Preclinical Ultra-High Dose Rate (FLASH) Proton Radiation Therapy System for Small Animal Studies.

Purpose: Animal studies with ultrahigh dose-rate radiation therapy (FLASH, >40 Gy/s) preferentially spare normal tissues without sacrificing antitumor efficacy compared with conventional dose-rate radiation therapy (CONV). At the University of Washington, we developed a cyclotron-generated preclinical scattered proton beam with FLASH dose rates. We present the technical details of our FLASH radiation system and preliminary biologic results from whole pelvis radiation. Methods and Materials: A Scanditronix MC50 compact cyclotron beamline has been modified to produce a 48.7 MeV proton beam at dose rates between 0.1 and 150 Gy/s. The system produces a 6 cm diameter scattered proton beam (flat to ± 3%) at the target location. Female C57BL/6 mice 5 to 6 weeks old were used for all experiments. To study normal tissue effects in the distal colon, mice were irradiated using the entrance region of the proton beam to the whole pelvis, 18.5 Gy at different dose rates: control, CONV (0.6-1 Gy/s) and FLASH (50-80 Gy/s). Survival was monitored daily and EdU (5-ethynyl-2´-deoxyuridine) staining was performed at 24- and 96-hours postradiation. Cleaved caspase-3 staining was performed 24-hours postradiation. To study tumor control, allograft B16F10 tumors were implanted in the right flank and received 18 Gy CONV or FLASH proton radiation. Tumor growth and survival were monitored. Results: After 18.5 Gy whole pelvis radiation, survival was 100% in the control group, 0% in the CONV group, and 44% in the FLASH group (P < .01). EdU staining showed cell proliferation was significantly higher in the FLASH versus CONV group at both 24-hours and 96-hours postradiation in the distal colon, although both radiation groups showed decreased proliferation compared with controls (P < .05). Lower cleaved caspase-3 staining was seen in the FLASH versus conventional group postradiation (P < .05). Comparable flank tumor control was observed in the CONV and FLASH groups. Conclusions: We present our preclinical FLASH proton radiation system and biologic results showing improved survival after whole pelvis radiation, with equivalent tumor control.

Extreme coronary radiation doses from intravascular brachytherapy.

PURPOSE: To evaluate coronary artery integrity after very high radiation doses from intravascular brachytherapy (IVBT) in the setting of source asymmetry. METHODS: Ten patients treated for right coronary artery (RCA) in-stent restenosis (ISR) between 2017 and 2021 and for whom follow-up angiograms were available were identified from departmental records. Procedural angiograms, taken to document source position, were used to estimate vascular wall doses. The 2.5 mm proximal source marker was used to estimate the distance from source center to the media and adventitia. Distances were converted to dose (Gy) using the manufacturers' dose fall-off table, measured in water. Follow-up films were scrutinized for any sign of late vascular damage. RESULTS: The average minimal distance from catheter center to the adjacent media and the adventitia was 0.9 mm (±0.2) mm and 1.4 mm (±0.2), respectively. The average maximum media and adventitial doses adjacent to the source were 75 Gy (±26) and 39 Gy (±14), respectively. Follow-up angiograms were available from 0.6 years to 3.9 years following IVBT (median: 1.6 years). No IVBT-treated vascular segment showed signs of degeneration, dissection or aneurysm. CONCLUSION: IVBT vascular wall doses are frequently far higher than prescribed. The lack of complications in this unselected group of patients gives a modicum of reassurance that raising the prescription dose is unlikely to lead to a sudden appearance of complications.

Effects of tissue heterogeneity and comparisons of collapsed cone and Monte Carlo fast neutron patient dosimetry using the University of Washington clinical neutron therapy system (CNTS).

Fast neutron therapy is a high linear energy transfer (LET) radiation treatment modality offering advantages over low LET radiations. Multileaf collimator technology reduces normal-tissue dose (toxicity) and makes neutron therapy more comparable to MV x-ray treatments. Published clinical-trial and other experiences with fast neutron therapy are reported. Early comparative studies failed to consider differences in target-dose spatial conformality between x-ray and neutron treatments, which is especially important for organs-at-risk close to tumor targets. Treatments planning systems (TPS) for high-energy neutrons lag behind TPS tools for MV x-rays, creating challenges for comparative studies of clinical outcomes. A previously published Monte Carlo model of the University of Washington (UW) Clinical Neutron Therapy System (CNTS) is refined and integrated with the RayStation TPS as an external dose planning/verification tool. The collapsed cone (CC) dose calculations in the TPS are based on measured dose profiles and output factors in water, with the absolute dose determined using a tissue-equivalent ionization chamber. For comparison, independent (external) Monte Carlo simulation computes dose on a voxel-by-voxel basis using an atlas that maps Hounsfield Unit (HU) numbers to elemental composition and density. Although the CC algorithm in the TPS accurately computes neutron dose to water compared to Monte Carlo calculations, calculated dose to water differs from bone or tissue depending largely on hydrogen content. Therefore, the elemental composition of tissue and bone, rather than the material or electron density, affects fast neutron dose. While the CC algorithm suffices for reproducible patient dosimetry in fast neutron therapy, adopting methods that consider tissue heterogeneity would enhance patient-specific neutron dose accuracy relative to national standards for other types of ionizing radiation. Corrections for tissue composition have a significant impact on absolute dose and the relative biological effectiveness (RBE) of neutron treatments compared to other radiation types (MV x-rays, protons, and carbon ions).

Increased prescription dose for large vessel intravascular brachytherapy.

BACKGROUND: Most randomized studies testing the effectiveness of IVBT were limited to vessels less than 4 mm diameter. In fact, it is now common to treat vessels larger than 4 mm. Accordingly, the authors instituted a prescription dose increase to 34 Gy at 2 mm from source center for vessels greater than 4.0 mm. The increase in prescription dose to 34 Gy at 2 mm from center is substantial, being 50% higher than the conventional maximum of 23 Gy. AIM: To take a close look at group of patients treated to 34 Gy, and for whom follow-up angiograms are available. METHODS: Ten patients treated for ISR with a prescription dose of 34 Gy and for whom follow-up angiograms were available were studied. Beta-radiation brachytherapy was performed with a Novoste Beta-Cath System using a strontium-90 (beta) source (Best Vascular, Springfield, VA). Source lengths of 40 or 60 mm were used. A dose of 34 Gy was prescribed at 2 mm from the source center. RESULTS: Patients were re-catheterized from 2 to 21 months (median: 16 months) following IVBT, all for symptoms suggested of restenosis. All patients had some degree of ISR of the target vessel, but no IVBT-treated vascular segment showed angiographic signs of degeneration, dissection or aneurysm. CONCLUSION: The authors' clinical impression, along with detailed review of the 10 cases, suggest that using a 34 Gy prescription dose at 2 mm from source center does not result in increased toxicity.

Scattering kernels for fast neutron therapy treatment planning.

The University of Washington (UW) Clinical Neutron Therapy System (CNTS) has been used to treat over 3300 patients. Treatment planning for these patients is currently performed using an MV x-ray model in Pinnacle® adapted to fit measurements of fast neutron output factors, wedge factors, depth-dose and lateral profiles. While this model has provided an adequate representation of the CNTS for 3D conformal treatment planning, later versions of Pinnacle did not allow for isocentric gantry rotation machines with a source-to-axis distance of 150 cm. This restriction limited the neutron model to version 9.0 while the photon and electron treatment planning at the UW had moved on to newer versions. Also, intensity modulated neutron therapy (IMNT) is underdevelopment at the UW, and the Pinnacle neutron model developed cannot be used for inverse treatment planning. We have used the MCNP6 Monte Carlo code system to develop Collapsed Cone (CC) and Singular Value Decomposition (SVD) neutron scattering kernels suitable for integration into the RayStation treatment planning system. Kernels were generated for monoenergetic neutrons with energies ranging from 1 keV to 51 MeV, i.e. the energy range most relevant to the CNTS. Percent depth dose (PDD) profiles computed in RayStation for the CC and SVD kernels are in excellent agreement with each other for depths beyond the beam's dose build-up region (depths greater than about 1.7 cm) for open 2.8 × 2.8 cm2, 10.3 × 10.3 cm2, and 28.8 × 32.8 cm2 fields. Lateral profiles at several depths, as well as the PDD, calculated using the CC kernels in RayStation for the full CNTS energy spectrum pass a 3%/3 mm gamma test for field sizes of 2.8 × 2.8 cm2, 10.0 × 10.3 cm2, and 28.8 × 32.8 cm2.

Reducing Cardiac Radiation Dose From Breast Cancer Radiation Therapy With Breath Hold Training and Cognitive Behavioral Therapy.

The delivery of radiation therapy shares many of the challenges encountered in imaging procedures. As in imaging, such as MRI, organ motion must be reduced to a minimum, often for lengthy time periods, to effectively target the tumor during imaging-guided therapy while reducing radiation dose to nearby normal tissues. For patients, radiation therapy is frequently a stress- and anxiety-provoking medical procedure, evoking fear from negative perceptions about irradiation, confinement from immobilization devices, claustrophobia, unease with equipment, physical discomfort, and overall cancer fear. Such stress can be a profound challenge for cancer patients' emotional coping and tolerance to treatment, and particularly interferes with advanced radiation therapy procedures where active, complex and repetitive high-level cooperation is often required from the patient.In breast cancer, the most common cancer in women worldwide, radiation therapy is an indispensable component of treatment to improve tumor control and outcome in both breast-conserving therapy for early-stage disease and in advanced-stage patients. High technological complexity and high patient cooperation is required to mitigate the known cardiac toxicity and mortality from breast cancer radiation by reducing the unintended radiation dose to the heart from left breast or left chest wall irradiation. To address this, radiation treatment in daily deep inspiration breath hold (DIBH), to create greater distance between the treatment target and the heart, is increasingly practiced. While holding the promise to decrease cardiac toxicity, DIBH procedures often augment patients' baseline stress and anxiety reaction toward radiation treatment. Patients are often overwhelmed by the physical and mental demands of daily DIBH, including the nonintuitive timed and sustained coordination of abdominal thoracic muscles for prolonged breath holding.While technologies, such as DIBH, have advanced to millimeter-precision in treatment delivery and motion tracking, the "human factor" of patients' ability to cooperate and perform has been addressed much less. Both are needed to optimally deliver advanced radiation therapy with minimized normal tissue effects, while alleviating physical and cognitive distress during this challenging phase of breast cancer therapy.This article discusses physical training and psychotherapeutic integrative health approaches, applied to radiation oncology, to leverage and augment the gains enabled by advanced technology-based high-precision radiation treatment in breast cancer. Such combinations of advanced technologies with training and cognitive integrative health interventions hold the promise to provide simple feasible and low-cost means to improve patient experience, emotional outcomes and quality of life, while optimizing patient performance for advanced imaging-guided treatment procedures - paving the way to improve cardiac outcomes in breast cancer survivors.

Dosimetric characteristics of the University of Washington Clinical Neutron Therapy System.

The University of Washington (UW) Clinical Neutron Therapy System (CNTS), which generates high linear energy transfer fast neutrons through interactions of 50.5 MeV protons incident on a Be target, has depth-dose characteristics similar to 6 MV x-rays. In contrast to the fixed beam angles and primitive blocking used in early clinical trials of neutron therapy, the CNTS has a gantry with a full 360° of rotation, internal wedges, and a multi-leaf collimator (MLC). Since October of 1984, over 3178 patients have received conformal neutron therapy treatments using the UW CNTS. In this work, the physical and dosimetric characteristics of the CNTS are documented through comparisons of measurements and Monte Carlo simulations. A high resolution computed tomography scan of the model 17 ionization chamber (IC-17) has also been used to improve the accuracy of simulations of the absolute calibration geometry. The response of the IC-17 approximates well the kinetic energy released per unit mass (KERMA) in water for neutrons and photons for energies from a few tens of keV up to about 20 MeV. Above 20 MeV, the simulated model 17 ion chamber response is 20%-30% higher than the neutron KERMA in water. For CNTS neutrons, simulated on- and off-axis output factors in water match measured values within ~2% ± 2% for rectangular and irregularly shaped field with equivalent square areas ranging in a side dimension from 2.8 cm to 30.7 cm. Wedge factors vary by less than 1.9% of the measured dose in water for clinically relevant field sizes. Simulated tissue maximum ratios in water match measured values within 3.3% at depths up to 20 cm. Although the absorbed dose for water and adipose tissue are within 2% at a depth of 1.7 cm, the absorbed dose in muscle and bone can be as much as 12 to 40% lower than the absorbed dose in water. The reported studies are significant from a historical perspective and as additional validation of a new tool for patient quality assurance and as an aid in ongoing efforts to clinically implement advanced treatment techniques, such as intensity modulated neutron therapy, at the UW.

4D computed tomography scans for conformal thoracic treatment planning: is a single scan sufficient to capture thoracic tumor motion?

Four dimensional computed tomography (4DCT) scans are routinely used in radiation therapy to determine the internal treatment volume for targets that are moving (e.g. lung tumors). The use of these studies has allowed clinicians to create target volumes based upon the motion of the tumor during the imaging study. The purpose of this work is to determine if a target volume based on a single 4DCT scan at simulation is sufficient to capture thoracic motion. Phantom studies were performed to determine expected differences between volumes contoured on 4DCT scans and those on the evaluation CT scans (slow scans). Evaluation CT scans acquired during treatment of 11 patients were compared to the 4DCT scans used for treatment planning. The images were assessed to determine if the target remained within the target volume determined during the first 4DCT scan. A total of 55 slow scans were compared to the 11 planning 4DCT scans. Small differences were observed in phantom between the 4DCT volumes and the slow scan volumes, with a maximum of 2.9%, that can be attributed to minor differences in contouring and the ability of the 4DCT scan to adequately capture motion at the apex and base of the motion trajectory. Larger differences were observed in the patients studied, up to a maximum volume difference of 33.4%. These results demonstrate that a single 4DCT scan is not adequate to capture all thoracic motion throughout treatment.

Does Neutron Radiation Therapy Potentiate an Immune Response to Merkel Cell Carcinoma?

BACKGROUND: Merkel cell carcinoma (MCC) is a rare and aggressive cutaneous malignancy. In the advanced setting, MCC is often treated with immune checkpoint inhibitors such as anti-PD-1/PD-L1 antibodies. X-ray radiation therapy (XRT) is commonly used for palliation. There is an unmet need for new treatment options in patients progressing on immunotherapy and XRT. We present 2 patients with progressive MCC who were successfully treated with high linear energy transfer neutron radiation therapy (NRT). CLINICAL OBSERVATIONS: Patient A, an 85-year-old white male with chronic lymphocytic leukemia had progressive MCC with multiple tumors on the face despite prior XRT and ongoing treatment with pembrolizumab. The 5 most symptomatic lesions were treated with a short course of NRT (2 × 3 Gy) while continuing pembrolizumab. All irradiated facial lesions demonstrated a complete response 2 weeks after NRT. Remarkably, an additional 4 lesions located outside the NRT fields also completely resolved. Patient B, a 78-year-old white male with no immunosuppressive condition had recurrent MCC in the scalp and bilateral cervical nodes. The painful, ulcerative tumors on his scalp were progressing despite multiple courses of XRT and multiple immunotherapy regimens, including pembrolizumab. He was treated with NRT (16-18 Gy) to the scalp and had a complete response with successful palliation. While his disease subsequently progressed outside the NRT fields, the response to NRT bridged him to receive further investigational immunotherapies, and he remains disease free 3 years later. CONCLUSION: Short courses of high linear energy transfer particle therapy deserve consideration as a promising modality for local tumor control in XRT refractory tumors. The out-of-field response suggests that NRT has potential for synergizing with immunotherapy. While more data are required to identify optimal NRT parameters, the NRT dose that potentiates an antitumor immune response appears to be well below organ-at-risk tolerance.

Tumor radiomic heterogeneity: Multiparametric functional imaging to characterize variability and predict response following cervical cancer radiation therapy.

BACKGROUND: Robust approaches to quantify tumor heterogeneity are needed to provide early decision support for precise individualized therapy. PURPOSE: To conduct a technical exploration of longitudinal changes in tumor heterogeneity patterns on dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI), diffusion-weighted imaging (DWI) and FDG positron emission tomography / computed tomography (PET/CT), and their association to radiation therapy (RT) response in cervical cancer. STUDY TYPE: Prospective observational study with longitudinal MRI and PET/CT pre-RT, early-RT (2 weeks), and mid-RT (5 weeks). POPULATION: Twenty-one FIGO IB2 -IVA cervical cancer patients receiving definitive external beam RT and brachytherapy. FIELD STRENGTH/SEQUENCE: 1.5T, precontrast axial T1 -weighted, axial and sagittal T2 -weighted, sagittal DWI (multi-b values), sagittal DCE MRI (<10 sec temporal resolution), postcontrast axial T1 -weighted. ASSESSMENT: Response assessment 1 month after completion of treatment by a board-certified radiation oncologist from manually delineated tumor volume changes. STATISTICAL TESTS: Intensity histogram (IH) quantiles (DCE SI10% and DWI ADC10% , FDG-PET SUVmax ) and distribution moments (mean, variance, skewness, kurtosis) were extracted. Differences in IH features between timepoints and modalities were evaluated by Skillings-Mack tests with Holm's correction. Area under receiver-operating characteristic curve (AUC) and Mann-Whitney testing was performed to discriminate treatment response using IH features. RESULTS: Tumor IH means and quantiles varied significantly during RT (SUVmean : ↓28-47%, SUVmax : ↓30-59%, SImean : ↑8-30%, SI10% : ↑8-19%, ADCmean : ↑16%, P < 0.02 for each). Among IH heterogeneity features, FDG-PET SUVCoV (↓16-30%, P = 0.011) and DW-MRI ADCskewness decreased (P = 0.001). FDG-PET SUVCoV was higher than DCE-MRI SICoV and DW-MRI ADCCoV at baseline (P < 0.001) and 2 weeks (P = 0.010). FDG-PET SUVkurtosis was lower than DCE-MRI SIkurtosis and DW-MRI ADCkurtosis at baseline (P = 0.001). Some IH features appeared to associate with favorable tumor response, including large early RT changes in DW-MRI ADCskewness (AUC = 0.86). DATA CONCLUSION: Preliminary findings show tumor heterogeneity was variable between patients, modalities, and timepoints. Radiomic assessment of changing tumor heterogeneity has the potential to personalize treatment and power outcome prediction. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2018;47:1388-1396.

Biological and dosimetric characterisation of spatially fractionated proton minibeams.

The biological effectiveness of proton beams varies with depth, spot size and lateral distance from the beam central axis. The aim of this work is to incorporate proton relative biological effectiveness (RBE) and equivalent uniform dose (EUD) considerations into comparisons of broad beam and highly modulated proton minibeams. A Monte Carlo model of a small animal proton beamline is presented. Dose and variable RBE is calculated on a per-voxel basis for a range of energies (30-109 MeV). For an open beam, the RBE values at the beam entrance ranged from 1.02-1.04, at the Bragg peak (BP) from 1.3 to 1.6, and at the distal end of the BP from 1.4 to 2.0. For a 50 MeV proton beam, a minibeam collimator designed to produce uniform dose at the depth of the BP peak, had minimal impact on the open beam RBE values at depth. RBE changes were observed near the surface when the collimator was placed flush with the irradiated object, due to a higher neutron contribution derived from proton interactions with the collimator. For proton minibeams, the relative mean RBE weighted entrance dose (RWD) was ~25% lower than the physical mean dose. A strong dependency of the EUD with fraction size was observed. For 20 Gy fractions, the EUD varied widely depending on the radiosensitivity of the cells. For radiosensitive cells, the difference was up to ~50% in mean dose and ~40% in mean RWD and the EUD trended towards the valley dose rather than the mean dose. For comparative studies of uniform dose with spatially fractionated proton minibeams, EUD derived from a per-voxel RWD distribution is recommended for biological assessments of reproductive cell survival and related endpoints.

Functional lung avoidance and response-adaptive escalation (FLARE) RT: Multimodality plan dosimetry of a precision radiation oncology strategy.

PURPOSE: Nonsmall cell lung cancer (NSCLC) patient radiation therapy (RT) is planned without consideration of spatial heterogeneity in lung function or tumor response. We assessed the dosimetric and clinical feasibility of functional lung avoidance and response-adaptive escalation (FLARE) RT to reduce dose to [99m Tc]MAA-SPECT/CT perfused lung while redistributing an escalated boost dose within [18 F]FDG-PET/CT-defined biological target volumes (BTV). METHODS: Eight stage IIB-IIIB NSCLC patients underwent FDG-PET/CT and MAA-SPECT/CT treatment planning scans. Perfused lung objectives were derived from scatter/collimator/attenuation-corrected MAA-SPECT uptake relative to ITV-subtracted lung to maintain < 20 Gy mean lung dose (MLD). Prescriptions included 60 Gy to the planning target volume (PTV) and concomitant boost of 74 Gy mean to biological target volumes (BTV = GTV + PET gradient segmentation) scaled to each BTV voxel by relative FDG-PET SUV. Dose-painting-by-numbers prescriptions were integrated into commercial treatment planning systems via uptake threshold discretization. Dose constraints for lung, heart, cord, and esophagus were defined. FLARE RT plans were optimized with volumetric modulated arc therapy (VMAT), proton pencil beam scanning (PBS) with 3%-3 mm robust optimization, and combination of PBS (avoidance) plus VMAT (escalation). The high boost dose region was evaluated within a standardized SUVpeak structure. FLARE RT plans were compared to reference VMAT plans. Linear regression between radiation dose to BTV and normalized FDG PET SUV at every voxel was conducted, from which Pearson linear correlation coefficients and regression slopes were extracted. Spearman rank correlation coefficients were estimated between radiation dose to lung and normalized SPECT uptake. Dosimetric differences between treatment modalities were evaluated by Friedman nonparametric paired test with multiple sampling correction. RESULTS: No unacceptable violations of PTV and normal tissue objectives were observed in 24 FLARE RT plans. Compared to reference VMAT plans, FLARE VMAT plans achieved a higher mean dose to BTV (73.7 Gy 98195. 61.3 Gy), higher mean dose to SUVpeak (89.7 Gy vs. 60.8 Gy), and lower mean dose to highly perfused lung (7.3 Gy vs. 14.9 Gy). These dosimetric gains came at the expense of higher mean heart dose (9.4 Gy vs. 5.8 Gy) and higher maximum cord dose (50.1 Gy vs. 44.6 Gy) relative to the reference VMAT plans. Between FLARE plans, FLARE VMAT achieved higher dose to the SUVpeak ROI than FLARE PBS (89.7 Gy vs. 79.2 Gy, P = 0.01), while FLARE PBS delivered lower dose to lung than FLARE VMAT (11.9 Gy vs. 15.6 Gy, P < 0.001). Voxelwise linear dose redistribution slope between BTV dose and FDG PET uptake was higher in magnitude for FLARE PBS + VMAT (0.36 Gy per %SUVmax ) compared to FLARE VMAT (0.27 Gy per %SUVmax ) or FLARE PBS alone (0.17 Gy per %SUVmax ). CONCLUSIONS: FLARE RT is clinically feasible with VMAT and PBS. A combination of PBS for functional lung avoidance and VMAT for FDG PET dose escalation balanced target and normal tissue objective tradeoffs. These results provide a technical platform for testing of FLARE RT safety and efficacy within a precision radiation oncology trial.

Iterative volume morphing and learning for mobile tumor based on 4DCT.

During image-guided cancer radiation treatment, three-dimensional (3D) tumor volumetric information is important for treatment success. However, it is typically not feasible to image a patient's 3D tumor continuously in real time during treatment due to concern over excessive patient radiation dose. We present a new iterative morphing algorithm to predict the real-time 3D tumor volume based on time-resolved computed tomography (4DCT) acquired before treatment. An offline iterative learning process has been designed to derive a target volumetric deformation function from one breathing phase to another. Real-time volumetric prediction is performed to derive the target 3D volume during treatment delivery. The proposed iterative deformable approach for tumor volume morphing and prediction based on 4DCT is innovative because it makes three major contributions: (1) a novel approach to landmark selection on 3D tumor surfaces using a minimum bounding box; (2) an iterative morphing algorithm to generate the 3D tumor volume using mapped landmarks; and (3) an online tumor volume prediction strategy based on previously trained deformation functions utilizing 4DCT. The experimental performance showed that the maximum morphing deviations are 0.27% and 1.25% for original patient data and artificially generated data, which is promising. This newly developed algorithm and implementation will have important applications for treatment planning, dose calculation and treatment validation in cancer radiation treatment.

Collimator design for spatially-fractionated proton beams for radiobiology research.

Preclinical and translational research is an imperative to improve the efficacy of proton radiotherapy. We present a feasible and practical method to produce spatially-modulated proton beams for cellular and small animal research for clinical and research facilities. The University of Washington (UW) 50.5 MeV proton research beamline hosting a brass collimation system was modeled using Monte Carlo simulations. This collimator consisted of an array of 2 cm long slits to cover an area of 2 × 2 cm(2). To evaluate the collimator design effects on dose rate, valley dose and the peak-to-valley dose ratios (PVDR) the following parameters were varied; slit width (0.1-1.0 mm), peak center-to-center distance (1-3 mm), collimator thickness (1-7 cm) and collimator location along the beam axis. Several combinations of slit widths and 1 mm spacing achieved uniform dose at the Bragg peak while maintaining spatial modulation on the beam entrance. A more detailed analysis was carried out for the case of a slit width of 0.3 mm, peak center-to-center distance of 1 mm, a collimator thickness of 5 cm and with the collimator flush against the water phantom. The dose rate at 5 mm depth dropped relative to an open field by a factor of 12 and produced a PVDR of 10.1. Technical realization of proton mini-beams for radiobiology small animal research is demonstrated to be feasible. It is possible to obtain uniform dose at depth while maintaining reasonable modulation at shallower depths near the beam entrance. While collimator design is important the collimator location has a strong influence on the entrance region PVDRs and on dose rate. These findings are being used to manufacture a collimator for installation on the UW cyclotron proton beam nozzle. This collimator will enable comparative studies on the radiobiological efficacy of x-rays and proton beams.

Measuring total liver function on sulfur colloid SPECT/CT for improved risk stratification and outcome prediction of hepatocellular carcinoma patients.

BACKGROUND: Assessment of liver function is critical in hepatocellular carcinoma (HCC) patient management. We evaluated parameters of [(99m)Tc] sulfur colloid (SC) SPECT/CT liver uptake for association with clinical measures of liver function and outcome in HCC patients. METHODS: Thirty patients with HCC and variable Child-Turcotte-Pugh scores (CTP A5-C10) underwent [(99m)Tc]SC SPECT/CT scans for radiotherapy planning. Gross tumor volume (GTV), anatomic liver volume (ALV), and spleen were contoured on CT. SC SPECT image parameters include threshold-based functional liver volumes (FLV) relative to ALV, mean liver-to-spleen uptake ratio (L/Smean), and total liver function (TLF) ratio derived from the product of FLV and L/Smean. Optimal SC uptake thresholds were determined by ROC analysis for maximizing CTP classification accuracy. Image metrics were tested for rank correlation to composite scores and clinical liver function parameters. Image parameters of liver function were tested for association to overall survival with Cox proportional hazard regression. RESULTS: Optimized thresholds on SC SPECT were 58 % of maximum uptake for FLV, 38 % for L/Smean, and 58 % for TLF. TLF produced the highest CTP classification accuracy (AUC = 0.93) at threshold of 0.35 (sensitivity = 0.88, specificity = 0.86). Higher TLF was associated with lower CTP score: TLFA = 0.6 (0.4-0.8) versus TLFB = 0.2 (0.1-0.3), p < 10(-4). TLF was rank correlated to albumin and bilirubin (|R| > 0.63). Only TLF >0.30 was independently associated with overall survival when adjusting for CTP class (HR = 0.12, 95 % CI = 0.02-0.58, p = 0.008). CONCLUSIONS: SC SPECT/CT liver uptake correlated with differential liver function. TLF was associated with improved overall survival and may aid in personalized oncologic management of HCC patients.

Electron beam energy QA - a note on measurement tolerances.

Monthly QA is recommended to verify the constancy of high-energy electron beams generated for clinical use by linear accelerators. The tolerances are defined as 2%/2 mm in beam penetration according to AAPM task group report 142. The practical implementation is typically achieved by measuring the ratio of readings at two different depths, preferably near the depth of maximum dose and at the depth corresponding to half the dose maximum. Based on beam commissioning data, we show that the relationship between the ranges of energy ratios for different electron energies is highly nonlinear. We provide a formalism that translates measurement deviations in the reference ratios into change in beam penetration for electron energies for six Elekta (6-18 MeV) and eight Varian (6-22 MeV) electron beams. Experimental checks were conducted for each Elekta energy to compare calculated values with measurements, and it was shown that they are in agreement. For example, for a 6 MeV beam a deviation in the measured ionization ratio of ± 15% might still be acceptable (i.e., be within ± 2 mm), whereas for an 18 MeV beam the corresponding tolerance might be ± 6%. These values strongly depend on the initial ratio chosen. In summary, the relationship between differences of the ionization ratio and the corresponding beam energy are derived. The findings can be translated into acceptable tolerance values for monthly QA of electron beam energies.

Commissioning optically stimulated luminescence in vivo dosimeters for fast neutron therapy.

PURPOSE: Clinical in vivo dosimeters intended for use with photon and electron therapies have not been utilized for fast neutron therapy because they are highly susceptible to neutron damage. The objective of this work was to determine if a commercial optically stimulated luminescence (OSL) in vivo dosimetry system could be adapted for use in fast neutron therapy. METHODS: A 50.5 MeV fast neutron beam generated by a clinical neutron therapy cyclotron was used to irradiate carbon doped aluminum oxide (Al2O3:C) optically simulated luminescence dosimeters (OSLDs) in a solid water phantom under standard calibration conditions, 150 cm SAD, 1.7 cm depth, and 10.3 × 10.0 cm field size. OSLD fading and electron trap depletion studies were performed with the OSLDs irradiated with 20 and 50 cGy and monitored over a 24-h period to determine the optimal time for reading the dosimeters during calibration. Four OSLDs per group were calibrated over a clinical dose range of 0-150 cGy. RESULTS: OSLD measurement uncertainties were lowered to within ±2%-3% of the expected dose by minimizing the effect of transient fading that occurs with neutron irradiation and maintaining individual calibration factors for each dosimeter. Dose dependent luminescence fading extended beyond the manufacturer's recommended 10 min period for irradiation with photon or electron beams. To minimize OSL variances caused by inconsistent fading among dosimeters, the observed optimal time for reading the OSLDs postirradiation was between 30 and 90 min. No field size, wedge factor, or gantry angle dependencies were observed in the OSLDs irradiated by the studied fast neutron beam. CONCLUSIONS: Measurements demonstrated that uncertainties less than ±3% were attainable in OSLDs irradiated with fast neutrons under clinical conditions. Accuracy and precision comparable to clinical OSL measurements observed with photons can be achieved by maintaining individual OSLD calibration factors and minimizing transient fading effects.

MCNP6 model of the University of Washington clinical neutron therapy system (CNTS).

A MCNP6 dosimetry model is presented for the Clinical Neutron Therapy System (CNTS) at the University of Washington. In the CNTS, fast neutrons are generated by a 50.5 MeV proton beam incident on a 10.5 mm thick Be target. The production, scattering and absorption of neutrons, photons, and other particles are explicitly tracked throughout the key components of the CNTS, including the target, primary collimator, flattening filter, monitor unit ionization chamber, and multi-leaf collimator. Simulations of the open field tissue maximum ratio (TMR), percentage depth dose profiles, and lateral dose profiles in a 40 cm × 40 cm × 40 cm water phantom are in good agreement with ionization chamber measurements. For a nominal 10 × 10 field, the measured and calculated TMR values for depths of 1.5 cm, 5 cm, 10 cm, and 20 cm (compared to the dose at 1.7 cm) are within 0.22%, 2.23%, 4.30%, and 6.27%, respectively. For the three field sizes studied, 2.8 cm × 2.8 cm, 10.4 cm × 10.3 cm, and 28.8 cm × 28.8 cm, a gamma test comparing the measured and simulated percent depth dose curves have pass rates of 96.4%, 100.0%, and 78.6% (depth from 1.5 to 15 cm), respectively, using a 3% or 3 mm agreement criterion. At a representative depth of 10 cm, simulated lateral dose profiles have in-field (⩾ 10% of central axis dose) pass rates of 89.7% (2.8 cm × 2.8 cm), 89.6% (10.4 cm × 10.3 cm), and 100.0% (28.8 cm × 28.8 cm) using a 3% and 3 mm criterion. The MCNP6 model of the CNTS meets the minimum requirements for use as a quality assurance tool for treatment planning and provides useful insights and information to aid in the advancement of fast neutron therapy.

Dental amalgam artifact: Adverse impact on tumor visualization and proton beam treatment planning in oral and oropharyngeal cancers.

PURPOSE: We evaluated the incidence and impact of dental filling artifacts on the definition of clinical target volume (CTV) for oropharyngeal/oral cavity cancers receiving radiation therapy. We performed phantom proton beam dosimetric analyses using a low-density composite filling to investigate artifact reduction and dose distribution. METHODS AND MATERIALS: We reviewed oral cavity/oropharynx radiation treatment plans between 2010 and 2012. Plans were evaluated for artifacts and impact on CTV visualization. We constructed a head and neck phantom, obtaining planning computed tomography images at baseline (native tooth) and for each filling (composite and metal amalgam) interchanged into a tooth adjacent to the tumor. We performed uniform scanning proton plans with each filling, evaluating for planning target volume (PTV) coverage and overall dose distribution. RESULTS: A total of 110 treatment plans were reviewed (71 oropharynx, 39 oral cavity). Artifacts were identified in 81 plans (73.6%), including 53 oropharynx (74.6%) and 28 oral cavity (71.8%). Artifacts obscured the CTV in 77 cases (95%), including 49 of 53 oropharynx cases (92.5%) and all 28 oral cavity cases. On phantom testing, the metal amalgam obscured the tumor while the composite did not. Hounsfield unit (HU) values (range, mean) for the tumor were: baseline (-484.0 to 700.0 HU, 104 HU), composite (-728.5 to 1038.0 HU, 105 HU), metal amalgam (-1023.0 to 807.0 HU, 90.74 HU). The percent of planning target volume receiving 95% of prescription dose of the PTV was baseline (100%), composite (100%), and metal amalgam (92.3%). PTV dose ranges were baseline (98%-106%), composite (98%-107%), and metal amalgam (66%-111%). PTV coverage and dose distributions of the composite and native tooth plans were identical. CONCLUSIONS: A high incidence of artifacts was found on the planning scans of oral/oropharyngeal cancer patients, adversely impacting CTV visualization. In our phantom model, metal amalgam impacted tumor and tissue density. The PTV was underdosed with the metal amalgam compared with the composite filling. A potential solution involves exchanging metal fillings with composite before proton treatment planning for improved tumor visualization and dosimetry.

Ill-posed problem and regularization in reconstruction of radiobiological parameters from serial tumor imaging data.

The main objective of this article is to improve the stability of reconstruction algorithms for estimation of radiobiological parameters using serial tumor imaging data acquired during radiation therapy. Serial images of tumor response to radiation therapy represent a complex summation of several exponential processes as treatment induced cell inactivation, tumor growth rates, and the rate of cell loss. Accurate assessment of treatment response would require separation of these processes because they define radiobiological determinants of treatment response and, correspondingly, tumor control probability. However, the estimation of radiobiological parameters using imaging data can be considered an inverse ill-posed problem because a sum of several exponentials would produce the Fredholm integral equation of the first kind which is ill posed. Therefore, the stability of reconstruction of radiobiological parameters presents a problem even for the simplest models of tumor response. To study stability of the parameter reconstruction problem, we used a set of serial CT imaging data for head and neck cancer and a simplest case of a two-level cell population model of tumor response. Inverse reconstruction was performed using a simulated annealing algorithm to minimize a least squared objective function. Results show that the reconstructed values of cell surviving fractions and cell doubling time exhibit significant nonphysical fluctuations if no stabilization algorithms are applied. However, after applying a stabilization algorithm based on variational regularization, the reconstruction produces statistical distributions for survival fractions and doubling time that are comparable to published in vitro data. This algorithm is an advance over our previous work where only cell surviving fractions were reconstructed. We conclude that variational regularization allows for an increase in the number of free parameters in our model which enables development of more-advanced parameter reconstruction algorithms.