Esophageal Cancer Outcomes After Definitive Chemotherapy With Intensity Modulated Proton Therapy.

Purpose: The effectiveness of intensity-modulated proton therapy (IMPT) for esophageal cancer treated with definitive concurrent chemoradiation therapy remains inadequately explored. We investigated long-term outcomes and toxicity experienced by patients who received IMPT as part of definitive esophageal cancer treatment. Patients and Methods: We retrospectively identified and analyzed 34 patients with locally advanced esophageal cancer who received IMPT with concurrent chemotherapy as a definitive treatment regimen at The University of Texas MD Anderson Cancer Center from 2011 to 2021. The median IMPT dose was 50.4 GyRBE in 28 fractions; concurrent chemotherapy consisted of fluorouracil and/or taxane and/or platinum. Survival outcomes were determined by the Kaplan-Meier method, and toxicity was scored according to the Common Terminology Criteria for Adverse Events version 4.0. Results: The median age of all patients was 71.5 years. Most patients had stage III (cT3 cM0) adenocarcinoma of the lower esophagus. At a median follow-up time of 39 months, the 5-year overall survival rate was 41.1%; progression-free survival, 34.6%; local regional recurrence-free survival, 78.1%; and distant metastasis-free survival, 65.0%. Common acute chemoradiation therapy-related toxicities included hematologic toxicity, esophagitis (and late-onset), fatigue, weight loss, and nausea (and late-onset); grade 3 toxicity rates were 26.0% for hematologic, 18.0% for esophagitis and 9.0% for nausea. No patient had grade ≥3 wt loss or radiation pneumonitis, and no patients had pulmonary fibrosis or esophageal fistula. No grade ≥4 events were observed except for hematologic toxicity (lymphopenia) in 2 patients. Conclusion: Long-term survival and toxicity were excellent after IMPT for locally advanced esophageal cancer treated definitively with concurrent chemoradiation therapy. When available, IMPT should be offered to such patients to minimize treatment-related cardiopulmonary toxicity without sacrificing outcomes.

Framework for Quality Assurance of Ultrahigh Dose Rate Clinical Trials Investigating FLASH Effects and Current Technology Gaps.

FLASH radiation therapy (FLASH-RT), delivered with ultrahigh dose rate (UHDR), may allow patients to be treated with less normal tissue toxicity for a given tumor dose compared with currently used conventional dose rate. Clinical trials are being carried out and are needed to test whether this improved therapeutic ratio can be achieved clinically. During the clinical trials, quality assurance and credentialing of equipment and participating sites, particularly pertaining to UHDR-specific aspects, will be crucial for the validity of the outcomes of such trials. This report represents an initial framework proposed by the NRG Oncology Center for Innovation in Radiation Oncology FLASH working group on quality assurance of potential UHDR clinical trials and reviews current technology gaps to overcome. An important but separate consideration is the appropriate design of trials to most effectively answer clinical and scientific questions about FLASH. This paper begins with an overview of UHDR RT delivery methods. UHDR beam delivery parameters are then covered, with a focus on electron and proton modalities. The definition and control of safe UHDR beam delivery and current and needed dosimetry technologies are reviewed and discussed. System and site credentialing for large, multi-institution trials are reviewed. Quality assurance is then discussed, and new requirements are presented for treatment system standard analysis, patient positioning, and treatment planning. The tables and figures in this paper are meant to serve as reference points as we move toward FLASH-RT clinical trial performance. Some major questions regarding FLASH-RT are discussed, and next steps in this field are proposed. FLASH-RT has potential but is associated with significant risks and complexities. We need to redefine optimization to focus not only on the dose but also on the dose rate in a manner that is robust and understandable and that can be prescribed, validated, and confirmed in real time. Robust patient safety systems and access to treatment data will be critical as FLASH-RT moves into the clinical trials.

Photon beam modeling variations predict errors in IMRT dosimetry audits.

BACKGROUND & PURPOSE: To evaluate treatment planning system (TPS) beam modeling parameters as contributing factors to IMRT audit performance. MATERIALS & METHODS: We retrospectively analyzed IROC Houston phantom audit performance and concurrent beam modeling survey responses from 337 irradiations performed between August 2017 and November 2019. Irradiation results were grouped based on the reporting of typical or atypical beam modeling parameter survey responses (<10th or >90th percentile values), and compared for passing versus failing (>7% error) or "poor" (>5% error) irradiation status. Additionally, we assessed the impact on the planned dose distribution from variations in modeling parameter value. Finally, we estimated the overall impact of beam modeling parameter variance on dose calculations, based on reported community variations. RESULTS: Use of atypical modeling parameters were more frequently seen with failing phantom audit results (p = 0.01). Most pronounced was for Eclipse AAA users, where phantom irradiations with atypical values of dosimetric leaf gap (DLG) showed a greater incidence of both poor-performing (p = 0.048) and failing phantom audits (p = 0.014); and in general, DLG value was correlated with dose calculation accuracy (r = 0.397, p < 0.001). Manipulating TPS parameters induced systematic changes in planned dose distributions which were consistent with prior observations of how failures manifest. Dose change estimations based on these dose calculations agreed well with true dosimetric errors identified. CONCLUSION: Atypical TPS beam modeling parameters are associated with failing phantom audits. This is identified as an important factor contributing to the observed failing phantom results, and highlights the need for accurate beam modeling.

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

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

Author Correction: Ultra high dose rate (35 Gy/sec) radiation does not spare the normal tissue in cardiac and splenic models of lymphopenia and gastrointestinal syndrome.

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

Sensitivity of IROC phantom performance to radiotherapy treatment planning system beam modeling parameters based on community-driven data.

PURPOSE: Treatment planning system (TPS) dose calculations have previously been shown to be sensitive to modeling errors, especially when treating with complex strategies like intensity-modulated radiation therapy (IMRT). This work investigates the dosimetric impact of several dosimetric and nondosimetric beam modeling parameters, based on their distribution in the radiotherapy community, in two commercial TPSs in order to understand the realistic potential for dose deviations and their clinical effects. METHODS AND MATERIALS: Beam models representing standard 120-leaf Varian Clinac-type machines were developed in Eclipse 13.5 (AAA algorithm) and RayStation 9A (v8.99, collapsed-cone algorithm) based upon median values of dosimetric measurements from Imaging and Radiation Oncology Core (IROC) Houston site visit data and community beam modeling parameter survey data in order to represent a baseline linear accelerator. Five clinically acceptable treatment plans (three IMRT, two VMAT) were developed for the IROC head and neck phantom. Dose distributions for each plan were recalculated after individually modifying parameters of interest (e.g., MLC transmission, percent depth doses [PDDs], and output factors) according to the 2.5th to 97.5th percentiles of community survey and machine performance data to encompass the realistic extent of variance in the radiotherapy community. The resultant dose distributions were evaluated by examining relative changes in average dose for thermoluminescent dosimeter (TLD) locations across the two target volumes and organ at risk (OAR). Interplay was also examined for parameters generating changes in target dose greater than 1%. RESULTS: For Eclipse, dose calculations were sensitive to changes in the dosimetric leaf gap (DLG), which resulted in differences from -5% to +3% to the targets relative to the baseline beam model. Modifying the MLC transmission factor introduced differences up to ± 1%. For RayStation, parameters determining MLC behaviors likewise contributed substantially; the MLC offset introduced changes in dose from -4% to +7%, and the MLC transmission caused changes of -4% to +2%. Among the dosimetric qualities examined, changes in PDD implementation resulted in the most substantial changes, but these were only up to ±1%. Other dosimetric factors had <1% impact on dose accuracy. Interplay between impactful parameters was found to be minimal. CONCLUSION: Factors related to the modeling of the MLC, particularly relating to the leaf offset, can cause clinically significant changes in the calculated dose for IMRT and VMAT plans. This should be of concern to the radiotherapy community because the clinical effects of poor TPS commissioning were based on reported data from clinically implemented beam models. These results further reinforce that dose errors caused by poor TPS calculations are often involved in IROC phantom failures.

Dose calculation errors as a component of failing IROC lung and spine phantom irradiations.

PURPOSE: Between July 2013 and August 2019, 22% of the imaging and radiation oncology core (IROC) spine, and 15% of the moving lung phantom irradiations have failed to meet established acceptability criteria. The spine phantom simulates a highly modulated stereotactic body radiation therapy (SBRT) case, whereas the lung phantom represents a low-to-none modulation moving target case. In this study, we assessed the contribution of dose calculation errors to these phantom results and evaluated their effects on failure rates. METHODS: We evaluated dose calculation errors by comparing the calculation accuracy of various institutions' treatment planning systems (TPSs) vs IROC-Houston's previously established independent dose recalculation system (DRS). Each calculation was compared with the measured dose actually delivered to the phantom; cases in which the recalculation was more accurate were interpreted as a deficiency in the institution's TPS. A total of 258 phantom irradiation plans (172 lung and 86 spine) were recomputed. RESULTS: Overall, the DRS performed better than the TPSs in 47% of the spine phantom cases. However, the DRS was more accurate in 93% of failing spine phantom cases (with an average improvement of 2.35%), indicating a deficiency in the institution's treatment planning system. Deficiencies in dose calculation accounted for 60% of the overall discrepancy between measured and planned doses among spine phantoms. In contrast, lung phantom DRS calculations were more accurate in only 35% and 42% of all and failing lung phantom cases respectively, indicating that dose calculation errors were not substantially present. These errors accounted for only 30% of the overall discrepancy between measured and planned doses. CONCLUSIONS: Dose calculation errors are common and substantial in IROC spine phantom irradiations, highlighting a major failure mode in this phantom and in clinical treatment management of these cases. In contrast, dose calculation accuracy had only a minimal contribution to failing lung phantom results, indicating that other failure modes drive problems with this phantom and similar clinical treatments.

Reference dataset of users' photon beam modeling parameters for the Eclipse, Pinnacle, and RayStation treatment planning systems.

PURPOSE: The aim of this work was to provide a novel description of how the radiotherapy community configures treatment planning system (TPS) radiation beam models for clinically used treatment machines. Here we describe the results of a survey of self-reported TPS beam modeling parameter values across different C-arm linear accelerators, beam energies, and multileaf collimator (MLC) configurations. ACQUISITION AND VALIDATION METHODS: Beam modeling data were acquired via electronic survey implemented through the Imaging and Radiation Oncology Core (IROC) Houston Quality Assurance Center's online facility questionnaire. The survey was open to participation from January 2018 through January 2019 for all institutions monitored by IROC. After quality control, 2818 beam models were collected from 642 institutions. This survey, designed for Eclipse, Pinnacle, and RayStation, instructed physicists to report parameter values used to model the radiation source and MLC for each treatment machine and beam energy used clinically for intensity-modulated radiation therapy. Parameters collected included the effective source/spot size, MLC transmission, dosimetric leaf gap, tongue and groove effect, and other nondosimetric parameters specific to each TPS. To facilitate survey participation, instructions were provided on how to identify requested beam modeling parameters within each TPS environment. DATA FORMAT AND USAGE NOTES: Numeric values of the beam modeling parameters are compiled and tabulated according to TPS and calculation algorithm, linear accelerator model class, beam energy, and MLC configuration. Values are also presented as distributions, ranging from the 2.5th to the 97.5th percentile. POTENTIAL APPLICATIONS: These data provide an independent guide describing how the radiotherapy community mathematically represents its clinical radiation beams. These distributions may be used by the community for comparison during the commissioning or verification of their TPS beam models. Ultimately, we hope that the current work will allow institutions to spot potentially suspicious parameter values and help ensure more accurate radiotherapy delivery.

Ultra high dose rate (35 Gy/sec) radiation does not spare the normal tissue in cardiac and splenic models of lymphopenia and gastrointestinal syndrome.

Recent reports have shown that very high dose rate radiation (35-100 Gy/second) referred to as FLASH tends to spare the normal tissues while retaining the therapeutic effect on tumor. We undertook a series of experiments to assess if ultra-high dose rate of 35 Gy/second can spare the immune system in models of radiation induced lymphopenia. We compared the tumoricidal potency of ultra-high dose rate and conventional dose rate radiation using a classical clonogenic assay in murine pancreatic cancer cell lines. We also assessed the lymphocyte sparing potential in cardiac and splenic irradiation models of lymphopenia and assessed the severity of radiation-induced gastrointestinal toxicity triggered by the two dose rate regimes in vivo. Ultra-high dose rate irradiation more potently induces clonogenic cell death than conventional dose rate irradiation with a dose enhancement factor at 10% survival (DEF10) of 1.310 and 1.365 for KPC and Panc02 cell lines, respectively. Ultra-high dose rate was equally potent in depleting CD3, CD4, CD8, and CD19 lymphocyte populations in both cardiac and splenic irradiation models of lymphopenia. Radiation-induced gastrointestinal toxicity was more pronounced and mouse survival (7 days vs. 15 days, p = 0.0001) was inferior in the ultra-high dose rate arm compared to conventional dose rate arm. These results suggest that, contrary to published data in other models of radiation-induced acute and chronic toxicity, dose rates of 35 Gy/s do not protect mice from the detrimental side effects of irradiation in our models of cardiac and splenic radiation-induced lymphopenia or gastrointestinal mucosal injury.

Radiation-induced lung toxicity in mice irradiated in a strong magnetic field.

Strong magnetic fields affect radiation dose deposition in MRI-guided radiation therapy systems, particularly at interfaces between tissues of differing densities such as those in the thorax. In this study, we evaluated the impact of a 1.5 T magnetic field on radiation-induced lung damage in C57L/J mice. We irradiated 140 mice to the whole thorax with parallel-opposed Co-60 beams to doses of 0, 9.0, 10.0, 10.5, 11.0, 12.0, or 13.0 Gy (20 mice per dose group). Ten mice per dose group were irradiated while a 1.5 T magnetic field was applied transverse to the radiation beam and ten mice were irradiated with the magnetic field set to 0 T. We compared survival and noninvasive assays of radiation-induced lung damage, namely respiratory rate and metrics derived from thoracic cone-beam CTs, between the two sets of mice. We report two main results. First, the presence of a transverse 1.5 T field during irradiation had no impact on survival of C57L/J mice. Second, there was a small but statistically significant effect on noninvasive assays of radiation-induced lung damage. These results provide critical safety data for the clinical introduction of MRI-guided radiation therapy systems.

Treatment plan complexity does not predict IROC Houston anthropomorphic head and neck phantom performance.

Previous works indicate that intensity-modulated radiotherapy (IMRT) and volumetric modulated arc therapy (VMAT) plans that are highly complex may produce more errors in dose calculation and treatment delivery. Multiple complexity metrics have been proposed and associated with IMRT QA results, but their relationships with plan performance using in situ dose measurements have not been thoroughly investigated. This study aimed to evaluate the relationships between IMRT treatment plan complexity and anthropomorphic phantom performance in order to assess the extent to which plan complexity is related to dosimetric performance in the IROC phantom credentialing program. Sixteen complexity metrics, including the modulation complexity score (MCS), several modulation indices, and total monitor units (MU) delivered, were evaluated for 343 head and neck phantom irradiations, comprising both IMRT (step-and-shoot and sliding window techniques) and VMAT. Spearman's correlations were used to explore the relationship between complexity and plan performance, as measured by the dosimetric differences between the treatment planning system (TPS) and thermoluminescent dosimeter (TLD) measurement, as well as film gamma analysis. Relationships were likewise determined for several combinations of subpopulations, based on the linear accelerator model, TPS used, and delivery modality. Evaluation of the complexity metrics presented here yielded no significant relationships (p > 0.01, Bonferroni-corrected) and all correlations were weak (less than ±0.30). These results indicate that complexity metrics have limited predictive utility in assessing plan performance in multi-institutional comparisons of IMRT plans. Other factors affecting plan accuracy, such as dosimetric modeling or multileaf collimator (MLC) performance, should be investigated to determine a more probable cause for dose delivery errors.