Superior antitumor immune response achieved with proton over photon immunoradiotherapy is amplified by the nanoradioenhancer NBTXR3.

Recent findings suggest that immunoradiotherapy (IRT), combining photon radiotherapy (XRT) or proton radiotherapy (PRT) with immune checkpoint blockade, can enhance systemic tumor control. However, the comparative efficacy of XRT and PRT in IRT remains understudied. To address this, we compared outcomes between XRT + αPD1 and PRT + αPD1 in murine αPD1-resistant lung cancer (344SQR). We also assessed the impact of the nanoparticle radioenhancer NBTXR3 on both XRT + αPD1 and PRT + αPD1 for tumor control and examined the tumor immune microenvironment using single-cell RNA sequencing (scRNAseq). Additionally, mice cured by NBTXR3 + PRT + αPD1 were rechallenged with three lung cancer cell lines to evaluate memory antitumor immunity. PRT + αPD1 showed superior local tumor control and abscopal effects compared to XRT + αPD1. NBTXR3 + PRT + αPD1 significantly outperformed NBTXR3 + XRT + αPD1 in tumor control, promoting greater infiltration of antitumor lymphocytes into irradiated tumors. Unirradiated tumors treated with NBTXR3 + PRT + αPD1 had more NKT cells, CD4 T cells, and B cells, with fewer Tregs, than those treated with NBTXR3 + XRT + αPD1. NBTXR3 + PRT + αPD1 also stimulated higher expression of IFN-γ, GzmB, and Nkg7 in lymphocytes, reduced the TGF-ß pathway, and increased tumor necrosis factor alpha expression compared to NBTXR3 + XRT + αPD1. Moreover, NBTXR3 + PRT + αPD1 resulted in greater M1 macrophage polarization in both irradiated and unirradiated tumors. Mice achieving remission through NBTXR3 + PRT + αPD1 exhibited a robust memory immune response, effectively inhibiting growth of subsequent tumors from three distinct lung cancer cell lines. Proton IRT combined with NBTXR3 offers enhanced tumor control and survival rates over photon-based treatments in managing αPD1-resistant lung cancer, indicating its potential as a potent systemic therapy.

Mimicking large spot-scanning radiation fields for proton FLASH preclinical studies with a robotic motion platform.

Previously, a synchrotron-based horizontal proton beamline (87.2 MeV) was successfully commissioned to deliver radiation doses in FLASH and conventional dose rate modes to small fields and volumes. In this study, we developed a strategy to increase the effective radiation field size using a custom robotic motion platform to automatically shift the positions of biological samples. The beam was first broadened with a thin tungsten scatterer and shaped by customized brass collimators for irradiating cell/organoid cultures in 96-well plates (a 7-mm-diameter circle) or for irradiating mice (1-cm2 square). Motion patterns of the robotic platform were written in G-code, with 9-mm spot spacing used for the 96-well plates and 10.6-mm spacing for the mice. The accuracy of target positioning was verified with a self-leveling laser system. The dose delivered in the experimental conditions was validated with EBT-XD film attached to the 96-well plate or the back of the mouse. Our film-measured dose profiles matched Monte Carlo calculations well (1D gamma pass rate >95%). The FLASH dose rates were 113.7 Gy/s for cell/organoid irradiation and 191.3 Gy/s for mouse irradiation. These promising results indicate that this robotic platform can be used to effectively increase the field size for preclinical experiments with proton FLASH.

Proton therapy toxicity outcomes for localized prostate cancer: Long-term results at a comprehensive cancer center.

Background: Proton therapy (PT) has unique biologic properties with excellent clinical outcomes for the management of localized prostate cancer. Here, we aim to characterize the toxicity of PT for patients with localized prostate cancer and propose mitigation strategies using a large institutional database. Methods: We reviewed medical records of 2772 patients with localized prostate cancer treated with definitive PT between May 2006 through January 2020. Disease risk was stratified according to National Comprehensive Cancer Network guidelines as low [LR, n = 640]; favorable-intermediate [F-IR, n = 849]; unfavorable-intermediate [U-IR, n = 851]; high [HR, n = 315]; or very high [VHR, n = 117]. Descriptive statistics and Kaplan-Meier estimates assessed toxicity and freedom from biochemical relapse (FFBR). Results: Median follow-up was 7.0 years. The median dose was 78 Gy(RBE)(range: 72-79.2 Gy) in 2.0 Gy(RBE) fractions; 63 % of patients received 78 Gy(RBE) in 39 fractions, and 29 % received 76 Gy(RBE) in 38 fractions. Overall rates of late grade ≥3 GU and GI toxicity were 0.87 % and 1.01 %, respectively. Two patients developed grade 4 late GU toxicity and seven patients with grade 4 late GI toxicity. All patients experiencing severe late grade 4 toxicities were treated to 78 Gy(RBE) in 39 fractions with 80 Gy(RBE) dose to the anterior rectal wall and/or bladder neck. The 10-year FFBR rates for patients with LR to U-IR disease were compared between those treated with 76 and 78 Gy(RBE); the rates were 94.5 % (95 % confidence interval [CI] 92.4-96.0 %) and 93.2 % (95 % CI 91.3-95.7 %), respectively (log-rank p = 0.22). Conclusions: Proton therapy is associated with low rates of late grade ≥3 GU and GI toxicity. While rare, late grade 4 toxicities occurred in nine (0.3 %) patients. De-escalation to a total dose of 76 Gy(RBE) yields excellent clinical outcomes for patients with LR to U-IR disease with the potential for significant reductions in grade ≥3 late toxicity.

A Novel Polymer-Encapsulated Multi-Imaging Modality Fiducial Marker with Positive Signal Contrast for Image-Guided Radiation Therapy.

BACKGROUND: Current fiducial markers (FMs) in external-beam radiotherapy (EBRT) for prostate cancer (PCa) cannot be positively visualized on magnetic resonance imaging (MRI) and create dose perturbation and significant imaging artifacts on computed tomography (CT) and MRI. We report our initial experience with clinical imaging of a novel multimodality FM, NOVA. METHODS: We tested Gold Anchor [G-FM], BiomarC [carbon, C-FM], and NOVA FMs in phantoms imaged with kilovoltage (kV) X-rays, transrectal ultrasound (TRUS), CT, and MRI. Artifacts of the FMs on CT were quantified by the relative streak artifacts level (rSAL) metric. Proton dose perturbations (PDPs) were measured with Gafchromic EBT3 film, with FMs oriented either perpendicular to or parallel with the beam axis. We also tested the performance of NOVA-FMs in a patient. RESULTS: NOVA-FMs were positively visualized on all 4 imaging modalities tested. The rSAL on CT was 0.750 ± 0.335 for 2-mm reconstructed slices. In F-tests, PDP was associated with marker type and depth of measurement (p < 10-6); at 5-mm depth, PDP was significantly greater for the G-FM (12.9%, p = 10-6) and C-FM (6.0%, p = 0.011) than NOVA (4.5%). EBRT planning with MRI/CT image co-registration and daily alignments using NOVA-FMs in a patient was feasible and reproducible. CONCLUSIONS: NOVA-FMs were positively visible and produced less PDP than G-FMs or C-FMs. NOVA-FMs facilitated MRI/CT fusion and identification of regions of interest.

Stereotactic body proton therapy for early stage non-small cell lung cancer - Technical challenges and solutions: The MD Anderson experience.

Our randomized clinical study comparing stereotactic body radiotherapy (SBRT) and stereotactic body proton therapy (SBPT) for early stage non-small cell lung cancer (NSCLC) was closed prematurely owing to poor enrollment, largely because of lack of volumetric imaging and difficulty in obtaining insurance coverage for the SBPT group. In this article, we describe technology improvements in our new proton therapy center, particularly in image guidance with cone beam CT (CBCT) and CT on rail (CTOR), as well as motion management with real-time gated proton therapy (RGPT) and optical surface imaging. In addition, we have a treatment planning system that provides better treatment plan optimization and more accurate dose calculation. We expect to re-start the SBPT program, including for early stage NSCLC as well as for other disease sites soon after starting patient treatment at our new proton therapy center.

Dosimetric response of Gafchromic™ EBT-XD film to therapeutic protons.

EBT-XD model of Gafchromic™ films has a broader optimal dynamic dose range, up to 40 Gy, compared to its predecessor models. This characteristic has made EBT-XD films suitable for high-dose applications such as stereotactic body radiotherapy and stereotactic radiosurgery, as well as ultra-high dose rate FLASH radiotherapy. The purpose of the current study was to characterize the dependence of EBT-XD film response on linear energy transfer (LET) and dose rate of therapeutic protons from a synchrotron. A clinical spot-scanning proton beam was used to study LET dependence at three dose-averaged LET (LETd) values of 1.0 keV/µm, 3.6 keV/µm, and 7.6 keV/µm. A research proton beamline was used to study dose rate dependence at 150 Gy/second in the FLASH mode and 0.3 Gy/second in the non-FLASH mode. Film response data from LETd values of 0.9 keV/µm and 9.0 keV/µm of the proton FLASH beam were also compared. Film response data from a clinical 6 MV photon beam were used as a reference. Both gray value method and optical density (OD) method were used in film calibration. Calibration results using a specific OD calculation method and a generic OD calculation method were compared. The four-parameter NIH Rodbard function and three-parameter rational function were compared in fitting the calibration curves. Experimental results showed that the response of EBT-XD film is proton LET dependent but independent of dose rate. Goodness-of-fit analysis showed that using the NIH Rodbard function is superior for both protons and photons. Using the "specific OD + NIH Rodbard function" method for EBT-XD film calibration is recommended.

Ultrashort pulse laser patterning of zirconia (3Y-TZP) for enhanced adhesion to resin-matrix cements used in dentistry: An integrative review.

Surface modification of yttria-stabilized tetragonal zirconia polycrystals (Y-TZP) using lasers for adhesion enhancement with resin-matrix cement has been increasingly explored. However, Y-TZP is chemically inert and non-reactive, demanding surface modification using alternative approaches to enhance its bond strength to resin-matrix cements. The main aim of this study was to conduct an integrative review on the influence of ultrashort pulse laser patterning of zirconia (3Y-TZP) for enhanced bonding to resin-matrix cements. An electronic search was performed on web of science, SCOPUS, Pubmed/Medline, Google Scholar and EMBASE using a combination of the following search items: zirconia, 3Y-TZP, surface modification, laser surface treatment, AND laser, ultrashortpulse laser, bonding, adhesion, and resin cement. Articles published in the English language, up to January 2022, were included regarding the influence of surface patterning on bond strength of Y-TZP to resin-matrix cements. Out of the 12 studies selected for the present review 10 studies assessed femtosecond lasers while 2 studies assessed picosecond lasers. Ultrashort pulsed laser surface patterning successfully produced different surface morphological aspects without damaging the bulk properties of zirconia. Contrarily, defects such as micro-cracks occurs after surface modification using traditional methods such as grit-blasting or long-pulsed laser patterning. Ultrashort pulsed laser surface patterning increase bond strength of zirconia to resin-matrix cements and therefore such alternative physical method should be considered in dentistry. Also, surface defects were avoided using ultrashort pulsed laser surface patterning, which become the major advantage when compared with traditional physical methods or long pulse laser patterning.

Nanoparticle-enhanced proton beam immunoradiotherapy drives immune activation and durable tumor rejection.

The combination of radiation therapy (RT) and immunotherapy has emerged as a promising treatment option in oncology. Historically, x-ray radiation (XRT) has been the most commonly used form of RT. However, proton beam therapy (PBT) is gaining recognition as a viable alternative, as it has been shown to produce similar outcomes to XRT while minimizing off-target effects. The effects of PBT on the antitumor immune response have only just begun to be described, and to our knowledge no studies to date have examined the effect of PBT as part of a combinatorial immunoradiotherapeutic strategy. Here, using a 2-tumor model of lung cancer in mice, we show that PBT in tandem with an anti-PD1 antibody substantially reduced growth in both irradiated and unirradiated tumors. This was accompanied by robust activation of the immune response, as evidenced by whole-tumor and single-cell RNA sequencing showing upregulation of a multitude of immune-related transcripts. This response was further significantly enhanced by the injection of the tumor to be irradiated with NBTXR3 nanoparticles. Tumors of mice treated with the triple combination exhibited increased infiltration and activation of cytotoxic immune cells. This triple combination eradicated both tumors in 37.5% of the treated mice and showed robust long-term immunity to cancer.

Intensity modulated proton arc therapy via geometry-based energy selection for ependymoma.

PURPOSE: We developed and tested a novel method of creating intensity modulated proton arc therapy (IMPAT) plans that uses computing resources similar to those for regular intensity-modulated proton therapy (IMPT) plans and may offer a dosimetric benefit for patients with ependymoma or similar tumor geometries. METHODS: Our IMPAT planning method consists of a geometry-based energy selection step with major scanning spot contributions as inputs computed using ray-tracing and single-Gaussian approximation of lateral spot profiles. Based on the geometric relation of scanning spots and dose voxels, our energy selection module selects a minimum set of energy layers at each gantry angle such that each target voxel is covered by sufficient scanning spots as specified by the planner, with dose contributions above the specified threshold. Finally, IMPAT plans are generated by robustly optimizing scanning spots of the selected energy layers using a commercial proton treatment planning system (TPS). The IMPAT plan quality was assessed for four ependymoma patients. Reference three-field IMPT plans were created with similar planning objective functions and compared with the IMPAT plans. RESULTS: In all plans, the prescribed dose covered 95% of the clinical target volume (CTV) while maintaining similar maximum doses for the brainstem. While IMPAT and IMPT achieved comparable plan robustness, the IMPAT plans achieved better homogeneity and conformity than the IMPT plans. The IMPAT plans also exhibited higher relative biological effectiveness (RBE) enhancement than did the corresponding reference IMPT plans for the CTV in all four patients and brainstem in three of them. CONCLUSIONS: The proposed method demonstrated potential as an efficient technique for IMPAT planning and may offer a dosimetric benefit for patients with ependymoma or tumors in close proximity to critical organs. IMPAT plans created using this method had elevated RBE enhancement associated with increased linear energy transfer (LET) in both targets and abutting critical organs.

Adaptation and dosimetric commissioning of a synchrotron-based proton beamline for FLASH experiments.

Objective. Irradiation with ultra-high dose rates (>40 Gy s-1), also known as FLASH irradiation, has the potential to shift the paradigm of radiation therapy because of its reduced toxicity to normal tissues compared to that of conventional irradiations. The goal of this study was to (1) achieve FLASH irradiation conditions suitable for pre-clinicalin vitroandin vivobiology experiments using our synchrotron-based proton beamline and (2) commission the FLASH irradiation conditions achieved.Approach. To achieve these suitable FLASH conditions, we made a series of adaptations to our proton beamline, including modifying the spill length and size of accelerating cycles, repurposing the reference monitor for dose control, and expanding the field size with a custom double-scattering system. We performed the dosimetric commissioning with measurements using an Advanced Markus chamber and EBT-XD films as well as with Monte Carlo simulations.Main results. Through adaptations, we have successfully achieved FLASH irradiation conditions, with an average dose rate of up to 375 Gy s-1. The Advanced Markus chamber was shown to be appropriate for absolute dose calibration under our FLASH conditions with a recombination factor ranging from 1.002 to 1.006 because of the continuous nature of our synchrotron-based proton delivery within a spill. Additionally, the absolute dose measured using the Advanced Markus chamber and EBT-XD films agreed well, with average and maximum differences of 0.32% and 1.63%, respectively. We also performed a comprehensive temporal analysis for FLASH spills produced by our system, which helped us identify a unique relationship between the average dose rate and the dose in our FLASH irradiation.Significance.We have established a synchrotron-based proton FLASH irradiation platform with accurate and precise dosimetry that is suitable for pre-clinical biology experiments. The unique time structure of the FLASH irradiation produced by our synchrotron-based system may shed new light onto the mechanism behind the FLASH effect.

Predictive performance of different NTCP techniques for radiation-induced esophagitis in NSCLC patients receiving proton radiotherapy.

This study aimed to compare the predictive performance of different modeling methods in developing normal tissue complication probability (NTCP) models for predicting radiation-induced esophagitis (RE) in non-small cell lung cancer (NSCLC) patients receiving proton radiotherapy. The dataset was composed of 328 NSCLC patients receiving passive-scattering proton therapy and 41.6% of the patients experienced ≥ grade 2 RE. Five modeling methods were used to build NTCP models: standard Lyman-Kutcher-Burman (sLKB), generalized LKB (gLKB), multivariable logistic regression using two variable selection procedures-stepwise forward selection (Stepwise-MLR), and least absolute shrinkage and selection operator (LASSO-MLR), and support vector machines (SVM). Predictive performance was internally validated by a bootstrap approach for each modeling method. The overall performance, discriminative ability, and calibration were assessed using the Negelkerke R2, area under the receiver operator curve (AUC), and Hosmer-Lemeshow test, respectively. The LASSO-MLR model showed the best discriminative ability with an AUC value of 0.799 (95% confidence interval (CI): 0.763-0.854), and the best overall performance with a Negelkerke R2 value of 0.332 (95% CI: 0.266-0.486). Both of the optimism-corrected Negelkerke R2 values of the SVM and sLKB models were 0.301. The optimism-corrected AUC of the gLKB model (0.796) was higher than that of the SVM model (0.784). The sLKB model had the smallest optimism in the model variation and discriminative ability. In the context of classification and probability estimation for predicting the NTCP for radiation-induced esophagitis, the MLR model developed with LASSO provided the best predictive results. The simplest LKB modeling had similar or even better predictive performance than the most complex SVM modeling, and it was least likely to overfit the training data. The advanced machine learning approach might have limited applicability in clinical settings with a relatively small amount of data.

Design and validation of a synchrotron proton beam line for FLASH radiotherapy preclinical research experiments.

PURPOSE: The main purpose of this work was to generate and validate the dosimetric accuracy of proton beams of dimensions that are appropriate for in vivo small animal and in vitro ultrahigh dose rate (FLASH) radiotherapy experiments using a synchrotron-based treatment delivery system. This study was performed to enable future investigations of the relevance of a spread-out Bragg peak (SOBP) under FLASH conditions. METHODS: The spill characteristics of the small field fixed horizontal beam line were modified to deliver accelerated protons in times as short as 2 ms and to control the dose delivered. A Gaussian-like transverse beam profile was transformed into a square uniform one at FLASH dose rates, while avoiding low-dose regions, a crucial requirement to protect normal tissue during FLASH irradiation. Novel beam-shaping devices were designed using Monte Carlo techniques to produce up to about 6 cm3 of uniform dose in SOBPs while maximizing the dose rate. These included a scattering foil, a conical flattening filter to maximize the flux of protons into the region of interest, energy filters, range compensators, and collimators. The shapes, sizes, and positions of the components were varied to provide the required field sizes and SOBPs. RESULTS: The designed and fabricated devices were used to produce 10-, 15-, and 20-mm diameter, circular field sizes and 10-, 15-, and 20-mm SOBP modulation widths at uniform physical dose rates of up to 375 Gy/s at the center of the SOBP and a minimum dose rate of about 255 Gy/s at the entrance, respectively, in cylindrical volumes. The flatness of lateral dose profiles at the center could be adjusted to within ±1.5% at the center of the SOBP. Assessment of systematic uncertainties, such as impact of misalignments and positioning uncertainties, was performed using simulations, and the results were used to provide appropriate adjustments to ensure high-accuracy FLASH beam delivery for both in vitro and in vivo preclinical experiments. CONCLUSIONS: It is feasible to use synchrotron-generated proton beams of sufficient dimensions for FLASH radiobiology experiments. We expect to use the system we developed to acquire in vitro and in vivo small animal FLASH radiobiology data as a function of dose, dose rate, oxygen content, and linear energy transfer to help us understand the underlying mechanisms of the FLASH phenomenon.

Intensity-modulated proton therapy for oropharyngeal cancer reduces rates of late xerostomia.

BACKGROUND AND PURPOSE: To determine rates of xerostomia after intensity-modulated radiotherapy (IMRT) or intensity-modulated proton therapy (IMPT) for oropharyngeal cancer (OPC) and identify dosimetric factors associated with xerostomia risk. MATERIALS AND METHODS: Patients with OPC who received IMRT (n = 429) or IMPT (n = 103) from January 2011 through June 2015 at a single institution were studied retrospectively. Every 3 months after treatment, each patient completed an eight-item self-reported xerostomia-specific questionnaire (XQ; summary XQ score, 0-100). An XQ score of 50 was selected as the demarcation value for moderate-severe (XQs ≥ 50) and no-mild (XQs < 50) xerostomia. The mean doses and percent volumes of organs at risk receiving various doses (V5-V70) were extracted from the initial treatment plans. The dosimetric variables and xerostomia risk were compared using an independent-sample t-test or chi-square test. RESULTS: The median follow-up time was 36.2 months. The proportions of patients with moderate-severe xerostomia were similar in the two treatment groups up to 18 months after treatment. However, moderate-severe xerostomia was less common in the IMPT group than in the IMRT group at 18-24 months (6% vs. 20%; p = 0.025) and 24-36 months (6% vs. 20%; p = 0.01). During the late xerostomia period (24-36 months), high dose/volume exposures (V25-V70) in the oral cavity were associated with high proportions of patients with moderate-severe xerostomia (all p < 0.05), but dosimetric variables regarding the salivary glands were not associated with late xerostomia. CONCLUSION: IMPT was associated with less late xerostomia than was IMRT in OPC patients. Oral cavity dosimetric variables were related to the occurrence of late xerostomia.

Our Experience Leading a Large Medical Physics Practice During the COVID-19 Pandemic.

PURPOSE: To provide a series of suggestions for other Medical Physics practices to follow in order to provide effective radiation therapy treatments during the COVID-19 pandemic. METHODS AND MATERIALS: We reviewed our entire Radiation Oncology infrastructure to identify a series of workflows and policy changes that we implemented during the pandemic that yielded more effective practices during this time. RESULTS: We identified a structured list of several suggestions that can help other Medical Physics practices overcome the challenges involved in delivering high quality radiotherapy services during this pandemic. CONCLUSIONS: Our facility encompasses 4 smaller Houston Area Locations (HALs), a main campus with 8 distinct services based on treatment site (ie. Thoracic, Head and Neck, Breast, Gastrointestinal, Gynecology, Genitourinary, Hematologic Malignancies, Melanoma and Sarcoma and Central Nervous System/Pediatrics), a Proton Center facility, an MR-Linac, a Gamma Knife clinic and an array of brachytherapy services. Due to the scope of our services, we have gained experience in dealing with the rapidly changing pandemic effects on our clinical practice. Our paper provides a resource to other Medical Physics practices in search of workflows that have been resilient during these challenging times.

Clinical commissioning of intensity-modulated proton therapy systems: Report of AAPM Task Group 185.

Proton therapy is an expanding radiotherapy modality in the United States and worldwide. With the number of proton therapy centers treating patients increasing, so does the need for consistent, high-quality clinical commissioning practices. Clinical commissioning encompasses the entire proton therapy system's multiple components, including the treatment delivery system, the patient positioning system, and the image-guided radiotherapy components. Also included in the commissioning process are the x-ray computed tomography scanner calibration for proton stopping power, the radiotherapy treatment planning system, and corresponding portions of the treatment management system. This commissioning report focuses exclusively on intensity-modulated scanning systems, presenting details of how to perform the commissioning of the proton therapy and ancillary systems, including the required proton beam measurements, treatment planning system dose modeling, and the equipment needed.

Author Correction: Exploring the advantages of intensity-modulated proton therapy: experimental validation of biological effects using two different beam intensity-modulation patterns.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Pilot study of neurologic toxicity in mice after proton minibeam therapy.

Proton minibeams (MBs) comprised of parallel planar beamlets were evaluated for their ability to spare healthy brain compared to proton broad beams (BBs). Juvenile mice were given partial brain irradiation of 10 or 30 Gy integral dose using 100 MeV protons configured either as BBs or arrays of 0.3-mm planar MBs spaced 1.0 mm apart on center. Neurologic toxicity was evaluated during an 8-month surveillance: no overt constitutional or neurologic dysfunction was noted for any study animals. Less acute epilation was observed in MB than BB mice. Persistent chronic inflammation was noted along the entire BB path in BB mice whereas inflammation was confined to just within the MB peak regions in MB mice. The potential neurologic sparing, possibly via reduced volume of chronic inflammation, offers a compelling rationale for clinical advancement of this proton technique.

Evaluation of the high definition field of view option of a large-bore computed tomography scanner for radiation therapy simulation.

BACKGROUND AND PURPOSE: Computed tomography (CT) scanning is the basis for radiation treatment planning, but the 50-cm standard scanning field of view (sFOV) may be too small for imaging larger patients. We evaluated the 65-cm high-definition (HD) FOV of a large-bore CT scanner for CT number accuracy, geometric distortion, image quality degradation, and dosimetric accuracy of photon treatment plans. MATERIALS AND METHODS: CT number accuracy was tested by placing two 16-cm acrylic phantoms on either side of a 40-cm phantom to simulate a large patient extending beyond the 50-cm-diameter standard scanning FOV. Dosimetric accuracy was tested using anthropomorphic pelvis and thorax phantoms, with additional acrylic body parts on either side of the phantoms. Two volumetric modulated arc therapy beams (a 15-MV and a 6-MV) were used to cover the planning target volumes. Two-dimensional dose distributions were evaluated with GAFChromic film and point dose accuracy was checked with multiple thermoluminescent dosimeter (TLD) capsules placed in the phantoms. Image quality was tested by placing an American College of Radiology accreditation phantom inside the 40-cm phantom. RESULTS: The HD FOV showed substantial changes in CT numbers, with differences of 314 HU-725 HU at different density levels. The volume of the body parts extending into the HD FOV was distorted. However, TLD-reported doses for all PTVs agreed within ± 3%. Dose agreement in organs at risk were within the passing criteria, and the gamma index pass rate was >97%. Image quality was degraded. CONCLUSIONS: The HD FOV option is adequate for RT simulation and met accreditation standards, although care should be taken during contouring because of reduced image quality.

Proton and photon radiosensitization effects of niraparib, a PARP-1/-2 inhibitor, on human head and neck cancer cells.

BACKGROUND: Combining photon or proton radiotherapy with targeted therapy shows promise for head and neck cancer (HNSCC). The poly (adenosine diphosphate [ADP]-ribose) polymerase-1/2 inhibitor niraparib targets DNA damage repair (DDR). We evaluated the effects of niraparib in combination with photons or protons, and its effects on the relative biological effectiveness (RBE) of protons, in human HNSCC cell lines. METHODS: Radiosensitivity was assessed and RBE was calculated with clonogenic survival assays; unrepaired DNA double-strand breaks were evaluated using immunocytochemical analysis of 53BP1 foci. RESULTS: Niraparib reduced colony formation in two of the four cell lines tested (P < .05), enhanced radiosensitivity in all four cell lines, delayed DDR (P < .05), and increased proton vs photon RBE. CONCLUSION: Niraparib enhanced the sensitivity of four HNSCC cell lines to both photons and protons and increased the RBE of protons, possibly by inhibiting DDR. Niraparib may enhance the effectiveness of both photon and proton radiotherapy for patients with HNSCC.

Lyman-Kutcher-Burman normal tissue complication probability modeling for radiation-induced esophagitis in non-small cell lung cancer patients receiving proton radiotherapy.

PURPOSE: To develop and test an Lyman-Kutcher-Burman (LKB) normal tissue complication probability (NTCP) model to predict radiation-induced esophagitis (RE) in non-small cell lung cancer (NSCLC) patients receiving passive-scattering proton therapy (PSPT). MATERIAL AND METHODS: We retrospectively reviewed 328 NSCLC patients receiving PSPT at our institution. Esophagitis severity was graded by physicians according to the Common Toxicity Criteria for Adverse Events version 3.0, and the primary endpoint was grade ≥2 RE within 6 months from the first treatment. LKB model parameters (n, m, and TD50) were determined using maximum likelihood estimation. Overall performance of the model was quantified by Nagelkerke's R2 and the scaled Brier score. Discriminative ability was evaluated using the area under the receiver operating curve (AUC), and calibration was assessed with the Hosmer-Lemeshow goodness-of-fit test. Bootstrap internal validation was performed to assess the model uncertainty and generalizability. RESULTS: Grade 2-3 RE was observed in 136 (41.5%) patients, and no grade 4-5 RE was reported. The optimal LKB parameters were: n = 0.24, m = 0.51, and TD50 = 44.83 Gy (relative biological effectiveness). The optimism-corrected AUC was 0.783, and the Hosmer-Lemeshow test showed significant agreement between predicted and observed morbidity. Bootstrap validation verified that the model was robust to similar future populations. CONCLUSION: Our LKB NTCP model to predict grade ≥2 RE in NSCLC patients who received PSPT showed good predictive performance and robustness to similar future populations, and a smaller volume effect than the previously observed in photon-treated populations. External validation of the model is warranted.