Reproducibility of chestwall and heart position using surface-guided versus RPM-guided DIBH radiotherapy for left breast cancer.

This study compared the reproducibility of chestwall and heart position using surface-guided versus RPM (real-time position management)-guided deep inspiration breath hold (DIBH) radiotherapy for left sided breast cancer. Forty DIBH patients under either surface-guided radiotherapy (SGRT) or RPM guidance were studied. For patients treated with tangential fields, reproducibility was measured as the displacements in central lung distance (CLD) and heart shadow to field edge distance (HFD) between pretreatment MV (megavoltage) images and planning DRRs (digitally reconstructed radiographs). For patients treated with volumetric modulated arc therapy (VMAT), sternum to isocenter (ISO) distance (StID), spine to rib edge distance (SpRD), and heart shadow to central axis (CAX) distance (HCD) between pretreatment kV images and planning DRRs were measured. These displacements were compared between SGRT and RPM-guided DIBH. In tangential patients, the mean absolute displacements of SGRT versus RPM guidance were 0.19 versus 0.23 cm in CLD, and 0.33 versus 0.62 cm in HFD. With respect to planning DRR, heart appeared closer to the field edge by 0.04 cm with surface imaging versus 0.62 cm with RPM. In VMAT patients, the displacements of surface imaging versus RPM guidance were 0.21 versus 0.15 cm in StID, 0.24 versus 0.19 cm in SpRD, and 0.72 versus 0.41 cm in HCD. Heart appeared 0.41 cm further away from CAX with surface imaging, whereas 0.10 cm closer to field CAX with RPM. None of the differences between surface imaging and RPM guidance was statistically significant. In conclusion, the displacements of chestwall were small and were comparable with SGRT- or RPM-guided DIBH. The position deviations of heart were larger than those of chestwall with SGRT or RPM. Although none of the differences between SGRT and RPM guidance were statistically significant, there was a trend that the position deviations of heart were smaller and more favorable with SGRT than with RPM guidance in tangential patients.

A uniform and versatile surface-guided radiotherapy procedure and workflow for high-quality breast deep-inspiration breath-hold treatment in a multi-center institution.

PURPOSE: We share our experiences on uniformly implementing an effective and efficient SGRT procedure with a new clinical workflow for treating breast patients in deep-inspiration breath-hold (DIBH) among 9 clinical centers using 26 optical surface imaging (OSI) systems. METHODS: Our procedures have five major components: (1) acquiring both free-breathing (FB) and DIBH computed tomography (CT) at simulation to quantify the rise of the anterior surface, (2) defining uniformly a large region of interest (ROI) to accommodate large variations in patient anatomy and treatment techniques, (3) performing two-step setup in FB by first aligning the arm and chin to minimize breast deformation and reproduce local lymphnode positions and then aligning the ROI, (4) aligning the vertical shift precisely from FB to DIBH, and (5) capturing a new on-site reference image at DIBH to separate residual setup errors from the DIBH motion monitoring uncertainties. Moreover, a new clinical workflow was developed for patient data preparation using 4 OSI offline workstations without interruption of SGRT treatment at 22 OSI online workstations. This procedure/workflow is suitable for all photon planning techniques, including 2-field, 3-field, 4-field, partial breast irradiation (PBI), and volumetric-modulated arc therapy (VMAT) with or without bolus. RESULTS: Since 2019, we have developed and applied the uniform breast SGRT DIBH procedure with optimized clinical workflow and ensured treatment accuracy among the nine clinics within our institution. About 150 breast DIBH patients are treated daily and two major upgrades are achieved smoothly throughout our institution, owing to the uniform and versatile procedure, adequate staff training, and efficient workflow with effective clinical supports and backup strategies. CONCLUSION: The uniform and versatile breast SGRT DIBH procedure and workflow have been developed to ensure smooth and optimal clinical operations, simplify clinical staff training and clinical troubleshooting, and allow high-quality SGRT delivery in a busy multi-center institution.

Accuracy and efficiency of respiratory gating comparable to deep inspiration breath hold for pancreatic cancer treatment.

PURPOSE: Deep inspiration breath hold (DIBH) and respiratory gating (RG) are widely used to reduce movement of target and healthy organs caused by breathing during irradiation. We hypothesized that accuracy and efficiency comparable to DIBH can be achieved with RG for pancreas treatment. METHODS AND MATERIALS: Twenty consecutive patients with pancreatic cancer treated with DIBH (eight) or RG (twelve) volumetric modulated arc therapy during 2017-2019 were included in this study, with radiopaque markers implanted near or in the targets. Seventeen patients received 25 fractions, while the other three received 15 fractions. Only patients who could not tolerate DIBH received RG treatment. While both techniques relied on respiratory signals from external markers, internal target motions were monitored with kV X-ray imaging during treatment. A 3-mm external gating window was used for DIBH treatment; RG treatment was centered on end-expiration with a duty cycle of 40%, corresponding to an external gating window of 2-3 mm. During dose delivery, kV images were automatically taken every 20◦ or 40◦ gantry rotation, from which internal markers were identified. The marker displacement from their initial positions and the residual motion amplitudes were calculated. For the analysis of treatment efficiency, the treatment time of every session was calculated from the motion management waveform files recorded at the treatment console. RESULTS: Within one fraction, the displacement was 0-5 mm for DIBH and 0-6 mm for RG. The average magnitude of displacement for each patient during the entire course of treatment ranged 0-3 mm for both techniques. No statistically significant difference in displacement or residual motion was observed between the two techniques. The average treatment time was 15 min for DIBH and 17 min for RG, with no statistical significance. CONCLUSIONS: The accuracy and efficiency were comparable between RG and DIBH treatment for pancreas irradiation. RG is a feasible alternative strategy to DIBH.

Treatment planning and outcomes effects of reducing the preferred mean esophagus dose for conventionally fractionated non-small cell lung cancer radiotherapy.

Based on an analysis of published literature, our department recently lowered the preferred mean esophagus dose (MED) constraint for conventionally fractionated (2 Gy/fraction in approximately 30 fractions) treatment of locally advanced non-small cell lung cancer (LA-NSCLC) with the goal of reducing the incidence of symptomatic acute esophagitis (AE). The goal of the change was to encourage treatment planners to achieve a MED close to 21 Gy while still permitting MED to go up to the previous guideline of 34 Gy in difficult cases. We compared all our suitable LA-NSCLC patients treated with plans from one year before through one year after the constraint change. The primary endpoint for this study was achievability of the new constraint by the planners; the secondary endpoint was reduction in symptomatic AE. Planners were able to achieve the new constraint in statistically significantly more cases during the year following its explicit implementation than in the year before (P = 0.0025). Furthermore, 38% of patients treated after the new constraint developed symptomatic AE during their treatment as opposed to 48% of the patients treated before. This is a clinically desirable endpoint although the observed difference was not statistically significant. A subsequent power calculation suggests that this is due to the relatively small number of patients in the study.

Failure mode and effect analysis for linear accelerator-based paraspinal stereotactic body radiotherapy.

INTRODUCTION: Paraspinal stereotactic body radiotherapy (SBRT) involves risks of severe complications. We evaluated the safety of the paraspinal SBRT program in a large academic hospital by applying failure modes and effects analysis. METHODS: The analysis was conducted by a multidisciplinary committee (two therapists, one dosimetrist, four physicists, and two radiation oncologists). The paraspinal SBRT workflow was segmented into four phases (simulation, treatment planning, delivery, and machine quality assurance (QA)). Each phase was further divided into a sequence of sub-processes. Potential failure modes (PFM) were identified from each subprocess and scored in terms of the frequency of occurrence, severity and detectability, and a risk priority number (RPN). High-risk PFMs were identified based on RPN and were studied for root causes using fault tree analysis. RESULTS: Our paraspinal SBRT process was characterized by eight simulations, 11 treatment planning, nine delivery, and two machine QA sub-processes. There were 18, 29, 19, and eight PFMs identified from simulation, planning, treatment, and machine QA, respectively. The median RPN of the PFMs was 62.9 for simulation, 68.3 for planning, 52.9 for delivery, and 22.0 for machine QA. The three PFMs with the highest RPN were: previous radiotherapy outside the institution is not accurately evaluated (RPN: 293.3), incorrect registration between diagnostic magnetic resonance imaging and simulation computed tomography causing incorrect contours (273.0), and undetected patient movement before ExacTrac baseline (217.8). Remedies to the high RPN failures were implemented, including staff education, standardized magnetic resonance imaging acquisition parameters, and an image fusion process, and additional QA on beam steering. CONCLUSIONS: A paraspinal SBRT workflow in a large clinic was evaluated using a multidisciplinary and systematic risk analysis, which led to feasible solutions to key root causes. Treatment planning was a major source of PFMs that systematically affect the safety and quality of treatments. Accurate evaluation of external treatment records remains a challenge.

Intrafraction tumor motion during deep inspiration breath hold pancreatic cancer treatment.

PURPOSE: Beam gating with deep inspiration breath hold (DIBH) has been widely used for motion management in radiotherapy. Normally it relies on some external surrogate for estimating the internal target motion, while the exact internal motion is unknown. In this study, we used the intrafraction motion review (IMR) application to directly track an internal target and characterized the residual motion during DIBH treatment for pancreatic cancer patients through their full treatment courses. METHODS AND MATERIALS: Eight patients with pancreatic cancer treated with DIBH volumetric modulated arc therapy in 2017 and 2018 were selected for this study, each with some radiopaque markers (fiducial or surgical clips) implanted near or inside the target. The Varian Real-time Position Management (RPM) system was used to monitor the breath hold, represented by the anterior-posterior displacement of an external surrogate, namely reflective markers mounted on a plastic block placed on the patient's abdomen. Before each treatment, a cone beam computed tomography (CBCT) scan under DIBH was acquired for patient setup. For scan and treatment, the breath hold reported by RPM had to lie within a 3 mm window. IMR kV images were taken every 20° or 40° gantry rotation during dose delivery, resulting in over 5000 images for the cohort. The internal markers were manually identified in the IMR images. The residual motion amplitudes of the markers as well as the displacement from their initial positions located in the setup CBCT images were analyzed. RESULTS: Even though the external markers indicated that the respiratory motion was within 3 mm in DIBH treatment, significant residual internal target motion was observed for some patients. The range of average motion was from 3.4 to 7.9 mm, with standard deviation ranging from 1.2 to 3.5 mm. For all patients, the target residual motions seemed to be random with mean positions around their initial setup positions. Therefore, the absolute target displacement relative to the initial position was small during DIBH treatment, with the mean and the standard deviation 0.6 and 2.9 mm, respectively. CONCLUSIONS: Internal target motion may differ from external surrogate motion in DIBH treatment. Radiographic verification of target position at the beginning and during each fraction is necessary for precise RT delivery. IMR can serve as a useful tool to directly monitor the internal target motion.

Evaluation of respiratory motion-corrected cone-beam CT at end expiration in abdominal radiotherapy sites: a prospective study.

BACKGROUND: Cone beam computed tomography (CBCT) for radiotherapy image guidance suffers from respiratory motion artifacts. This limits soft tissue visualization and localization accuracy, particularly in abdominal sites. We report on a prospective study of respiratory motion-corrected (RMC)-CBCT to evaluate its efficacy in localizing abdominal organs and improving soft tissue visibility at end expiration. MATERIAL AND METHODS: In an IRB approved study, 11 patients with gastroesophageal junction (GEJ) cancer and five with pancreatic cancer underwent a respiration-correlated CT (4DCT), a respiration-gated CBCT (G-CBCT) near end expiration and a one-minute free-breathing CBCT scan on a single treatment day. Respiration was recorded with an external monitor. An RMC-CBCT and an uncorrected CBCT (NC-CBCT) were computed from the free-breathing scan, based on a respiratory model of deformations derived from the 4DCT. Localization discrepancy was computed as the 3D displacement of the GEJ region (GEJ patients), or gross tumor volume (GTV) and kidneys (pancreas patients) in the NC-CBCT and RMC-CBCT relative to their positions in the G-CBCT. Similarity of soft-tissue features was measured using a normalized cross correlation (NCC) function. RESULTS: Localization discrepancy from the end-expiration G-CBCT was reduced for RMC-CBCT compared to NC-CBCT in eight of eleven GEJ cases (mean ± standard deviation, respectively, 0.21 ± 0.11 and 0.43 ± 0.28 cm), in all five pancreatic GTVs (0.26 ± 0.21 and 0.42 ± 0.29 cm) and all ten kidneys (0.19 ± 0.13 and 0.51 ± 0.25 cm). Soft-tissue feature similarity around GEJ was higher with RMC-CBCT in nine of eleven cases (NCC =0.48 ± 0.20 and 0.43 ± 0.21), and eight of ten kidneys (0.44 ± 0.16 and 0.40 ± 0.17). CONCLUSIONS: In a prospective study of motion-corrected CBCT in GEJ and pancreas, RMC-CBCT yielded improved organ visibility and localization accuracy for gated treatment at end expiration in the majority of cases.

Stereotactic body radiation therapy (SBRT) improves local control and overall survival compared to conventionally fractionated radiation for stage I non-small cell lung cancer (NSCLC).

BACKGROUND: Stereotactic body radiotherapy (SBRT) has been adopted as the standard of care for inoperable early-stage non-small cell lung cancer (NSCLC), with local control rates consistently >90%. However, data directly comparing the outcomes of SBRT with those of conventionally fractionated radiotherapy (CONV) is lacking. MATERIAL AND METHODS: Between 1990 and 2013, 497 patients (525 lesions) with early-stage NSCLC (T1-T2N0M0) were treated with CONV (n = 127) or SBRT (n = 398). In this retrospective analysis, five endpoints were compared, with and without adjusting for clinical and dosimetric factors. Competing risks analysis was performed to estimate and compare the cumulative incidence of local failure (LF), nodal failure (NF), distant failure (DF) and disease progression. Overall survival (OS) was estimated by the Kaplan-Meier method and compared by the Cox regression model. Propensity score (PS) matched analysis was performed based on seven patient and clinical variables: age, gender, Karnofsky performance status (KPS), histology, T stage, biologically equivalent dose (BED), and history of smoking. RESULTS: The median dose delivered for CONV was 75.6 Gy in 1.8-2.0 Gy fractions (range 60-90 Gy; median BED = 89.20 Gy) and for SBRT 48 Gy in four fractions (45-60 Gy in three to five fractions; median BED = 105.60 Gy). Median follow-up was 24.4 months, and 3-year LF rates were 34.1% with CONV and 13.6% with SBRT (p < .001). Three-year OS rates were 38.9 and 53.1%, respectively (p = .018). PS matching showed a significant improvement of OS (p = .0497) for SBRT. T stage was the only variable correlating with all five endpoints. CONCLUSION: SBRT compared to CONV is associated with improved LF rates and OS. Our data supports the continued use and expansion of SBRT as the standard of care treatment for inoperable early-stage NSCLC.

Are fiducial markers useful surrogates when using respiratory gating to reduce motion of gastroesophageal junction tumors?

BACKGROUND: Radiation therapy (RT) is an integral component of the management of gastroesophageal junction (GEJ) tumors. We evaluated the use of implanted radiopaque fiducials as tumor surrogates to allow for more focal delivery of RT to these mobile tumors when using respiratory gating (RG) to reduce motion. MATERIAL AND METHODS: We analyzed four-dimensional computed tomography scans of 20 GEJ patients treated with RG and assessed correlation between tumor and implanted fiducial motion over the whole respiratory cycle and within a clinically realistic gate around end-exhalation. We evaluated fiducial motion concordance in 11 patients with multiple fiducials. RESULTS: Gating reduced anterior-posterior (AP) and superior-inferior (SI) mean tumor and fiducial motions by over 50%. Fiducials and primary tumor motions were moderately correlated: R(2) for AP and SI linear fits to the entire group were 0.54 and 0.68, respectively, but the correlation had strong inter-patient variation. For all patients with multiple fiducials, relative in-gate displacements were below 3 mm; results were similar for eight of 11 patients over the whole cycle. CONCLUSION: Implanted fiducial and gross tumor volume (GTV) motions correlate well but the correlation is patient-specific and may be dependent on the location of the fiducials with respect to the GTV.

Late urinary toxicity modeling after stereotactic body radiotherapy (SBRT) in the definitive treatment of localized prostate cancer.

BACKGROUND: Late urinary symptom flare has been shown to occur in a small subset of men treated with ultra- hypofractionated stereotactic body radiotherapy (SBRT) for prostate cancer. The purpose of this study was to use normal tissue complication probability modeling in an effort to derive SBRT specific dosimetric predictor's of late urinary flare. MATERIAL AND METHODS: Two hundred and sixteen men were treated for localized prostate cancer using ultra- hypofractionated SBRT. A dose of 35-36.25 Gy in 5 fractions was delivered to the prostate and proximal seminal vesicles. Functional surveys were conducted before and after treatment to assess late toxicity. Phenomenologic NTCP models were fit to bladder DVHs and late urinary flare outcomes using maximum likelihood estimation. RESULTS: Twenty-nine patients experienced late urinary flare within two years of completion of treatment. Fitting of bladder DVH data to a Lyman NTCP model resulted in parameter estimates of m, TD50, and n of 0.19 (0-0.47), 38.7 Gy (31.1-46.4), and 0.13 (-0.14-0.41), respectively. Subsequent fit to a hottest volume probit model revealed a significant association of late urinary flare with dose to the hottest 12.7% of bladder volume. Multivariate analysis resulted in a final model that included patient age and hottest volume probit model predictions. Kaplan-Meier analysis demonstrated a two-year urinary flare free survival of 95.7% in patients 65 years or older with a bladder D12.7% of 33.5 Gy or less, compared to 74.5% in patients meeting none of these criteria. CONCLUSION: NTCP modeling of late urinary flare after ultra-hypofractionated prostate SBRT demonstrates a relatively small volume effect for dose to the bladder, suggesting that reduction of volume receiving elevated dose will result in decreased incidence of late urinary toxicity. Future studies will be needed to examine the impact of dose to other potential sources of late genitourinary toxicity.

Geometric dose prediction model for hemithoracic intensity-modulated radiation therapy in mesothelioma patients with two intact lungs.

The presence of two intact lungs makes it challenging to reach a tumoricidal dose with hemithoracic pleural intensity-modulated radiation therapy (IMRT) in patients with malignant pleural mesothelioma (MPM) who underwent pleurectomy/decortications or have unresectable disease. We developed an anatomy-based model to predict attainable prescription dose before starting optimization. Fifty-six clinically delivered IMRT plans were analyzed regarding correlation of prescription dose and individual and total lung volumes, planning target volume (PTV), ipsilateral normal lung volume and ratios: contralateral/ipsilateral lung (CIVR); contralateral lung/PTV (CPVR); ipsilateral lung /PTV (IPVR); ipsilateral normal lung /total lung (INTLVR); ipsilateral normal lung/PTV (INLPVR). Spearman's rank correlation and Fisher's exact test were used. Correlation between mean ipsilateral lung dose (MILD) and these volume ratios and between prescription dose and single lung mean doses were studied. The prediction models were validated in 23 subsequent MPM patients. CIVR showed the strongest correlation with dose (R=0.603,p<0.001) and accurately predicted prescription dose in the validation cases. INLPVR and MILD as well as MILD and prescription dose were significantly correlated (R=-0.784,p<0.001 and R=0.554,p<0.001, respectively) in the training and validation cases. Parameters obtainable directly from planning scan anatomy predict achievable prescription doses for hemithoracic IMRT treatment of MPM patients with two intact lungs. PACS number(s): 87.55.de, 87.55.dk.

Flattening filter-free accelerators: a report from the AAPM Therapy Emerging Technology Assessment Work Group.

This report describes the current state of flattening filter-free (FFF) radiotherapy beams implemented on conventional linear accelerators, and is aimed primarily at practicing medical physicists. The Therapy Emerging Technology Assessment Work Group of the American Association of Physicists in Medicine (AAPM) formed a writing group to assess FFF technology. The published literature on FFF technology was reviewed, along with technical specifications provided by vendors. Based on this information, supplemented by the clinical experience of the group members, consensus guidelines and recommendations for implementation of FFF technology were developed. Areas in need of further investigation were identified. Removing the flattening filter increases beam intensity, especially near the central axis. Increased intensity reduces treatment time, especially for high-dose stereotactic radiotherapy/radiosurgery (SRT/SRS). Furthermore, removing the flattening filter reduces out-of-field dose and improves beam modeling accuracy. FFF beams are advantageous for small field (e.g., SRS) treatments and are appropriate for intensity-modulated radiotherapy (IMRT). For conventional 3D radiotherapy of large targets, FFF beams may be disadvantageous compared to flattened beams because of the heterogeneity of FFF beam across the target (unless modulation is employed). For any application, the nonflat beam characteristics and substantially higher dose rates require consideration during the commissioning and quality assurance processes relative to flattened beams, and the appropriate clinical use of the technology needs to be identified. Consideration also needs to be given to these unique characteristics when undertaking facility planning. Several areas still warrant further research and development. Recommendations pertinent to FFF technology, including acceptance testing, commissioning, quality assurance, radiation safety, and facility planning, are presented. Examples of clinical applications are provided. Several of the areas in which future research and development are needed are also indicated.

Hypofractionated Stereotactic Radiation Therapy Dosimetric Tolerances for the Inferior Aspect of the Brachial Plexus: A Systematic Review.

We sought to systematically review and summarize dosimetric factors associated with radiation-induced brachial plexopathy (RIBP) after stereotactic body radiation therapy (SBRT) or hypofractionated image guided radiation therapy (HIGRT). From published studies identified from searches of PubMed and Embase databases, data quantifying risks of RIBP after 1- to 10-fraction SBRT/HIGRT were extracted and summarized. Published studies have reported <10% risks of RIBP with maximum doses (Dmax) to the inferior aspect of the brachial plexus of 32 Gy in 5 fractions and 25 Gy in 3 fractions. For 10-fraction HIGRT, risks of RIBP appear to be low with Dmax < 40 to 50 Gy. For a given dose value, greater risks are anticipated with point volume-based metrics (ie, D0.03-0.035cc: minimum dose to hottest 0.03-0.035 cc) versus Dmax. With SBRT/HIGRT, there were insufficient published data to predict risks of RIBP relative to brachial plexus dose-volume exposure. Minimizing maximum doses and possibly volume exposure of the brachial plexus can reduce risks of RIBP after SBRT/HIGRT. Further study is needed to better understand the effect of volume exposure on the brachial plexus and whether there are location-specific susceptibilities along or within the brachial plexus structure.

Creating patient-specific digital phantoms with a longitudinal atlas for evaluating deformable CT-CBCT registration in adaptive lung radiotherapy.

BACKGROUND: Quality assurance of deformable image registration (DIR) is challenging because the ground truth is often unavailable. In addition, current approaches that rely on artificial transformations do not adequately resemble clinical scenarios encountered in adaptive radiotherapy. PURPOSE: We developed an atlas-based method to create a variety of patient-specific serial digital phantoms with CBCT-like image quality to assess the DIR performance for longitudinal CBCT imaging data in adaptive lung radiotherapy. METHODS: A library of deformations was created by extracting the longitudinal changes observed between a planning CT and weekly CBCT from an atlas of lung radiotherapy patients. The planning CT of an inquiry patient was first deformed by mapping the deformation pattern from a matched atlas patient, and subsequently appended with CBCT artifacts to imitate a weekly CBCT. Finally, a group of digital phantoms around an inquiry patient was produced to simulate a series of possible evolutions of tumor and adjacent normal structures. We validated the generated deformation vector fields (DVFs) to ensure numerically and physiologically realistic transformations. The proposed framework was applied to evaluate the performance of the DIR algorithm implemented in the commercial Eclipse treatment planning system in a retrospective study of eight inquiry patients. RESULTS: The generated DVFs were inverse consistent within less than 3 mm and did not exhibit unrealistic folding. The deformation patterns adequately mimicked the observed longitudinal anatomical changes of the matched atlas patients. Worse Eclipse DVF accuracy was observed in regions of low image contrast or artifacts. The structure volumes exhibiting a DVF error magnitude of equal or more than 2 mm ranged from 24.5% (spinal cord) to 69.2% (heart) and the maximum DVF error exceeded 5 mm for all structures except the spinal cord. Contour-based evaluations showed a high degree of alignment with dice similarity coefficients above 0.8 in all cases, which underestimated the overall DVF accuracy within the structures. CONCLUSIONS: It is feasible to create and augment digital phantoms based on a particular patient of interest using multiple series of deformation patterns from matched patients in an atlas. This can provide a semi-automated procedure to complement the quality assurance of CT-CBCT DIR and facilitate the clinical implementation of image-guided and adaptive radiotherapy that involve longitudinal CBCT imaging studies.

Reporting Standards for Complication Studies of Radiation Therapy for Pediatric Cancer: Lessons From PENTEC.

The major aim of Pediatric Normal Tissue Effects in the Clinic (PENTEC) was to synthesize quantitative published dose/-volume/toxicity data in pediatric radiation therapy. Such systematic reviews are often challenging because of the lack of standardization and difficulty of reporting outcomes, clinical factors, and treatment details in journal articles. This has clinical consequences: optimization of treatment plans must balance between the risks of toxicity and local failure; counseling patients and their parents requires knowledge of the excess risks encountered after a specific treatment. Studies addressing outcomes after pediatric radiation therapy are particularly challenging because: (a) survivors may live for decades after treatment, and the latency time to toxicity can be very long; (b) children's maturation can be affected by radiation, depending on the developmental status of the organs involved at time of treatment; and (c) treatment regimens frequently involve chemotherapies, possibly modifying and adding to the toxicity of radiation. Here we discuss: basic reporting strategies to account for the actuarial nature of the complications; the reporting of modeling of abnormal development; and the need for standardized, comprehensively reported data sets and multivariate models (ie, accounting for the simultaneous effects of radiation dose, age, developmental status at time of treatment, and chemotherapy dose). We encourage the use of tools that facilitate comprehensive reporting, for example, electronic supplements for journal articles. Finally, we stress the need for clinicians to be able to trust artificial intelligence models of outcome of radiation therapy, which requires transparency, rigor, reproducibility, and comprehensive reporting. Adopting the reporting methods discussed here and in the individual PENTEC articles will increase the clinical and scientific usefulness of individual reports and associated pooled analyses.

Improving Pediatric Normal Tissue Radiation Dose-Response Modeling in Children With Cancer: A PENTEC Initiative.

The development of normal tissue radiation dose-response models for children with cancer has been challenged by many factors, including small sample sizes; the long length of follow-up needed to observe some toxicities; the continuing occurrence of events beyond the time of assessment; the often complex relationship between age at treatment, normal tissue developmental dynamics, and age at assessment; and the need to use retrospective dosimetry. Meta-analyses of published pediatric outcome studies face additional obstacles of incomplete reporting of critical dosimetric, clinical, and statistical information. This report describes general methods used to address some of the pediatric modeling issues. It highlights previous single- and multi-institutional pediatric dose-response studies and summarizes how each PENTEC taskforce addressed the challenges and limitations of the reviewed publications in constructing, when possible, organ-specific dose-effect models.

Clinical and Dosimetric Risk Factors Associated With Radiation-Induced Lung Toxicities After Multiple Courses of Lung Stereotactic Body Radiation Therapy.

Purpose: Data are limited on radiation-induced lung toxicities (RILT) after multiple courses of lung stereotactic body radiation therapy (SBRT). We herein analyze a large cohort of patients to explore the clinical and dosimetric risk factors associated with RILT in such settings. Methods and Materials: A single institutional database of patients treated with multiple courses of lung SBRT between January 2014 and December 2019 was analyzed. Grade 2 or higher (G2+) RILT after the last course of SBRT was the primary endpoint. Composite plans were generated with advanced algorithms including deformable registration and equivalent dose adjustment. Logistic regression analyses were performed to examine correlations between patient or treatment factors including dosimetry and G2+ RILT. Risk stratification of patients and lung constraints based on acceptable normal tissue complication probability were calculated based on risk factors identified. Results: Among 110 eligible patients (56 female and 54 male), there were 64 synchronous (58.2%; defined as 2 courses of SBRT delivered within 30 days) and 46 metachronous (41.8%) courses of SBRT. The composite median lung V20, lung V5, and mean lung dose were 9.9% (interquartile range [IQR], 7.3%-12.4%), 32.2% (IQR, 25.5%-40.1%), and 7.0 Gy (IQR, 5.5 Gy-8.6 Gy), respectively. With a median follow-up of 21.1 months, 30 patients (27.3%) experienced G2+ RILT. Five patients (4.5%) developed G3 RILT, and 1 patient (0.9%) developed G4 RILT, and no patients developed G5 RILT. On multivariable regression analysis, female sex (odds ratio [OR], 4.35; 95% CI, 1.49%-14.3%; P = .01), synchronous SBRT (OR, 8.78; 95% CI, 2.27%-47.8%; P = .004), prior G2+ RILT (OR, 29.8; 95% CI, 2.93%-437%; P = .007) and higher composite lung V20 (OR, 1.18; 95% CI, 1.02%-1.38%; P = .030) were associated with significantly higher likelihood of G2+ RILT. Conclusions: Our data suggest an acceptable incidence of G2+ RILT after multiple courses of lung SBRT. Female sex, synchronous SBRT, prior G2+ RILT, and higher composite lung V20 may be risk factors for G2+ RILT.

Exploring published and novel pre-treatment CT and PET radiomics to stratify risk of progression among early-stage non-small cell lung cancer patients treated with stereotactic radiation.

PURPOSE: Disease progression after definitive stereotactic body radiation therapy (SBRT) for early-stage non-small cell lung cancer (NSCLC) occurs in 20-40% of patients. Here, we explored published and novel pre-treatment CT and PET radiomics features to identify patients at risk of progression. MATERIALS/METHODS: Published CT and PET features were identified and explored along with 15 other CT and PET features in 408 consecutively treated early-stage NSCLC patients having CT and PET < 3 months pre-SBRT (training/set-aside validation subsets: n = 286/122). Features were associated with progression-free survival (PFS) using bootstrapped Cox regression (Bonferroni-corrected univariate predictor: p ≤ 0.002) and only non-strongly correlated predictors were retained (|Rs|<0.70) in forward-stepwise multivariate analysis. RESULTS: Tumor diameter and SUVmax were the two most frequently reported features associated with progression/survival (in 6/20 and 10/20 identified studies). These two features and 12 of the 15 additional features (CT: 6; PET: 6) were candidate PFS predictors. A re-fitted model including diameter and SUVmax presented with the best performance (c-index: 0.78; log-rank p-value < 0.0001). A model built with the two best additional features (CTspiculation1 and SUVentropy) had a c-index of 0.75 (log-rank p-value < 0.0001). CONCLUSIONS: A re-fitted pre-treatment model using the two most frequently published features - tumor diameter and SUVmax - successfully stratified early-stage NSCLC patients by PFS after receiving SBRT.

A Prospective Study on Deep Inspiration Breath Hold Thoracic Radiation Therapy Guided by Bronchoscopically Implanted Electromagnetic Transponders.

BACKGROUND: Electromagnetic transponders bronchoscopically implanted near the tumor can be used to monitor deep inspiration breath hold (DIBH) for thoracic radiation therapy (RT). The feasibility and safety of this approach require further study. METHODS: We enrolled patients with primary lung cancer or lung metastases. Three transponders were implanted near the tumor, followed by simulation with DIBH, free breathing, and 4D-CT as backup. The initial gating window for treatment was ±5 mm; in a second cohort, the window was incrementally reduced to determine the smallest feasible gating window. The primary endpoint was feasibility, defined as completion of RT using transponder-guided DIBH. Patients were followed for assessment of transponder- and RT-related toxicity. RESULTS: We enrolled 48 patients (35 with primary lung cancer and 13 with lung metastases). The median distance of transponders to tumor was 1.6 cm (IQR 0.6-2.8 cm). RT delivery ranged from 3 to 35 fractions. Transponder-guided DIBH was feasible in all but two patients (96% feasible), where it failed because the distance between the transponders and the antenna was >19 cm. Among the remaining 46 patients, 6 were treated prone to keep the transponders within 19 cm of the antenna, and 40 were treated supine. The smallest feasible gating window was identified as ±3 mm. Thirty-nine (85%) patients completed one year of follow-up. Toxicities at least possibly related to transponders or the implantation procedure were grade 2 in six patients (six incidences, cough and hemoptysis), grade 3 in three patients (five incidences, cough, dyspnea, pneumonia, and supraventricular tachycardia), and grade 4 pneumonia in one patient (occurring a few days after implantation but recovered fully and completed RT). Toxicities at least possibly related to RT were grade 2 in 18 patients (41 incidences, most commonly cough, fatigue, and pneumonitis) and grade 3 in four patients (seven incidences, most commonly pneumonia), and no patients had grade 4 or higher toxicity. CONCLUSIONS: Bronchoscopically implanted electromagnetic transponder-guided DIBH lung RT is feasible and safe, allowing for precise tumor targeting and reduced normal tissue exposure. Transponder-antenna distance was the most common challenge due to a limited antenna range, which could sometimes be circumvented by prone positioning.

Brain and Brain Stem Necrosis After Reirradiation for Recurrent Childhood Primary Central Nervous System Tumors: A PENTEC Comprehensive Review.

PURPOSE: Reirradiation is increasingly used in children and adolescents/young adults (AYA) with recurrent primary central nervous system tumors. The Pediatric Normal Tissue Effects in the Clinic (PENTEC) reirradiation task force aimed to quantify risks of brain and brain stem necrosis after reirradiation. METHODS AND MATERIALS: A systematic literature search using the PubMed and Cochrane databases for peer-reviewed articles from 1975 to 2021 identified 92 studies on reirradiation for recurrent tumors in children/AYA. Seventeen studies representing 449 patients who reported brain and brain stem necrosis after reirradiation contained sufficient data for analysis. While all 17 studies described techniques and doses used for reirradiation, they lacked essential details on clinically significant dose-volume metrics necessary for dose-response modeling on late effects. We, therefore, estimated incidences of necrosis with an exact 95% CI and qualitatively described data. Results from multiple studies were pooled by taking the weighted average of the reported crude rates from individual studies. RESULTS: Treated cancers included ependymoma (n = 279 patients; 7 studies), medulloblastoma (n = 98 patients; 6 studies), any CNS tumors (n = 62 patients; 3 studies), and supratentorial high-grade gliomas (n = 10 patients; 1 study). The median interval between initial and reirradiation was 2.3 years (range, 1.2-4.75 years). The median cumulative prescription dose in equivalent dose in 2-Gy fractions (EQD22; assuming α/ß value = 2 Gy) was 103.8 Gy (range, 55.8-141.3 Gy). Among 449 reirradiated children/AYA, 22 (4.9%; 95% CI, 3.1%-7.3%) developed brain necrosis and 14 (3.1%; 95% CI, 1.7%-5.2%) developed brain stem necrosis with a weighted median follow-up of 1.6 years (range, 0.5-7.4 years). The median cumulative prescription EQD22 was 111.4 Gy (range, 55.8-141.3 Gy) for development of any necrosis, 107.7 Gy (range, 55.8-141.3 Gy) for brain necrosis, and 112.1 Gy (range, 100.2-117 Gy) for brain stem necrosis. The median latent period between reirradiation and the development of necrosis was 5.7 months (range, 4.3-24 months). Though there were more events among children/AYA undergoing hypofractionated versus conventionally fractionated reirradiation, the differences were not statistically significant (P = .46). CONCLUSIONS: Existing reports suggest that in children/AYA with recurrent brain tumors, reirradiation with a total EQD22 of about 112 Gy is associated with an approximate 5% to 7% incidence of brain/brain stem necrosis after a median follow-up of 1.6 years (with the initial course of radiation therapy being given with conventional prescription doses of ≤2 Gy per fraction and the second course with variable fractionations). We recommend a uniform approach for reporting dosimetric endpoints to derive robust predictive models of late toxicities following reirradiation.