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.

Executive Summary of Clinical and Technical Guidelines for Esophageal Cancer Proton Beam Therapy From the Particle Therapy Co-Operative Group Thoracic and Gastrointestinal Subcommittees.

Radiation therapy (RT) is an integral component of potentially curative management of esophageal cancer (EC). However, RT can cause significant acute and late morbidity due to excess radiation exposure to nearby critical organs, especially the heart and lungs. Sparing these organs from both low and high radiation dose has been demonstrated to achieve clinically meaningful reductions in toxicity and may improve long-term survival. Accruing dosimetry and clinical evidence support the consideration of proton beam therapy (PBT) for the management of EC. There are critical treatment planning and delivery uncertainties that should be considered when treating EC with PBT, especially as there may be substantial motion-related interplay effects. The Particle Therapy Co-operative Group Thoracic and Gastrointestinal Subcommittees jointly developed guidelines regarding patient selection, treatment planning, clinical trials, and future directions of PBT for EC.

Proton Therapy for Head and Neck Cancer: A 12-Year, Single-Institution Experience.

PURPOSE: To characterize our experience and the disease control and toxicity of proton therapy (PT) for patients with head and neck cancer (HNC). PATIENTS AND METHODS: Clinical outcomes for patients with HNC treated with PT at our institution were prospectively collected in 2 institutional review board-approved prospective studies. Descriptive statistics were used to summarize patient characteristics and outcomes. Overall survival, local-regional control, and disease-free survival were estimated by the Kaplan-Meier method. Treatment-related toxicities were recorded according to the Common Terminology Criteria for Adverse Events (version 4.03) scale. RESULTS: The cohort consisted of 573 patients treated from February 2006 to June 2018. Median patient age was 61 years. Oropharynx (33.3%; n = 191), paranasal sinus (11%; n = 63), and periorbital tissues (11%; n = 62) were the most common primary sites. Patients with T3/T4 or recurrent disease comprised 46% (n = 262) of the cohort. The intent of PT was definitive in 53% (n = 303), postoperative in 37% (n = 211), and reirradiation in 10% (n = 59). Median dose was 66 Gy (radiobiological equivalent). Regarding systemic therapy, 43% had received concurrent (n = 244), 3% induction (n = 19), and 15% (n = 86) had both. At a median follow-up of 2.4 years, 88 patients (15%) had died and 127 (22%) developed disease recurrence. The overall survival, local-regional control, and disease-free survival at 2 and 5 years were, respectively, 87% and 75%, 87% and 78%, and 74% and 63%. Maximum toxicity (acute or late) was grade 3 in 293 patients (51%), grade 2 in 234 patients (41%), and grade 1 in 31 patients (5%). There were 381 acute grade 3 and 190 late grade 3 unique toxicities across 212 (37%) and 150 (26%) patients, respectively. There were 3 late-grade 4 events across 2 patients (0.3%), 2 (0.3%) acute-grade 5, and no (0%) late-grade 5 events. CONCLUSIONS: The overall results from this prospective study of our initial decade of experience with PT for HNC show favorable disease control and toxicity outcomes in a multidisease-site cohort and provide a reference benchmark for future comparison and study.

Transitioning from measurement-based to combined patient-specific quality assurance for intensity-modulated proton therapy.

OBJECTIVE: This study is part of ongoing efforts aiming to transit from measurement-based to combined patient-specific quality assurance (PSQA) in intensity-modulated proton therapy (IMPT). A Monte Carlo (MC) dose-calculation algorithm is used to improve the independent dose calculation and to reveal the beam modeling deficiency of the analytical pencil beam (PB) algorithm. METHODS: A set of representative clinical IMPT plans with suboptimal PSQA results were reviewed. Verification plans were recalculated using an MC algorithm developed in-house. Agreements of PB and MC calculations with measurements that quantified by the γ passing rate were compared. RESULTS: The percentage of dose planes that met the clinical criteria for PSQA (>90% γ passing rate using 3%/3 mm criteria) increased from 71.40% in the original PB calculation to 95.14% in the MC recalculation. For fields without beam modifiers, nearly 100% of the dose planes exceeded the 95% γ passing rate threshold using the MC algorithm. The model deficiencies of the PB algorithm were found in the proximal and distal regions of the SOBP, where MC recalculation improved the γ passing rate by 11.27% (p < 0.001) and 16.80% (p < 0.001), respectively. CONCLUSIONS: The MC algorithm substantially improved the γ passing rate for IMPT PSQA. Improved modeling of beam modifiers would enable the use of the MC algorithm for independent dose calculation, completely replacing additional depth measurements in IMPT PSQA program. For current users of the PB algorithm, further improving the long-tail modeling or using MC simulation to generate the dose correction factor is necessary. ADVANCES IN KNOWLEDGE: We justified a change in clinical practice to achieve efficient combined PSQA in IMPT by using the MC algorithm that was experimentally validated in almost all the clinical scenarios in our center. Deficiencies in beam modeling of the current PB algorithm were identified and solutions to improve its dose-calculation accuracy were provided.

Proton versus photon radiation-induced cell death in head and neck cancer cells.

BACKGROUND: Photon (X-ray) radiotherapy (XRT) kills cells via DNA damage, however, how proton radiotherapy (PRT) causes cell death in head and neck squamous cell carcinoma (HNSCC) is unclear. We investigated mechanisms of HNSCC cell death after XRT versus PRT. METHODS: We assessed type of death in 2 human papillomavirus (HPV)-positive and two HPV-negative cell lines: necrosis and apoptosis (Annexin-V fluorescein isothiocyanate [FITC]); senescence (ß-galactosidase); and mitotic catastrophe (γ-tubulin and diamidino-phenylindole [DAPI]). RESULTS: The XRT-induced or PRT-induced cellular senescence and mitotic catastrophe in all cell lines studied suggested that PRT caused cell death to a greater extent than XRT. After PRT, mitotic catastrophe peaked in HPV-negative and HPV-positive cells at 48 and 72 hours, respectively. No obvious differences were noted in the extent of cell necrosis or apoptosis after XRT versus PRT. CONCLUSION: Under the conditions and in the cell lines reported here, mitotic catastrophe and senescence were the major types of cell death induced by XRT and PRT, and PRT may be more effective.

Characterization of a new physical phantom for testing rigid and deformable image registration.

The purpose of this study was to describe a new user-friendly, low-cost phantom that was developed to test the accuracy of rigid and deformable image registration (DIR) systems and to demonstrate the functional efficacy of the new phantom. The phantom was constructed out of acrylic and includes a variety of inserts that simulate different tissue shapes and properties. It can simulate deformations and location changes in patient anatomy by changing the rotations of both the phantom and the inserts. CT scans of this phantom were obtained and used to test the rigid and deformable registration accuracy of the Velocity software. Eight rotation and translation scenarios were used to test the rigid registration accuracy, and 11 deformation scenarios were used to test the DIR accuracy. The mean rotation accuracies in the X-Y (axial) and X-Z (coronal) planes were 0.50° and 0.13°, respectively. The mean translation accuracy was 1 mm in both the X and Y direction and was tested in soft tissue and bone. The DIR accuracies for soft tissue and bone were 0.93 (mean Dice similarity coefficient), 8.3 and 4.5 mm (mean Hausdouff distance), 0.95 and 0.79 mm (mean distance), and 1.13 and 1.12 (mean volume ratio) for soft tissue content (DTE oil) and bone, respectively. The new phantom has a simple design and can be constructed at a low cost. This phantom will allow DIR systems to be effectively and efficiently verified to ensure system performance.

Multiple-CT optimization of intensity-modulated proton therapy - Is it possible to eliminate adaptive planning?

BACKGROUND AND PURPOSE: We hypothesized that a plan's robustness to anatomical changes can be improved by optimizing with multiple CT scans of a patient. The purpose of this study was to determine whether an intensity modulated proton therapy (IMPT) plan could be developed to meet dose criteria on both planning and adaptive CT plans. MATERIAL AND METHODS: Eight lung cancer patients who underwent adaptive IMPT were retrospectively selected. Each patient had two CTs: a primary planning CT (PCT) and an adaptive planning CT (ACT), and IMPT plans associated with the scans. PCT and ACT were then used in combination to optimize one plan (MCT plan). The doses to the target and organs at risk from the PCT plan, ACT plan, P-ACT plan (PCT plan calculated on ACT data), and MCT plans calculated on both CTs were compared. RESULTS: The MCT plan maintained the D95% on both CTs (mean, 65.99 Gy on PCT and 66.02 Gy on ACT). Target dose coverage on ACT was significantly better with the MCT plan than with the P-ACT plan (p = 0.01). MCT plans had slightly higher lung V20 (0.6%, p = 0.02) than did PCT plans. The various plans showed no statistically significant difference in heart and spinal cord dose. CONCLUSIONS: The results of this study indicate that an IMPT plan can meet the dose criteria on both PCT and ACT, and that MCT optimization can improve the plan's robustness to anatomical change.

Synchrotron-Based Pencil Beam Scanning Nozzle with an Integrated Mini-Ridge Filter: A Dosimetric Study to Optimize Treatment Delivery.

A mini-ridge filter is often used to widen the Bragg peak in the longitudinal direction at low energies but not high energies. To facilitate the clinical use of a mini-ridge filter, we performed a planning study for the feasibility of a mini-ridge filter as an integral part of the synchrotron nozzle (IMRF). Dose models with and without IMRF were commissioned in a commercial Treatment planning system (TPS). Dosimetric characteristics in a homogenous water phantom were compared between plans with and without IMRF for a fixed spread-out Bragg peak width of 4 cm with distal ranges varying from 8 to 30 g/cm². Six clinical cases were then used to compare the plan quality between plans. The delivery efficiency was also compared between plans in both the phantom and the clinical cases. The Bragg peak width was increased by 0.18 cm at the lowest energy and by only about 0.04 cm at the highest energy. The IMRF increased the spot size (σ) by up to 0.1 cm at the lowest energy and by only 0.02 cm at the highest energy. For the phantom, the IMRF negligibly affected dose at high energies but increased the lateral penumbra by up to 0.12 cm and the distal penumbra by up to 0.06 cm at low energies. For the clinical cases, the IMRF slightly increased dose to the organs at risk. However, the beam delivery time was reduced from 18.5% to 47.1% for the lung, brain, scalp, and head and neck cases, and dose uniformities of target were improved up to 2.9% for these cases owing to the reduced minimum monitor unit effect. In conclusion, integrating a mini-ridge filter into a synchrotron nozzle is feasible for improving treatment efficiency without significantly sacrificing the plan quality.

Life years lost attributable to late effects after radiotherapy for early stage Hodgkin lymphoma: The impact of proton therapy and/or deep inspiration breath hold.

BACKGROUND AND PURPOSE: Due to the long life expectancy after treatment, the risk of late effects after radiotherapy (RT) is of particular importance for patients with Hodgkin lymphoma (HL). Both deep inspiration breath hold (DIBH) and proton therapy have been shown to reduce the dose to normal tissues for mediastinal HL, but the impact of these techniques in combination is unknown. The purpose of this study was to compare the life years lost (LYL) attributable to late effects after RT for mediastinal HL using intensity modulated radiation therapy (IMRT) in free breathing (FB) and DIBH, and proton therapy in FB and DIBH. MATERIALS AND METHODS: Plans for each technique were created for 22 patients with HL. Doses were extracted and the risk of late effects and LYL were estimated. RESULTS: We found that the use of DIBH, proton therapy, and the combination significantly reduced the LYL compared to IMRT in FB. The lowest LYL was found for proton therapy in DIBH. However, when IMRT in DIBH was compared to proton therapy in FB, no significant difference was found. CONCLUSIONS: Patient-specific plan comparisons should be used to select the optimal technique when comparing IMRT in DIBH and proton therapy in FB.

Human papillomavirus status and the relative biological effectiveness of proton radiotherapy in head and neck cancer cells.

BACKGROUND: Human papillomavirus (HPV)-positive oropharyngeal carcinomas response better to X-ray therapy (XRT) than HPV-negative disease. Whether HPV status influences the sensitivity of head and neck cancer cells to proton therapy or the relative biological effectiveness (RBE) of protons versus XRT is unknown. METHODS: Clonogenic survival was used to calculate the RBE; immunocytochemical analysis and neutral comet assay were used to evaluate unrepaired DNA double-strand breaks. RESULTS: HPV-positive cells were more sensitive to protons and the unrepaired double-strand breaks were more numerous in HPV-positive cells than in HPV-negative cells (p < .001). Protons killed more cells than did XRT at all fraction sizes (all RBEs > 1.06). Cell line type and radiation fraction size influenced the RBE. CONCLUSION: HPV-positive cells were more sensitive to protons than HPV-negative cells maybe through the effects of HPV on DNA damage and repair. The RBE for protons depends more on cell type and fraction size than on HPV status. © 2016 Wiley Periodicals, Inc. Head Neck 39: 708-715, 2017.

Dosimetric Characteristics of a Two-Dimensional Diode Array Detector Irradiated with Passively Scattered Proton Beams.

PURPOSE: To evaluate the dosimetric characteristics of a two-dimensional (2D) diode array detector irradiated with passively scattered proton beams. MATERIALS AND METHODS: A diode array detector, MapCHECK (Model 1175, Sun Nuclear, Melbourne, FL, USA) was characterized in passive-scattered proton beams. The relative sensitivity of the diodes and absolute dose calibration were determined using a 250 MeV beam. The pristine Bragg curves (PBCs) measured by MapCHECK diodes were compared with those of an ion chamber using a range shift method. The water-equivalent thickness (WET) of the diode array detector's intrinsic buildup also was determined. The inverse square dependence, linearity, and other proton dosimetric quantities measured by MapCHECK were also compared with those of the ion chambers. The change in the absolute dose response of the MapCHECK as a function of accumulated radiation dose was used as an indicator of radiation damage to the diodes. 2D dose distribution with and without the compensator were measured and compared with the treatment planning system (TPS) calculations. RESULTS: The WET of the MapCHECK diode's buildup was determined to be 1.7 cm. The MapCHECK-measured PBC were virtually identical to those measured by a parallel-plate ion chamber for 160, 180, and 250 MeV proton beams. The inverse square results of the MapCHECK were within ±0.4% of the ion chamber results. The linearity of MapCHECK results was within 1% of those from the ion chamber as measured in the range between 10 and 300 MU. All other dosimetric quantities were within 1.3% of the ion chamber results. The 2D dose distributions for non-clinical fields without compensator and the patient treatment fields with the compensator were consistent with the TPS results. The absolute dose response of the MapCHECK was changed by 7.4% after an accumulated dose increased by 170 Gy. CONCLUSIONS: The MapCHECK is a convenient and useful tool for 2D dose distribution measurements using passively scattered proton beams. Variations in MapCHECK's dose response with increasing levels of total accumulated radiation dose should be carefully monitored.

A single-field integrated boost treatment planning technique for spot scanning proton therapy.

PURPOSE: Intensity modulated proton therapy (IMPT) plans are normally generated utilizing multiple field optimization (MFO) techniques. Similar to photon based IMRT, MFO allows for the utilization of a simultaneous integrated boost in which multiple target volumes are treated to discrete doses simultaneously, potentially improving plan quality and streamlining quality assurance and treatment delivery. However, MFO may render plans more sensitive to the physical uncertainties inherent to particle therapy. Here we present clinical examples of a single-field integrated boost (SFIB) technique for spot scanning proton therapy based on single field optimization (SFO) treatment-planning techniques. METHODS AND MATERIALS: We designed plans of each type for illustrative patients with central nervous system (brain and spine), prostate and head and neck malignancies. SFIB and IMPT plans were constructed to deliver multiple prescription dose levels to multiple targets using SFO or MFO, respectively. Dose and fractionation schemes were based on the current clinical practice using X-ray IMRT in our clinic. For inverse planning, dose constraints were employed to achieve the desired target coverage and normal tissue sparing. Conformality and inhomogeneity indices were calculated to quantify plan quality. We also compared the worst-case robustness of the SFIB, sequential boost SFUD, and IMPT plans. RESULTS: The SFIB technique produced more conformal dose distributions than plans generated by sequential boost using a SFUD technique (conformality index for prescription isodose levels; 0.585 ± 0.30 vs. 0.435 ± 0.24, SFIB vs. SFUD respectively, Wilcoxon matched-pair signed rank test, p < 0.01). There was no difference in the conformality index between SFIB and IMPT plans (0.638 ± 0.27 vs. 0.633 ± 0.26, SFIB vs. IMPT, respectively). Heterogeneity between techniques was not significantly different. With respect to clinical metrics, SFIB plans proved more robust than the corresponding IMPT plans. CONCLUSIONS: SFIB technique for scanning beam proton therapy (SSPT) is now routinely employed in our clinic. The SFIB technique is a natural application of SFO and offers several advantages over SFUD, including more conformal plans, seamless treatment delivery and more efficient planning and QA. SFIB may be more robust than IMPT and has been the treatment planning technique of choice for some patients.