA. Of these, BPA in particular shows promise in breast cancer given that is taken up by the LAT-1 amino acid transporter that is highly overexpressed in breast cancer cells. As the efficacy of BNCT is directly dependent on the extent of boron accumulation in tumors, extensive preclinical efforts to develop novel boron delivery agents have been undertaken in recent years. Preclinical studies have shown promise in antibody linked boron compounds targeting ER/HER2 receptors, boron encapsulating liposomes, and nanoparticle-based boron delivery systems. This review aims to summarize the physical and biological basis of BNCT, the preclinical and limited clinical data available to date, and discuss its potential to be utilized for the successful treatment of various breast cancer disease states.

Abstract Objective . To investigate similarities and differences in the formalism, processing, and the results of relative biological effectiveness (RBE) calculations with a biological weighting function (BWF), the microdosimetric kinetic model (MKM) and subsequent modifications (non-Poisson MKM, modified MKM). This includes: (a) the extension of the V79-RBE 10% BWF to model the RBE for other clonogenic survival levels; (b) a novel implementation of MKMs as weighting functions; (c) a benchmark against Chinese Hamster lung fibroblast (V79) in vitro data; (d) a study on the effect of pre- or post- processing the average biophysical quantities used for the RBE calculations; (e) a possible modification of the modified MKM parameters to improve the model accuracy at high linear energy transfer (LET). Methodology . Lineal energy spectra were simulated for two spherical targets (diameter = 0.464 or 1.0 μ m) using PHITS for 1 H, 4 He, 12 C, 20 Ne, 40 Ar, 56 Fe and 132 Xe ions. The results of the in silico calculations were compared with published in vitro data. Main results . All models appear to underestimate the RBE α of hydrogen ions. All MKMs generally overestimate the RBE 50% , RBE 10% and RBE 1% for ions with an LET greater than ∼200 keV μ m −1 . This overestimation is greater for small surviving fractions and is likely due to the assumption of a radiation-independent quadratic term of clonogenic survival ( ß ). The overall RBE trends seem to be best described by the novel ‘post-processing average’ implementation of the non-Poisson MKM. In case of calculations with the non-Poisson MKM, pre- or post- processing the average biophysical quantities affects the computed RBE values significantly. Significance . This study presents a systematic analysis of the formalism and results of widely used microdosimetric models of clonogenic survival for ions relevant for cancer particle therapy and space radiation protection. Points for improvements were highlighted and will contribute to the development of upgraded biophysical models.

Abstract Objective. 4D-CBCT provides phase-resolved images valuable for radiomics analysis for outcome prediction throughout treatment courses. However, 4D-CBCT suffers from streak artifacts caused by under-sampling, which severely degrades the accuracy of radiomic features. Previously we developed group-patient-trained deep learning methods to enhance the 4D-CBCT quality for radiomics analysis, which was not optimized for individual patients. In this study, a patient-specific model was developed to further improve the accuracy of 4D-CBCT based radiomics analysis for individual patients. Approach. This patient-specific model was trained with intra-patient data. Specifically, patient planning 4D-CT was augmented through image translation, rotation, and deformation to generate 305 CT volumes from 10 volumes to simulate possible patient positions during the onboard image acquisition. 72 projections were simulated from 4D-CT for each phase and were used to reconstruct 4D-CBCT using FDK back-projection algorithm. The patient-specific model was trained using these 305 paired sets of patient-specific 4D-CT and 4D-CBCT data to enhance the 4D-CBCT image to match with 4D-CT images as ground truth. For model testing, 4D-CBCT were simulated from a separate set of 4D-CT scan images acquired from the same patient and were then enhanced by this patient-specific model. Radiomics features were then extracted from the testing 4D-CT, 4D-CBCT, and enhanced 4D-CBCT image sets for comparison. The patient-specific model was tested using 4 lung-SBRT patients’ data and compared with the performance of the group-based model. The impact of model dimensionality, region of interest (ROI) selection, and loss function on the model accuracy was also investigated. Main results. Compared with a group-based model, the patient-specific training model further improved the accuracy of radiomic features, especially for features with large errors in the group-based model. For example, the 3D whole-body and ROI loss-based patient-specific model reduces the errors of the first-order median feature by 83.67%, the wavelet LLL feature maximum by 91.98%, and the wavelet HLL skewness feature by 15.0% on average for the four patients tested. In addition, the patient-specific models with different dimensionality (2D versus 3D) or loss functions (L1 versus L1 + VGG + GAN) achieved comparable results for improving the radiomics accuracy. Using whole-body or whole-body+ROI L1 loss for the model achieved better results than using the ROI L1 loss alone as the loss function. Significance. This study demonstrated that the patient-specific model is more effective than the group-based model on improving the accuracy of the 4D-CBCT radiomic features analysis, which could potentially improve the precision for outcome prediction in radiotherapy.

AbstractPurposeTo evaluate the relative biological effectiveness (RBE)‐weighted dose to the heart and to estimate RBE uncertainties when assuming a constant RBE of 1.1, for breast cancer patients receiving intensity‐modulated proton therapy (IMPT). Further, to study the impact of RBE uncertainties on the risk of an acute coronary event (ACE).Material and methodsWe analyzed 20 patients who received IMPT to either the left breast (n = 10) or left chest wall (n = 10) and regional lymph nodes. The Monte Carlo simulation engine, MCsquare, was used to simulate the dose‐averaged linear energy transfer (LETd) map. The RBE‐weighted dose to the heart and its substructures was calculated using three different RBE models. The risk of ACE was estimated per its linear relationship with mean heart dose (MHD) as established by Darby et al.ResultsThe median MHD increased from 1.33 GyRBE assuming an RBE of 1.1 to 1.64, 1.87, and 1.99 GyRBE when using the RBE‐weighted dose models. The median values (and ranges) of the excess absolute risk of ACE were 0.4% (0.1%–0.8%) when assuming an RBE of 1.1, and 0.6% (0.2%–1.0%), 0.6% (0.2%–1.1%), and 0.7% (0.2%–1.1%) with the RBE‐weighted models. For our patient cohort, the maximum excess absolute risk of ACE increased by 0.3% with the RBE‐weighted doses compared to the constant RBE of 1.1, reaching an excess absolute ACE risk of 1.1%. The interpatient LETd variation was small for the relevant high‐dose regions of the heart.ConclusionAll three RBE models predicted a higher biological dose compared to the clinical standard dose assuming a constant RBE of 1.1. An underestimation of the biological dose results in underestimation of the ACE risk. Analyzing the voxel‐by‐voxel biological dose and the LET map alongside clinical outcomes is warranted in the development of a more accurate normal‐tissue complication probability model.

AbstractIntroductionThis study presents a comprehensive collision avoidance framework based on three‐dimension (3D) computer‐aided design (CAD) modeling, a graphical user interface (GUI) as peripheral to the radiation treatment planning (RTP) environment, and patient‐specific plan parameters for intensity‐modulated proton therapy (IMPT).MethodsA stand‐alone software application was developed leveraging the Varian scripting application programming interface (API) for RTP database object accessibility. The Collision Avoider software models the Hitachi ProBeat‐V half gantry design and the Kuka robotic couch with triangle mesh structures. Patient‐specific plan parameters are displayed in the collision avoidance software for potential proximity evaluation. The external surfaces of the patients and the immobilization devices are contoured based on computed tomography (CT) images. A “table junction‐to‐CT‐origin” (JCT) measurement is made for every patient at the time of CT simulation to accurately provide reference location of the patient contours to the treatment couch. Collision evaluations were performed virtually with the program during treatment planning to prevent four major types of collisional events: collisions between the gantry head and the treatment couch, gantry head and the patient's body, gantry head and the robotic arm, and collisions between the gantry head and the immobilization devices.ResultsThe Collision Avoider software was able to accurately model the proton treatment delivery system and the robotic couch position. Commonly employed clinical beam configuration and JCT values were investigated. Brain and head and neck patients require more complex gantry and patient positioning system configurations. Physical measurements were performed to validate 3D CAD model geometry. Twelve clinical proton treatment plans were used to validate the accuracy of the software. The software can predict all four types of collisional events in our clinic since its full implementation in 2020.ConclusionA highly efficient patient‐specific collision prevention program for scanning proton therapy has been successfully implemented. The graphical program has provided accurate collision detection since its inception at our institution.

Abstract The primary objective is to evaluate the potential dosimetric gains of performing functional avoidance‐based proton treatment planning using 4DCT derived ventilation imaging. 4DCT data of 31 patients from a prospective functional avoidance clinical trial were evaluated with intensity modulated proton therapy (IMPT) plans and compared with clinical volumetric modulated arc therapy (VMAT) plans. Dosimetric parameters were compared between standard and functional plans with IMPT and VMAT with one‐way analysis of variance and post hoc paired student t‐test. Normal Tissue Complication Probability (NTCP) models were employed to estimate the risk of two toxicity endpoints for healthy lung tissues. Dose degradation due to proton motion interplay effect was evaluated. Functional IMPT plans led to significant dose reduction to functional lung structures when compared with functional VMAT without significant dose increase to Organ at Risk (OAR) structures. When interplay effect is considered, no significant dose degradation was observed for the OARs or the clinical target volume (CTV) volumes for functional IMPT. Using fV20 as the dose metric and Grade 2+ pneumonitis as toxicity endpoint, there is a mean 5.7% reduction in Grade 2+ RP with the functional IMPT and as high as 26% in reduction for individual patient when compared to the standard IMPT planning. Functional IMPT was able to spare healthy lung tissue to avoid excess dose to normal structures while maintaining satisfying target coverage. NTCP calculation also shows that the risk of pulmonary complications can be further reduced with functional based IMPT.

Abstract Proton therapy has a distinct dosimetric advantage over conventional photon therapy due to its Bragg peak profile. This allows greater accuracy in dose delivery and dose conformation to the target, however it requires greater precision in setup, delivery and for quality assurance (QA) procedures. The AAPM TG 224 report recommends daily range and spot position checks with tolerance on the order of a millimetre. Daily QA systems must therefore be efficient for daily use and be capable of sub-millimetre precision however few suitable commercial systems are available. In this work, a compact, real-time daily QA system is optimised and characterised for proton range verification using an ad-hoc Geant4 simulation. The system is comprised of a monolithic silicon diode array detector embedded in a perspex phantom. The detector is orientated at an angular offset to the incident proton beam to allow range in perspex to be determined for flat proton fields. The accuracy of the system for proton range in perspex measurements was experimentally evaluated over the full range of clinical proton energies. The mean R 100 , R 90 and R 80 ranges measured with the system were accurate within ±0.6 mm of simulated ranges in a perspex phantom for all energies assessed. This system allows real-time read-out of individual detector channels also making it appropriate for temporal beam delivery diagnostics and for spot position monitoring along one axis. The system presented provides a suitable, economical and efficient alternative for daily QA in proton therapy.

Abstract Proton Bragg peak irradiation has a higher ionizing density than conventional photon irradiation or the entrance of the proton beam profile. Whether targeting the DNA damage response (DDR) could enhance vulnerability to the distinct pattern of damage induced by proton Bragg peak irradiation is currently unknown. Here, we performed genetic or pharmacologic manipulation of key DDR elements and evaluated DNA damage signaling, DNA repair, and tumor control in cell lines and xenografts treated with the same physical dose across a radiotherapy linear energy transfer spectrum. Radiotherapy consisted of 6 MV photons and the entrance beam or Bragg peak of a 76.8 MeV spot scanning proton beam. More complex DNA double-strand breaks (DSB) induced by Bragg peak proton irradiation preferentially underwent resection and engaged homologous recombination (HR) machinery. Unexpectedly, the ataxia-telangiectasia mutated (ATM) inhibitor, AZD0156, but not an inhibitor of ATM and Rad3-related, rendered cells hypersensitive to more densely ionizing proton Bragg peak irradiation. ATM inhibition blocked resection and shunted more DSBs to processing by toxic ligation through nonhomologous end-joining, whereas loss of DNA ligation via XRCC4 or Lig4 knockdown rescued resection and abolished the enhanced Bragg peak cell killing. Proton Bragg peak monotherapy selectively sensitized cell lines and tumor xenografts with inherent HR defects, and the repair defect induced by ATM inhibitor coadministration showed enhanced efficacy in HR-proficient models. In summary, inherent defects in HR or administration of an ATM inhibitor in HR-proficient tumors selectively enhances the relative biological effectiveness of proton Bragg peak irradiation. Significance: Coadministration of an ATM inhibitor rewires DNA repair machinery to render cancer cells uniquely hypersensitive to DNA damage induced by the proton Bragg peak, which is characterized by higher density ionization. See related commentary by Nickoloff, p. 3156

Stereotactic radiosurgery (SRS) involves the delivery of a highly conformal ablative dose of radiation to both benign and malignant targets. This has traditionally been accomplished in a single fraction; however, fractionated approaches involving five or fewer treatments have been delivered for larger lesions, as well as lesions in close proximity to radiosensitive structures. The clinical utilization of SRS has overwhelmingly involved photon-based sources via dedicated radiosurgery platforms (e.g., Gamma Knife® and Cyberknife®) or specialized linear accelerators. While photon-based methods have been shown to be highly effective, advancements are sought for improved dose precision, treatment duration, and radiobiologic effect, among others, particularly in the setting of repeat irradiation. Particle-based techniques (e.g., protons and carbon ions) may improve many of these shortcomings. Specifically, the presence of a Bragg Peak with particle therapy at target depth allows for marked minimization of distal dose delivery, thus mitigating the risk of toxicity to organs at risk. Carbon ions also exhibit a higher linear energy transfer than photons and protons, allowing for greater relative biological effectiveness. While the data are limited, utilization of proton radiosurgery in the setting of brain metastases has been shown to demonstrate 1-year local control rates >90%, which are comparable to that of photon-based radiosurgery. Prospective studies are needed to further validate the safety and efficacy of this treatment modality. We aim to provide a comprehensive overview of clinical evidence in the use of particle therapy-based radiosurgery.