Passive Scattering Proton Therapy Research Articles

Probing thoracic dose patterns associated to pericardial effusion and mortality in patients treated with photons and protons for locally advanced non-small-cell lung cancer

PurposeTo investigate thoracic dose–response patterns for pericardial effusion (PCE) and mortality in patients treated for locally advanced Non-Small-Cell Lung Cancer (NSCLC) by Intensity Modulated RT (IMRT) or Passive-Scattering Proton Therapy (PSPT). MethodsAmong 178 patients, 43.5% developed grade ≥ 2 PCE. Clinical and dosimetric factors associated with PCE or overall survival (OS) were identified via multi-variable Cox proportional hazards modeling. The Voxel-Based Analyses (VBAs) of local dose differences between patients with and without PCE and mortality was performed. The robustness of VBA results was assessed by a novel characterization of spatial properties of dose distributions based on probabilistic independent component analysis (PICA) and connectograms. ResultsSeveral non-dosimetric variables were selected by the multivariable analysis for the considered outcomes, while the time-dependent PCE onset was uncorrelated with the OS (p = 0.34) at a multi-variable Cox analysis. Despite the significant PSPT dosimetric advantage, the RT technique did not affect the occurrence of PCE or OS.VBAs highlighted largely overlapping clusters significantly associated with PCE endpoints in heart and lungs. No significant dosimetric patterns related to mortality endpoints were found.PICA identified 43 components homogeneously scattered within thorax, while connectograms showed modest correlations between doses in main cardio-pulmonary substructures. ConclusionsSpatially resolved analysis highlighted dose patterns related to radiation-induced cardiac toxiciy and the observed organ-based dose–response mismatch in PSPT and IMRT. Indeed, the thoracic regions spared by PSPT poorly overlapped with the areas involved in PCE development, as highlited by VBA. PICA and connectograms proved valuable tools for assessing the robusteness of obtained VBA inferences.

The development of a treatment control system for a passive scattering proton therapy installation

Ocular melanoma has been treated using proton therapy at the Centre Antoine Lacassagne (CAL) since 1991, following the commissioning of the 65 MeV cyclotron MEDICYC and its associated beam-lines a few years earlier. The dedicated eye-line is optimized for shallow tumors and sharp penumbrae and provides state-of-the-art quality of care. The cyclotron, beam-lines and treatment systems, which are maintained exclusively by the staff at CAL, have proven to be exceptionally robust with up-times consistently above 95%. The systems are however aging and need to be replaced to ensure a continuation of ocular treatments with MEDICYC. This paper describes the development and performance of a new treatment control and dose measurement system for MEDICYC. Software and hardware architectural design choices are discussed in context of the requirements for dose delivery precision, robustness and patient safety. The performance of the treatment delivery, dose monitoring and beam quality assurance systems are presented.

Radiation-Induced Lymphopenia Risks of Photon Versus Proton Therapy for Esophageal Cancer Patients.

PurposeTo assess possible differences in radiation-induced lymphocyte depletion for esophageal cancer patients being treated with the following 3 treatment modalities: intensity-modulated radiation therapy (IMRT), passive scattering proton therapy (PSPT), and intensity-modulated proton therapy (IMPT).Methods and MaterialsWe used 2 prediction models to estimate lymphocyte depletion based on dose distributions. Model I used a piecewise linear relationship between lymphocyte survival and voxel-by-voxel dose. Model II assumes that lymphocytes deplete exponentially as a function of total delivered dose. The models can be fitted using the weekly absolute lymphocyte counts measurements collected throughout treatment. We randomly selected 45 esophageal cancer patients treated with IMRT, PSPT, or IMPT at our institution (15 per modality) to demonstrate the fitness of the 2 models. A different group of 10 esophageal cancer patients who had received PSPT were included in this study of in silico simulations of multiple modalities. One IMRT and one IMPT plan were created, using our standards of practice for each modality, as competing plans to the existing PSPT plan for each patient. We fitted the models by PSPT plans used in treatment and predicted absolute lymphocyte counts for IMRT and IMPT plans.ResultsModel validation on each modality group of patients showed good agreement between measured and predicted absolute lymphocyte counts nadirs with mean squared errors from 0.003 to 0.023 among the modalities and models. In the simulation study of IMRT and IMPT on the 10 PSPT patients, the average predicted absolute lymphocyte count (ALC) nadirs were 0.27, 0.35, and 0.37 K/μL after IMRT, PSPT, and IMPT treatments using Model I, respectively, and 0.14, 0.22, and 0.33 K/μL using Model II.ConclusionsProton plans carried a lower predicted risk of lymphopenia after the treatment course than did photon plans. Moreover, IMPT plans outperformed PSPT in terms of predicted lymphocyte preservation.

Dosimetric impact of range uncertainty in passive scattering proton therapy.

PurposeThe objective of this study was to investigate the dosimetric impact of range uncertainty in a large cohort of patients receiving passive scatter proton therapy.MethodsA cohort of 120 patients were reviewed in this study retrospectively, of which 61 were brain, 39 lung, and 20 prostate patients. Range uncertainties of ±3.5% (overshooting and undershooting by 3.5%, respectively) were added and recalculated on the original plans, which had been planned according to our clinical planning protocol while keeping beamlines, apertures, compensators, and dose grids intact. Changes in the coverage on CTV and DVH for critical organs were compared and analyzed. Correlation between dose change and minimal distance between CTV and critical organs were also investigated.ResultsAlthough CTV coverages and maximum dose to critical organs were largely maintained for most brain patients, large variations over 5% were still observed sporadically. Critical organs, such as brainstem and chiasm, could still be affected by range uncertainty at 4 cm away from CTV. Coverage and OARs in lung and prostate patients were less likely to be affected by range uncertainty with very few exceptions.ConclusionThe margin recipe in modern TPS leads to clinically acceptable OAR doses in the presence of range uncertainties. However, range uncertainties still pose a noticeable challenge for small but critical serial organs near tumors, and occasionally for large parallel organs that are located distal to incident proton beams.

Normal Tissue Injury Induced by Photon and Proton Therapies: Gaps and Opportunities.

Despite technological advances in radiation therapy (RT) and cancer treatment, patients still experience adverse effects. Proton therapy (PT) has emerged as a valuable RT modality that can improve treatment outcomes. Normal tissue injury is an important determinant of the outcome; therefore, for this review, we analyzed 2 databases: (1) clinical trials registered with ClinicalTrials.gov and (2) the literature on PT in PubMed, which shows a steady increase in the number of publications. Most studies in PT registered with ClinicalTrials.gov with results available are nonrandomized early phase studies with a relatively small number of patients enrolled. From the larger database of nonrandomized trials, we listed adverse events in specific organs/sites among patients with cancer who are treated with photons and protons to identify critical issues. The present data demonstrate dosimetric advantages of PT with favorable toxicity profiles and form the basis for comparative randomized prospective trials. A comparative analysis of 3 recently completed randomized trials for normal tissue toxicities suggests that for early stage non-small cell lung cancer, no meaningful comparison could be made between stereotactic body RT and stereotactic body PT due to low accrual (NCT01511081). In addition, for locally advanced non-small cell lung cancer, a comparison of intensity modulated RTwith passive scattering PT (now largely replaced by spot-scanned intensity modulated PT), PT did not provide any benefit in normal tissue toxicity or locoregional failure over photon therapy. Finally, for locally advanced esophageal cancer, proton beam therapy provided a lower total toxicity burden but did not improve progression-free survival and quality of life (NCT01512589). The purpose of this review is to inform the limitations of current trials looking at protons and photons, considering that advances in technology, physics, and biology are a continuum, and to advocate for future trials geared toward accurate precision RT that need to be viewed as an iterative process in a defined path toward delivering optimal radiation treatment. A foundational understanding of the radiobiologic differences between protons and photons in tumor and normal tissue responses is fundamental to, and necessary for, determining the suitability of a given type of biologically optimized RT to a patient or cohort.

Local Control After Proton Therapy for Pediatric Chordoma

Due to the location and high dose required for disease control, pediatric chordomas are theoretically well-suited for treatment with proton therapy, but their low incidence limits the clinical outcome data available in the literature. We sought to report the efficacy and toxicity of proton therapy among a single-institution cohort. Between 2008 and 2019, 29 patients with a median age of 14.8 years (range, 3.8-21.8) received passive-scattered proton therapy for nonmetastatic chordoma. No patient received prior irradiation. Twenty-four tumors arose in the clivus/cervical spine region and 5 in the lumbosacral spine. Twenty-six tumors demonstrated classic well-differentiated histology and 3 were dedifferentiated or not otherwise specified. Approximately half of the tumors underwent specialized testing: 14 were brachyury-positive and 10 retained INI-1. Three patients had locally recurrent tumors after surgery alone (n = 2) or surgery + chemotherapy (n = 1), and 17 patients had gross disease at the time of radiation. The median radiation dose was 73.8 Gy relative biological effectivness (range, 69-75.6). With a median follow-up of 4.3 years (range, 1.0-10.7), the 5-year estimates of local control, progression-free survival, and overall survival rates were 85%, 82%, and 86%, respectively. No disease progression was observed beyond 3 years. Excluding 3 patients with dedifferentiated/not-otherwise-specified chordoma, the 5-year local control, progression-free survival, and overall survival rates were 92%, 92%, and 91%, respectively. Serious toxicities included 3 patients with hardware failure or related infection requiring revision surgery, 2 patients with hormone deficiency, and 2 patients with Eustachian tube dysfunction causing chronic otitis media. No patient experienced brain stem injury, myelopathy, vision loss, or hearing loss after radiation. In pediatric patients with chordoma, proton therapy is associated with a low risk of serious toxicity and high efficacy, particularly in well-differentiated tumors. Complete resection may be unnecessary for local control, and destabilizing operations requiring instrumentation may result in additional complications after therapy.

Neutron radiation effects on microcomputers in radiation therapy environments

AbstractAim:Microcomputers play an increasingly important role in the delivery of radiation therapy. Exposure to neutron irradiation can produce undesirable effects in modern microcomputers. The objective of this study is to measure acute and cumulative effects of neutron exposure of Intel-based microcomputers in photon and proton therapy treatment environments.Materials and methods:Multiple computers were irradiated with neutrons produced from MEVION S250 passive scattering proton therapy and from Varian 21EX Linear Accelerator photon therapy systems. The energy of the proton beam was 232 MeV and the photon beam energies were 6 and 18 MV. Rates of fatal errors in computer processing unit (CPU) cores were measured.Results:Varying rates of fatal system errors due to upsets in the CPU cores were observed. Post-exposure routine stress testing revealed no permanent hardware defects in the random access memory (RAM) or hard disk drive (HDD) of any tested systems. Microchip manufacturers fit increasingly high numbers of transistors in the same volume and the susceptibility to radiation thus increases.Conclusions:This work explores if the process size of a microchip is the dominant factor and also looked at the short- and long-term effects of neutron irradiation on modern microprocessors in a clinical environment. Additionally, methods of effective shielding are proposed.

Dose-Volume Comparison of IMRT and PSPT Treatment Plans for Early-Stage Glottic Cancer.

PurposeTo clarify the dose distribution characteristics for early-stage glottic cancer by comparing the dose distribution between intensity-modulated radiation therapy (IMRT) and passive scattering proton therapy (PSPT) and to examine the usefulness of PSPT for early-stage glottic cancer.Materials and MethodsComputed tomography datasets of 8 patients with T1-2 glottic cancer who had been treated by PSPT were used to create an IMRT plan in Eclipse with 7 fields and a PSPT plan in XiO-M with 2 fields. Organs at risk (OARs) included the carotid arteries, arytenoids, inferior constrictor muscles, strap muscles, thyroid cartilage, cricoid cartilage, and spinal cord. The prescription dose was 66 GyRBE in 33 fractions to the planning target volume (PTV). All plans were optimized such that 95% of the PTV received 90% of the prescription dose considering that the skin was slightly spared.ResultsThe superiority of the PSPT was confirmed in all OARs. In the PSPT, the dose to the contralateral carotid artery and the spinal cord, which is slightly distant from the PTV, was dramatically reduced while maintaining the dose distribution uniformity of the PTV by comparison with IMRT.ConclusionPSPT for early-stage glottic cancer resulted in good target dose homogeneity and significantly spared the OARs as compared with the IMRT. PSPT is expected to be effective in reducing late effects and particularly useful for young people.

Investigation of the Dependency of the Output Factor on the Field Size in Passive Scattering Proton Therapy at the National Cancer Center in Korea

The dependency of the output factor on the field size in the passive scattering proton therapy at the National Cancer Center (NCC) in Korea was investigated through a comparison of the measured output factors. The output factor of the fields of the representative beam options was measured using a Pinpoint chamber with standard circular blocks of less than 5 cm in diameter. The measured output factors for different field sizes show that the dependency of the output factor on the field size is not negligible even in the field for the 5 cm in diameter for long-range proton beams. In addition, the conflicting dependency in shallow fields indicates that the potential contribution of scattered protons should be considered in predicting and modelling of the output factors in small fields.

Pro-con of proton: Dosimetric advantages of intensity-modulation over passive scatter for thoracic malignancies.

The use of passively scattered proton therapy (PSPT) or intensity modulated proton therapy (IMPT) opens the potential for dose escalation or critical structure sparing in thoracic malignancies. While the latter offers greater dose conformality, dose distributions are subjected to greater uncertainties, especially due to interplay effects. Exploration in this area is warranted to determine if there is any dosimetric advantages in using IMPT for thoracic malignancies. This review aims to both compare organs-at-risk sparing and plan robustness between PSPT and IMPT and examine the mitigation strategies for the reduction of interplay effects currently available. Early evidence suggests that IMPT is dosimetrically superior to PSPT in thoracic malignancies. Randomised control trials are required before any clinical benefit of IMPT can be confirmed.

Effect of Deep Inspiration Breath Hold on Normal Tissue Sparing With Intensity Modulated Radiation Therapy Versus Proton Therapy for Mediastinal Lymphoma

PurposeIntensity modulated radiation therapy delivered with deep-inspiration breath hold (IMRT-BH) provides favorable normal tissue dosimetric profiles when treating patients with mediastinal lymphoma. However, it is unclear if IMRT-BH plans are comparable to free breathing (FB) proton plans. We performed a retrospective, comparative dosimetric study between IMRT-BH and FB passive scatter proton therapy (P-FB) or intensity modulated proton therapy (IMPT-FB). Hypothesizing that BH would provide superior normal tissue sparing when added to proton therapy, we also compared plans to passive scatter BH (P-BH). Methods and MaterialsFor 15 patients who received involved-site RT with “butterfly” IMRT-BH, 3 additional proton plans (P-FB, IMPT-FB, P-BH) were optimized to deliver 30.6 Gy/Gy relative biological effectiveness. Dosimetric variables (mean dose, V30, V25, V15, and V5) for organs at risk (OARs) were calculated and compared using nonparametric Wilcoxon signed-rank tests. ResultsOf 57 studied OAR parameters, IMRT-BH plans were comparable in 37 (65%) parameters with P-FB plans, 32 (56%) of IMPT-FB parameters, and 30 (53%) of P-BH parameters. Doses to breasts were generally equivalent among plans while esophageal dosing was worse with IMRT-BH. Mean doses and V5 of the total lung and heart were the highest with IMRT-BH; however, IMRT-BH resulted in comparable coronary and superior lung V30 relative to proton plans. The addition of BH with proton therapy resulted in the greatest lung sparing, with mean lung dose reductions of 11% to 38%. ConclusionsThe use of BH with IMRT reduces the disparity in OAR doses with equivalence achieved in nearly two-thirds of OAR metrics compared with P-FB and 50% compared with IMPT-BH. Because each modality exhibited unique benefits, personalization of modality selection is recommended. Proton therapy via BH provides additional benefits in heart and lung sparing.

Quantitative proton radiation therapy dosimetry using the storage phosphor europium-doped potassium chloride.

To (a) characterize the fundamental optical and dosimetric properties of the storage phosphor europium-doped potassium chloride for quantitative proton dosimetry, and (b) investigate if its dose radiation response can be described by an analytic radiation transport model. Cylindrical KCl:Eu2+ dosimeters with dimensions of 6mm diameter and 1mm thickness were fabricated in-house. The dosimeters were irradiated using both a Mevion S250 passive scattering proton therapy system and a Varian Clinac iX linear accelerator. Photostimulated luminescence (PSL) emission spectra, excitation spectra, and luminescence lifetimes were measured for both proton and photon irradiations. Dosimetric properties including radiation hardness, dose linearity, signal stabilization, dose rate sensitivity, and energy dependence were studied using a laboratory optical reader after irradiations. The dosimeters were modeled using physical quantities including mass stopping powers in the storage phosphor and water for a given proton beam, and mass energy absorption coefficients and massing stopping powers in detector and water for a given photon beam. KCl:Eu2+ exhibited optical emission and stimulation peaks at 421 and 560nm, respectively, for both proton and photon irradiations, enabling postirradiation readouts using a visible light source while detecting the PSL using a photomultiplier tube. KCl:Eu2+ showed a linear response from 0 to 8Gy absorbed dose-to-water, a large dynamic range up to 60Gy, dose-rate independence measured from 83 to 500MU/min, and a PSL lifetime of <5ms that is sufficiently short for supporting rapid scanning in a two-dimensional geometry. KCl:Eu2+ was highly reusable with only a slight signal decrease of ~3% at accumulated doses over 100Gy, which could be managed by a periodic recalibration. The detected PSL signal strength of the dosimeter in the proton field had been calculated accurately to a maximum discrepancy of 2% using known physical quantities along with its prior signal strength as measured in a photon field at the same dose-to-water. This discrepancy might be attributed to an under-response due to linear energy transfer (LET) effect. However, comparisons of depth-dose measurements in a spread-out Bragg peak (SOBP) field with a parallel-plate ionization chamber showed no clear evidence of LET effects. Furthermore, range measurements agreed with ionization chamber measurements to within 1mm. KCl:Eu2+ showed linear response over a large dynamic range for proton irradiations and reliably reproduced SOBP measurements as measured by ionization chambers. Its relatively low atomic number of 18 and near LET independence make it suited for quantitative proton dosimetry. In addition, its high radiation hardness means that it can be reused numerous times. Any potential measurement artifacts encountered in complex irradiation conditions should be able to be corrected for using known physical quantities.

Conventionally fractionated large volume head and neck re-irradiation using multileaf collimator-based robotic technique: A feasibility study

PurposeTo report on the feasibility and performance of conventionally fractionated multileaf collimator (MLC)-based robotic stereotactic body re-irradiation of the head and neck region using MLC-based Cyberknife (CK) technology. MethodsPatients treated for recurrent or second primary head and neck cancer (HNC) with curative proton therapy to a target volume > 30 cm3 between 2011 and 2015 were included. MLC-based CK plans were generated using the CK M6 InCise2 MLC system. Dose statistics from MLC-based CK plans were compared to proton beam therapy (PBT) plans according to the following metrics: target coverage, target homogeneity index, gradient index, Paddick conformity index (CI), prescription isodose volume (PIV), treatment time (tTime) for one fraction as well as doses to organs at risk (OAR). Wilcoxon signed-rank test was used to compare dose metrics. ResultsEight patients were included; the tumor sites included: salivary glands, pharynx (oropharynx, hypopharynx and retropharynx) and sinonasal cavities. Five of 8 patients were treated with multifield optimisation intensity modulated proton therapy, 3 were treated with passive scattering proton therapy. Median dose was 67 Gy (range 60–70) in 32 fractions (range 30–35). The median high-dose planning target volume (PTV) was 45.4 cm3 (range 2.4 – 130.2 cm3) and the median elective PTV was 91.9 cm3 (range 61.2 – 269.7 cm3). Overall, the mean target coverage (mean 98.3% vs. 96.2% for CK vs. PBT, respectively), maximum dose to PTV (mean 111% vs. 111%, p = 0.2) and mean dose to PTV (mean 104% vs. 104%) were similar across modalities. Highly conformal plans were achieved with both modalities, but mean CI was better with PBT (0.5 vs. 0.6 for CK vs. PBT, p = 0.04). Homogeneity and gradient indexes were similar between the 2 modalities; mean tTime with PBT and CK was 17 vs. 18 min, respectively (p = 0.7). Case-based study revealed that CK and PBT plans allowed for excellent sparing of OAR, with some clinical scenarios associated with better performance of CK while others with better performance of PBT. ConclusionOur study has demonstrated the dosimetric performance of large volume head and neck re-irradiation using MLC-based CK in various clinical scenarios. While conformity was generally better achieved with PBT, MLC-based CK allowed for high dose gradient leading to rapid dose drop-off and sparing of OAR. Conventionally fractionated MLC-based CK could be a competitive alternative in large volume head and neck re-irradiation that deserves further investigation in the clinical setting.

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

PurposeTo 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 methodsWe 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. ResultsGrade 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. ConclusionOur 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.

NTCP Models for Severe Radiation Induced Dermatitis After IMRT or Proton Therapy for Thoracic Cancer Patients.

Radiation therapy (RT) of thoracic cancers may cause severe radiation dermatitis (RD), which impacts on the quality of a patient's life. Aim of this study was to analyze the incidence of acute RD and develop normal tissue complication probability (NTCP) models for severe RD in thoracic cancer patients treated with Intensity-Modulated RT (IMRT) or Passive Scattering Proton Therapy (PSPT). We analyzed 166 Non-Small-Cell Lung Cancer (NSCLC) patients prospectively treated at a single institution with IMRT (103 patients) or PSPT (63 patients). All patients were treated to a prescribed dose of 60 to 74 Gy in conventional daily fractionation with concurrent chemotherapy. RD was scored according to CTCAE v3 scoring system. For each patient, the epidermis structure (skin) was automatically defined by an in house developed segmentation algorithm. The absolute dose-surface histogram (DSH) of the skin were extracted and normalized using the Body Surface Area (BSA) index as scaling factor. Patient and treatment-related characteristics were analyzed. The Lyman-Kutcher-Burman (LKB) NTCP model recast for DSH and the multivariable logistic model were adopted. Models were internally validated by Leave-One-Out method. Model performance was evaluated by the area under the receiver operator characteristic curve, and calibration plot parameters. Fifteen of 166 (9%) patients developed severe dermatitis (grade 3). RT technique did not impact RD incidence. Total gross tumor volume (GTV) size was the only non dosimetric variable significantly correlated with severe RD (p = 0.027). Multivariable logistic modeling resulted in a single variable model including S20Gy, the relative skin surface receiving more than 20 Gy (OR = 31.4). The cut off for S20Gy was 1.1% of the BSA. LKB model parameters were TD50 = 9.5 Gy, m = 0.24, n = 0.62. Both NTCP models showed comparably high prediction and calibration performances. Despite skin toxicity has long been considered a potential limiting factor in the clinical use of PSPT, no significant differences in RD incidence was found between RT modalities. Once externally validated, the availability of NTCP models for prediction of severe RD may advance treatment planning optimization.

Anatomic change over the course of treatment for non\u2013small cell lung cancer patients and its impact on intensity-modulated radiation therapy and passive-scattering proton therapy deliveries

PurposeTo quantify tumor anatomic change of non-small cell lung cancer (NSCLC) patients given passive-scattering proton therapy (PSPT) and intensity-modulated radiation therapy (IMRT) through 6–7 weeks of treatment, and analyze the correlation between anatomic change and the need to adopt adaptive radiotherapy (ART).Materials and methodsWeekly 4D CT sets of 32 patients (8/8 IMRT with/without ART, 8/8 PSPT with/without ART) acquired during treatment, were registered to the planning CT using an in-house developed deformable registration algorithm. The anatomic change was quantified as the mean variation of the region of interest (ROI) relative to the planning CT by averaging the magnitude of deformation vectors of all voxels within the ROI contour. Mean variations of GTV and CTV were compared between subgroups classified by ART status and treatment modality using the independent t-test. Logistic regression analysis was performed to clarify the effect of anatomic change on the probability of ART adoption.ResultsThere was no significant difference (p = 0.679) for the time-averaged mean CTV variations from the planning CT between IMRT (7.61 ± 2.80 mm) and PSPT (7.21 ± 2.67 mm) patients. However, a significant difference (p = 0.001) was observed between ART (8.93 ± 2.19 mm) and non-ART (5.90 ± 2.33 mm) patients, when treatment modality was not considered. Mean CTV variation from the planning CT in all patients increases significantly (p < 0.001), with a changing rate of 1.77 mm per week. Findings for the GTV change was similar. The logistic regression model correctly predicted 71.9% of cases in ART adoption. The correlation is stronger in the PSPT group with a pseudo R2 value of 0.782, compared to that in the IMRT group (pseudo R2 = 0.182).ConclusionThe magnitude of target volume variation over time could be greater than the usual treatment margin. Mean target volume variation from the planning position can be used to identify lung cancer patients that may need ART.

Delayed response to proton beam treatment of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) has become one of the leading causes of cancer death worldwide. There has been anecdotal report regarding the effectiveness of proton beam treatment for HCC. In this pre-clinical investigation, the woodchuck model of viral hepatitis infection-induced HCC was used for proton beam treatment experiment. The radiopaque fiducial markers that are biodegradable were injected around the tumor under ultrasound guidance to facilitate positioning in sequential treatments. An α cradle mode was used to ensure reproducibility of animal positioning on the treatment couch. A CT scan was performed first for contouring by a radiation oncologist. The CT data set with contours was then exported for dose planning. Three fractionations, each 750 CcGyE, were applied every other day with a Mevion S250 passive scattering proton therapy system. Multiphase contrast-enhanced CT scans were performed after the treatment and at later times for follow-ups. 3 weeks post-treatment, shrinking of the HCC nodule was detected and constituted to a partial response (30% reduction along the long axis). By week nine after treatment, the nodule disappeared during the arterial phase of multiphase contrast-enhanced CT scan. Pathological evaluation corroborated with this imaging response. A delayed, but complete imaging response to proton beam treatment applied to HCC was achieved with this unique and clinically relevant animal model of HCC.

Investigating neutron activated contrast agent imaging for tumor localization in proton therapy: a feasibility study for proton neutron gamma-x detection (PNGXD)

Proton neutron gamma-x detection (PNGXD) is a novel imaging concept being investigated for tumor localization during proton therapy that uses secondary neutron interactions with a gadolinium contrast agent (GDCA) to produce characteristic photons within the 40–200 keV energy region. The purpose of this study is to experimentally investigate the feasibility of implementing this procedure by performing experimental measurements on a passive double scattering proton treatment unit. Five experimental measurements were performed with varying concentrations and irradiation conditions. Photon spectra were measured with a 25 mm2, 1 mm thick uncollimated X-123 CdTe spectrometer. For a 10.4 Gy administration on a 100 ml volume phantom with 10 mg g−1 Gd solution placed in a water phantom, 1129 ± 184 K-shell Gd counts were detected. For an administered dose of 21 Gy and the same Gd solution measured in air, resulted in 3296 ± 256 counts. A total of 1094 ± 171, 421 ± 150 and 23 ± 141 K-shell Gd counts were measured for Gd concentrations of 10 mg g−1, 1 mg g−1 and 0 mg g−1 for 7 Gy dose in air. The signal to noise ratio for these five measurements were: 7, 15, 6, 3, and 0.2, respectively. The spectrum contained 43 keV Kα and 49 keV Kβ peaks, however a small amount of 79.5 and 181.9 keV prompt gamma rays were detected from gadolinium neutron capture. This discrepancy is due to a drop in the intrinsic detection efficiency of the CdTe spectrometer over this energy range. The measurements were compared with Monte-Carlo simulation to determine the contributions of Gd neutron capture from internal and external neutrons on a passive scattering proton therapy unit and to investigate the discrepancy in detected characteristic x-rays versus prompt gamma rays.

ES16.01 Proton Therapy

Proton therapy is an attractive option for the treatment of lung cancer patients due to the physical properties of proton beams. Proton therapy allows a focused delivery of radiation at the Bragg peak, with very steep decline of the radiation dose beyond the target volume. These properties offer the possibility to 1) reduce toxicity by reducing the integral dose and the dose to adjacent normal tissues and 2) escalate the dose to the target in some patients. In this talk, I will summarise briefly the physics/radiobiology of protons and the need for adaptation. I will also discuss the rationale for the use of protons in patients with lung cancer, including reduction in integral dose, cardiac toxicity and reduction in haematological toxicity. The clinical trial evidence supporting the use of protons will be presented in early stage and locally advanced non-small cell lung cancer as well as in small-cell lung cancer. Finally I will discuss future research directions, including preclinical and drug-proton combination research, ongoing clinical trials, the model based-approach and the need for biomarkers. Liao Z, Lee JJ, Komaki R, eat l. Bayesian Adaptive Randomization Trial of Passive Scattering Proton Therapy and Intensity-Modulated Photon Radiotherapy for Locally Advanced Non-Small-Cell Lung Cancer. J Clin Oncol. 2018;36(18):1813-1822 Chang JY, Jabbour SK, De Ruysscher D, et al; International Particle Therapy Co-operative Group Thoracic Subcommittee.Consensus Statement on Proton Therapy in Early-Stage and Locally Advanced Non-Small Cell Lung Cancer. Int J Radiat Oncol Biol Phys. 2016;95(1):505-16. Vyfhuis MAL, Onyeuku N, Diwanji T, Mossahebi S, Amin NP, Badiyan SN, Mohindra P, Simone CB 2nd. Advances in proton therapy in lung cancer. Ther Adv Respir Dis. 2018 Jan-Dec;12:1753466618783878 C, Pawelke J, Seidlitz A, Peitzsch C, et al; “Radiobiology of Proton Therapy”: Results of an international expert workshop.Lühr A, von Neubeck Radiother Oncol. 2018; 128(1):56-67 Jin, J.Y., et al., Higher Radiation Dose to Immune System is Correlated With Poorer Survival in Patients With Stage III Non-small Cell Lung Cancer: A Secondary Study of a Phase 3 Cooperative Group Trial (NRG Oncology RTOG 0617). International Journal of Radiation Oncology Biology Physics, 2017. 99(2): p. S151-S152. Joseph, N., et al., Post-treatment lymphocytopaenia, integral body dose and overall survival in lung cancer patients treated with radical radiotherapy. Radiotherapy and Oncology, 2019. 135: p. 115-119. Durante, M., D.J. Brenner, and S.C. Formenti, Does Heavy Ion Therapy Work Through the Immune System? Int J Radiat Oncol Biol Phys, 2016. 96(5): p. 934-936. Lee, H.J., Jr., J. Zeng, and R. Rengan, Proton beam therapy and immunotherapy: an emerging partnership for immune activation in non-small cell lung cancer. Translational lung cancer research, 2018. 7(2): p. 180-188. Dess, R.T., et al., Cardiac Events After Radiation Therapy: Combined Analysis of Prospective Multicenter Trials for Locally Advanced Non-Small-Cell Lung Cancer. J Clin Oncol, 2017. 35(13): p. 1395-1402. McWilliam, A., et al., Radiation dose to heart base linked with poorer survival in lung cancer patients. Eur J Cancer, 2017. 85: p. 106-113. Schulz-Ertner, D. and H. Tsujii, Particle radiation therapy using proton and heavier ion beams. J Clin Oncol, 2007. 25(8): p. 953-64. Gameiro, S.R., et al., Tumor Cells Surviving Exposure to Proton or Photon Radiation Share a Common Immunogenic Modulation Signature, Rendering Them More Sensitive to T Cell-Mediated Killing. Int J Radiat Oncol Biol Phys, 2016. 95(1): p. 120-30.

Volumetric and actuarial analysis of brain necrosis in proton therapy using a novel mixture cure model

Background and purposeHigh-dose fractionated radiotherapy is often necessary to achieve long-term tumor control in several types of tumors involving or within close proximity to the brain. There is limited data to guide on optimal constraints to the adjacent nontarget brain. This investigation explored the significance of the three-dimensional (3D) dose distribution of passive scattering proton therapy to the brain with other clinicopathological factors on the development of symptomatic radiation necrosis. Materials and methodsAll patients with head and neck, skull base, or intracranial tumors who underwent proton therapy (minimum prescription dose of 59.4 Gy(RBE)) with collateral moderate to high dose radiation exposure to the nontarget brain were retrospectively reviewed. A mixture cure model with respect to necrosis-free survival was used to derive estimates for the normal tissue complication probability (NTCP) model while adjusting for potential confounding factors. ResultsOf 179 identified patients, 83 patients had intracranial tumors and 96 patients had primary extracranial tumors. The optimal dose measure obtained to describe the occurrence of radiation necrosis was the equivalent uniform dose (EUD) with parameter a = 9. The best-fit parameters of logistic NTCP models revealed D50 = 57.7 Gy for intracranial tumors, D50 = 39.5 Gy for extracranial tumors, and γ50 = 2.5 for both tumor locations. Multivariable analysis revealed EUD and primary tumor location to be the strongest predictors of brain radiation necrosis. ConclusionIn the current clinical volumetric data analyses with multivariable modelling, EUD was identified as an independent and strong predictor for brain radiation necrosis from proton therapy.