Dosimetric evaluation of cone-beam CT-based synthetic CTs in pediatric patients undergoing intensity-modulated proton therapy.

PURPOSE: To evaluate dosimetric changes detected using synthetic computed tomography (sCT) derived from online cone-beam CTs (CBCT) in pediatric patients treated using intensity-modulated proton therapy (IMPT). METHODS: Ten pediatric patients undergoing IMPT and aligned daily using proton gantry-mounted CBCT were identified for retrospective analysis with treated anatomical sites fully encompassed in the CBCT field of view. Dates were identified when the patient received both a CBCT and a quality assurance CT (qCT) for routine dosimetric evaluation. sCTs were generated based on a deformable registration between the initial plan CT (pCT) and CBCT. The clinical IMPT plans were re-computed on the same day qCT and sCT, and dosimetric changes due to tissue change or response from the initial plan were computed using each image. Linear regression analysis was performed to determine the correlation between dosimetric changes detected using the qCT and the sCT. Gamma analysis was also used to compare the dose distributions computed on the qCT and sCT. RESULTS: The correlation coefficients (p-values) between qCTs and sCTs for changes detected in target coverage, overall maximum dose, and organ at risk dose were 0.97 (< .001), 0.84 (.002) and 0.91 (< .001), respectively. Mean ± SD gamma pass rates of the sCT-based dose compared to the qCT-based dose at 3%/3 mm, 3%/2 mm, and 2%/2 mm criteria were 96.5%±4.5%, 93.2%±6.3%, and 91.3%±7.8%, respectively. Pass rates tended to be lower for targets near lung. CONCLUSION: While insufficient for re-planning, sCTs provide approximate dosimetry without administering additional imaging dose in pediatric patients undergoing IMPT. Dosimetric changes detected using sCTs are correlated with changes detected using clinically-standard qCTs; however, residual differences in dosimetry remain a limitation. Further improvements in sCT image quality may both improve online dosimetric evaluation and reduce imaging dose for pediatric patients by reducing the need for routine qCTs.

Radiation Versus Immune Checkpoint Inhibitor Associated Pneumonitis: Distinct Radiologic Morphologies.

BACKGROUND: Patients with non-small cell lung cancer may develop pneumonitis after thoracic radiotherapy (RT) and immune checkpoint inhibitors (ICIs). We hypothesized that distinct morphologic features are associated with different pneumonitis etiologies. MATERIALS AND METHODS: We systematically compared computed tomography (CT) features of RT- versus ICI-pneumonitis. Clinical and imaging features were tested for association with pneumonitis severity. Lastly, we constructed an exploratory radiomics-based machine learning (ML) model to discern pneumonitis etiology. RESULTS: Between 2009 and 2019, 82 patients developed pneumonitis: 29 after thoracic RT, 23 after ICI, and 30 after RT + ICI. Fifty patients had grade 2 pneumonitis, 22 grade 3, and 7 grade 4. ICI-pneumonitis was more likely bilateral (65% vs. 28%; p = .01) and involved more lobes (66% vs. 45% involving at least three lobes) and was less likely to have sharp border (17% vs. 59%; p = .004) compared with RT-pneumonitis. Pneumonitis morphology after RT + ICI was heterogeneous, with 47% bilateral, 37% involving at least three lobes, and 40% sharp borders. Among all patients, risk factors for severe pneumonitis included poor performance status, smoking history, worse lung function, and bilateral and multifocal involvement on CT. An ML model based on seven radiomic features alone could distinguish ICI- from RT-pneumonitis with an area under the receiver-operating curve of 0.76 and identified the predominant etiology after RT + ICI concordant with multidisciplinary consensus. CONCLUSION: RT- and ICI-pneumonitis exhibit distinct spatial features on CT. Bilateral and multifocal lung involvement is associated with severe pneumonitis. Integrating these morphologic features in the clinical management of patients who develop pneumonitis after RT and ICIs may improve treatment decision-making. IMPLICATIONS FOR PRACTICE: Patients with non-small cell lung cancer often receive thoracic radiation and immune checkpoint inhibitors (ICIs), both of which can cause pneumonitis. This study identified similarities and differences in pneumonitis morphology on computed tomography (CT) scans among pneumonitis due to radiotherapy (RT) alone, ICI alone, and the combination of both. Patients who have bilateral CT changes involving at least three lobes are more likely to have ICI-pneumonitis, whereas those with unilateral CT changes with sharp borders are more likely to have radiation pneumonitis. After RT and/or ICI, severe pneumonitis is associated with bilateral and multifocal CT changes. These results can help guide clinicians in triaging patients who develop pneumonitis after radiation and during ICI treatment.

Comparison of treatment planning approaches for spatially fractionated irradiation of deep tumors.

PURPOSE: The purpose of this work was to compare the dosimetry and delivery times of 3D-conformal (3DCRT)-, volumetric modulated arc therapy (VMAT)-, and tomotherapy-based approaches for spatially fractionated radiation therapy for deep tumor targets. METHODS: Two virtual GRID phantoms were created consisting of 7 "target" cylinders (1-cm diameter) aligned longitudinally along the tumor in a honey-comb pattern, mimicking a conventional GRID block, with 2-cm center-to-center spacing (GRID2 cm ) and 3-cm center-to-center spacing (GRID3 cm ), all contained within a larger cylinder (8 and 10 cm in diameter for the GRID2 cm and GRID3 cm , respectively). In a single patient, a GRID3 cm structure was created within the gross tumor volume (GTV). Tomotherapy, VMAT (6 MV + 6 MV-flattening-filter-free) and multi-leaf collimator segment 3DCRT (6 MV) plans were created using commercially available software. Two tomotherapy plans were created with field widths (TOMO2.5 cm ) 2.5 cm and (TOMO5 cm ) 5 cm. Prescriptions for all plans were set to deliver a mean dose of 15 Gy to the GRID targets in one fraction. The mean dose to the GRID target and the heterogeneity of the dose distribution (peak-to-valley and peak-to-edge dose ratios) inside the GRID target were obtained. The volume of normal tissue receiving 7.5 Gy was determined. RESULTS: The peak-to-valley ratios for GRID2 cm /GRID3 cm /Patient were 2.1/2.3/2.8, 1.7/1.5/2.8, 1.7/1.9/2.4, and 1.8/2.0/2.8 for the 3DCRT, VMAT, TOMO5 cm , and TOMO2.5 cm plans, respectively. The peak-to-edge ratios for GRID2 cm /GRID3 cm /Patient were 2.8/3.2/5.4, 2.1/1.8/5.4, 2.0/2.2/3.9, 2.1/2.7/5.2 and for the 3DCRT, VMAT, TOMO5 cm , and TOMO2.5 cm plans, respectively. The volume of normal tissue receiving 7.5 Gy was lowest in the TOMO2.5 cm plan (GRID2 cm /GRID3 cm /Patient = 54 cm3 /19 cm3 /10 cm3 ). The VMAT plans had the lowest delivery times (GRID2 cm /GRID3 cm /Patient = 17 min/8 min/9 min). CONCLUSION: Our results present, for the first time, preliminary evidence comparing IMRT-GRID approaches which result in high-dose "islands" within a target, mimicking what is achieved with a conventional GRID block but without high-dose "tail" regions outside of the target. These approaches differ modestly in their ability to achieve high peak-to-edge ratios and also differ in delivery times.

Pulmonary MRI morphometry modeling of airspace enlargement in chronic obstructive pulmonary disease and alpha-1 antitrypsin deficiency.

PURPOSE: We generated lung morphometry measurements using single-breath diffusion-weighted MRI and three different acinar duct models in healthy participants and patients with emphysema stemming from chronic obstructive lung disease (COPD) and alpha-1 antitrypsin deficiency (AATD). METHODS: Single-breath-inhaled 3 He MRI with five diffusion sensitizations (b-value = 0, 1.6, 3.2, 4.8, and 6.4 s/cm2 ) was used, and signal intensities were fit using a cylindrical and single-compartment acinar-duct model to estimate MRI-derived mean linear intercept (Lm ) and surface-to-volume ratio (S/V). A stretched exponential model was also developed to estimate the mean airway length and Lm . RESULTS: We evaluated 42 participants, including 15 elderly never-smokers (69 ± 5 years), 12 ex-smokers without COPD (67 ± 11 years), 9 COPD ex-smokers (80 ± 6 years), and 6 AATD patients (59 ± 6 years). In the never- and ex-smokers, the diffusing capacity of the lung for carbon monoxide (DLCO ) and computed tomography relative area of less than -950 Hounsfield units (RA950 ) were normal, but these were abnormal in the COPD and AATD patients, which is reflective of emphysema. Although cylindrical and stretched-exponential-model estimates of Lm and S/V were not significantly different, the single-compartment-model estimates were significantly different (P < 0.05) for the never- and ex-smoker subgroups. All models estimated significantly worse Lm and S/V in the AATD and COPD subgroups compared with the never- and ex-smokers without emphysema. CONCLUSIONS: Differences in airspace enlargement may be estimated using Lm and S/V, generated using MRI and a stretched-exponential or cylindrical model of the acinar ducts. Magn Reson Med 79:439-448, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Ultrashort echo time MRI biomarkers of asthma.

PURPOSE: To develop and assess ultrashort echo-time (UTE) magnetic resonance imaging (MRI) biomarkers of lung function in asthma patients. MATERIALS AND METHODS: Thirty participants including 13 healthy volunteers and 17 asthmatics provided written informed consent to UTE and pulmonary function tests in addition to hyperpolarized-noble-gas 3T MRI and computed tomography (CT) for asthmatics only. The difference in MRI signal-intensity (SI) across four lung volumes (full-expiration, functional-residual-capacity [FRC], FRC+1L, and full-inspiration) was determined on a voxel-by-voxel basis to generate dynamic proton-density (DPD) maps. MRI ventilation-defect-percent (VDP), UTE SI, and DPD values as well as CT radiodensity were determined for whole lung and individual lobes. RESULTS: Mean SI at full-expiration (P < 0.01), FRC (P < 0.05), and DPD (P < 0.01) were greater in healthy volunteers compared to asthmatics. In asthmatics, UTE SI at full-expiration and DPD were correlated with FEV1 /FVC (SI r = 0.73/P = 0.002; DPD r = 0.75/P = 0.003), RV/TLC (SI r = -0.57/P = 0.02), or RV (DPD r = -0.62/P = 0.02), CT radiodensity (SI r = 0.83/P = 0.006; DPD r = 0.71/P = 0.01), and lobar VDP (SI rs = -0.33/P = 0.02; DPD rs = -0.47/P = 0.01). CONCLUSION: In patients with asthma, UTE SI and dynamic proton-density were related to pulmonary function measurements, whole lung and lobar VDP, as well as CT radiodensity. Thus, UTE MRI biomarkers may reflect ventilation heterogeneity and/or gas-trapping in asthmatics using conventional equipment, making this approach potentially amenable for clinical use. LEVEL OF EVIDENCE: 2 J. Magn. Reson. Imaging 2017;45:1204-1215.

This is what COPD looks like.

Despite decades of research, and the growing healthcare and societal burden of chronic obstructive pulmonary disease (COPD), therapeutic COPD breakthroughs have not occurred. Sub-optimal COPD patient phenotyping, an incomplete understanding of COPD pathogenesis and a scarcity of sensitive tools that provide patient-relevant intermediate endpoints likely all play a role in the lack of new, efficacious COPD interventions. In other words, COPD patients are still diagnosed based on the presence of persistent airflow limitation measured using spirometry. Spirometry measurements reflect the global sum of all the different possible COPD pathologies and perhaps because of this, we lose sight of the different contributions of airway and parenchymal abnormalities. With recent advances in thoracic X-ray computed tomography (CT) and magnetic resonance imaging (MRI), lung structure and function abnormalities may be regionally identified and measured. These imaging endpoints may serve as biomarkers of COPD that can be used to better phenotype patients. Therefore, here we review novel CT and MRI measurements that help reveal COPD phenotypes and what COPD really 'looks' like, beyond spirometric indices. We discuss MR and CT imaging approaches for generating reproducible and sensitive measurements of COPD phenotypes related to pulmonary ventilation and perfusion as well as airway and parenchyma anatomical and morphological features. These measurements may provide a way to advance the development and testing of new COPD interventions and therapies.

Oscillatory Positive Expiratory Pressure in Chronic Obstructive Pulmonary Disease.

Evidence-based guidance for the use of airway clearance techniques (ACT) in chronic obstructive pulmonary disease (COPD) is lacking in-part because well-established measurements of pulmonary function such as the forced expiratory volume in 1s (FEV1) are relatively insensitive to ACT. The objective of this crossover study was to evaluate daily use of an oscillatory positive expiratory pressure (oPEP) device for 21-28 days in COPD patients who were self-identified as sputum-producers or non-sputum-producers. COPD volunteers provided written informed consent to daily oPEP use in a randomized crossover fashion. Participants completed baseline, crossover and study-end pulmonary function tests, St. George's Respiratory Questionnaire (SGRQ), Patient Evaluation Questionnaire (PEQ), Six-Minute Walk Test and (3)He magnetic resonance imaging (MRI) for the measurement of ventilation abnormalities using the ventilation defect percent (VDP). Fourteen COPD patients, self-identified as sputum-producers and 13 COPD-non-sputum-producers completed the study. Post-oPEP, the PEQ-ease-bringing-up-sputum was improved for sputum-producers (p = 0.005) and non-sputum-producers (p = 0.04), the magnitude of which was greater for sputum-producers (p = 0.03). There were significant post-oPEP improvements for sputum-producers only for FVC (p = 0.01), 6MWD (p = 0.04), SGRQ total score (p = 0.01) as well as PEQ-patient-global-assessment (p = 0.02). Clinically relevant post-oPEP improvements for PEQ-ease-bringing-up-sputum/PEQ-patient-global-assessment/SGRQ/VDP were observed in 8/7/9/6 of 14 sputum-producers and 2/0/3/3 of 13 non-sputum-producers. The post-oPEP change in (3)He MRI VDP was related to the change in PEQ-ease-bringing-up-sputum (r = 0.65, p = 0.0004) and FEV1 (r = -0.50, p = 0.009). In COPD patients with chronic sputum production, PEQ and SGRQ scores, FVC and 6MWD improved post-oPEP. FEV1 and PEQ-ease-bringing-up-sputum improvements were related to improved ventilation providing mechanistic evidence to support oPEP use in COPD. Clinical Trials # NCT02282189 and NCT02282202.

Ultra-short echo-time pulmonary MRI: evaluation and reproducibility in COPD subjects with and without bronchiectasis.

BACKGROUND: To evaluate ultra-short-echo-time (UTE) MRI pulmonary signal-intensity measurements and reproducibility in chronic obstructive pulmonary disease (COPD). METHODS: A two-dimensional sequence (echo-time = 0.05 ms; acquisition-time = 13 s) with interleaved half-pulse excitation and radial ramp-sampling was used with compressed-sensing to reconstruct UTE images from under-sampled data. Five healthy volunteers and 15 subjects with COPD provided written informed consent to imaging and pulmonary-function-tests. Healthy volunteers underwent MRI at four lung volumes: full-expiration, functional-residual-capacity (FRC), FRC+1L, and full-inhalation; COPD patients underwent computed-tomography (CT) and MRI at FRC+1L. Three-week reproducibility was evaluated and the relative area of the density histogram ≤ -950 HU (RA950 ) was compared with mean MRI signal-intensity. The 15th percentile of signal-intensity-histogram (SI15 ) was compared with the 15th percentile of the CT-density-histogram (HU15 ). RESULTS: In healthy subjects, signal-intensity correlated with the inverse of lung volume (r = 0.99; P = 0.007). Contrast-to-noise and signal-to-noise ratios were significantly improved for 32-channel UTE (P < 0.01). The coefficient of variation for 3-week repeated measurements was 4%. There were significant correlations for signal-intensity with RA950 (r = -0.71; P = 0.005), FEV1 /FVC (r = 0.59; P = 0.02), and for SI15 with HU15 (r = 0.62; P = 0.01). CONCLUSION: Pulmonary signal-intensity is reproducible and related to tissue density. In COPD subjects with and without bronchiectasis, signal-intensity was also related to pulmonary function and CT measurements.

Pulmonary abnormalities and carotid atherosclerosis in ex-smokers without airflow limitation.

It is well-established that COPD patients have a burden of vascular disease that cannot be fully-explained by smoking history but the mechanistic links between atherosclerosis and pulmonary disease in COPD patients are not well-understood. Moreover, in ex-smokers without symptoms or other evidence of COPD, subclinical pulmonary and vascular disease, although potentially present, has not been described or evaluated. Hence our aim was to use sensitive three-dimensional (3D) pulmonary and carotid imaging to quantify pulmonary airway/parenchyma abnormalities and atherosclerosis in ex-smokers without airflow limitation or symptoms consistent with COPD. We evaluated 61 subjects without airflow limitation including 34 never- (72 ± 6 years) and 27 ex-smokers (73 ± 9 years), who provided written informed consent to spirometry, plethysmography, (3)He magnetic resonance imaging (MRI) and carotid ultrasound (US) and, for ex-smokers alone, thoracic X-ray computed tomography (CT). Ex-smokers had significantly greater (3)He ventilation defect percent (VDP = 7%, p = 0.001) and carotid total plaque volume (TPV = 250 mm(3), p = 0.002) than never-smokers, although there were no significant differences for spirometry or plethysmography, and CT airway and emphysema measurements were normal. There were univariate relationships for (3)He VDP with carotid intima media thickness (IMT, r = 0.42, p = 0.004), TPV (r = 0.41, p = 0.006) and vessel wall volume (VWV, r = 0.40, p = 0.007). Multivariate models that included age, BMI, FEV1, DLCO and VDP showed that only VDP significantly predicted IMT (ß = 0.41, p = 0.001), VWV (ß = 0.45, p = 0.003) and TPV (ß = 0.38, p = 0.005). In summary, there was imaging evidence of mild airways disease and carotid plaque burden that were related and significantly greater in ex-smokers without airflow limitation than in never-smokers.

Functional lung avoidance for individualized radiotherapy (FLAIR): study protocol for a randomized, double-blind clinical trial.

BACKGROUND: Although radiotherapy is a key component of curative-intent treatment for locally advanced, unresectable non-small cell lung cancer (NSCLC), it can be associated with substantial pulmonary toxicity in some patients. Current radiotherapy planning techniques aim to minimize the radiation dose to the lungs, without accounting for regional variations in lung function. Many patients, particularly smokers, can have substantial regional differences in pulmonary ventilation patterns, and it has been hypothesized that preferential avoidance of functional lung during radiotherapy may reduce toxicity. Although several investigators have shown that functional lung can be identified using advanced imaging techniques and/or demonstrated the feasibility and theoretical advantages of avoiding functional lung during radiotherapy, to our knowledge this premise has never been tested via a prospective randomized clinical trial. METHODS/DESIGN: Eligible patients will have Stage III NSCLC with intent to receive concurrent chemoradiotherapy (CRT). Every patient will undergo a pre-treatment functional lung imaging study using hyperpolarized 3He MRI in order to identify the spatial distribution of normally-ventilated lung. Before randomization, two clinically-approved radiotherapy plans will be devised for all patients on trial, termed standard and avoidance. The standard plan will be designed without reference to the functional state of the lung, while the avoidance plan will be optimized such that dose to functional lung is as low as reasonably achievable. Patients will then be randomized in a 1:1 ratio to receive either the standard or the avoidance plan, with both the physician and the patient blinded to the randomization results. This study aims to accrue a total of 64 patients within two years. The primary endpoint will be a pulmonary quality of life (QOL) assessment at 3 months post-treatment, measured using the functional assessment of cancer therapy-lung cancer subscale. Secondary endpoints include: pulmonary QOL at other time-points, provider-reported toxicity, overall survival, progression-free survival, and quality-adjusted survival. DISCUSSION: This randomized, double-blind trial will comprehensively assess the impact of functional lung avoidance on pulmonary toxicity and quality of life in patients receiving concurrent CRT for locally advanced NSCLC. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT02002052.

The Peaks and Valleys of Photon Versus Proton Spatially Fractionated Radiotherapy.

Spatially-fractionated radiotherapy (SFRT) delivers high doses to small areas of tumor while sparing adjacent tissue, including intervening disease. In this review, we explore the evolution of SFRT technological advances, contrasting approaches with photon and proton beam radiotherapy. We discuss unique dosimetric considerations and physical properties of SFRT, as well as review the preclinical literature that provides an emerging understanding of biological mechanisms. We emphasize crucial areas of future study and highlight clinical trials that are underway to assess SFRT's safety and efficacy, with a focus on immunotherapeutic synergies. The review concludes with practical considerations for SFRT's clinical application, advocating for strategies that leverage its unique dosimetric and biological properties for improved patient outcomes.

Inversion-recovery ultrashort-echo-time (IR-UTE) MRI-based detection of radiation dose heterogeneity in gynecologic cancer patients treated with HDR brachytherapy.

PURPOSE: To evaluate the relationship between delivered radiation (RT) and post-RT inversion-recovery ultrashort-echo-time (IR-UTE) MRI signal-intensity (SI) in gynecologic cancer patients treated with high-dose-rate (HDR) brachytherapy (BT). METHODS: Seven patients underwent whole-pelvis RT (WPRT) followed by BT to the high-risk clinical target volume (HR-CTV). MR images were acquired at three time-points; pre-RT, post-WPRT/pre-BT, and 3-6 months post-BT. Diffuse-fibrosis (FDiffuse) was imaged with a non-contrast dual-echo IR (inversion time [TI] = 60 ms) UTE research application, with image-subtraction of the later echo, only retaining the ultrashort-echo SI. Dense-fibrosis (FDense) imaging utilized single-echo Late-Gadolinium-Enhanced IR-UTE, acquired ∼ 15 min post-Gadavist injection. Resulting FDiffuse and FDense SI were normalized to the corresponding gluteal-muscle SI. Images were deformably registered between time-points based on normal tissue anatomy. The remnant tumor at both time-points was segmented using multi-parametric MRI. Contours corresponding to the 50%, 100%, 150%, and 200% isodose lines (IDLs) of the prescription BT-dose were created. Mean FDiffuse and FDense SI within (i) each IDL contour and (ii) the remnant tumor were calculated. Post-BT FDiffuse and FDense SI were correlated with prescribed BT-dose. To determine the relationship between BT-dose and IR-UTE SI, the differences in the post-BT FDense across IDLs was determined using paired t-tests with Bonferroni correction. RESULTS: FDense was higher in regions of higher dose for 6/7 patients, with mean ± SD values of 357 ± 103% and 331 ± 97% (p = .03) in the 100% and 50% IDL, respectively. FDense was higher in regions of higher dose in the responsive regions with mean ± SD values of 380 ± 122% and 356 ± 135% (p = .03) in the 150% and 50% IDL, respectively. Within the segmented remnant tumor, an increase in prescribed dose correlated with an increase in FDense post-BT (n = 5, r = .89, p = .04). Post-BT FDiffuse inversely correlated (n = 7, r = -.83, p = .02) with prescribed BT-dose within the 100% IDL. CONCLUSIONS: Results suggest that FDense SI 3-6 months post-BT is a sensitive measure of tissue response to heterogeneous BT radiation-dose. Future studies will validate whether FDiffuse and FDense are accurate biomarkers of fibrotic radiation response.

Overview and Recommendations for Prospective Multi-institutional Spatially Fractionated Radiation Therapy Clinical Trials.

PURPOSE: The highly heterogeneous dose delivery of spatially fractionated radiation therapy (SFRT) is a profound departure from standard radiation planning and reporting approaches. Early SFRT studies have shown excellent clinical outcomes. However, prospective multi-institutional clinical trials of SFRT are still lacking. This NRG Oncology/American Association of Physicists in Medicine working group consensus aimed to develop recommendations on dosimetric planning, delivery, and SFRT dose reporting to address this current obstacle toward the design of SFRT clinical trials. METHODS AND MATERIALS: Working groups consisting of radiation oncologists, radiobiologists, and medical physicists with expertise in SFRT were formed in NRG Oncology and the American Association of Physicists in Medicine to investigate the needs and barriers in SFRT clinical trials. RESULTS: Upon reviewing the SFRT technologies and methods, this group identified challenges in several areas, including the availability of SFRT, the lack of treatment planning system support for SFRT, the lack of guidance in the physics and dosimetry of SFRT, the approximated radiobiological modeling of SFRT, and the prescription and combination of SFRT with conventional radiation therapy. CONCLUSIONS: Recognizing these challenges, the group further recommended several areas of improvement for the application of SFRT in cancer treatment, including the creation of clinical practice guidance documents, the improvement of treatment planning system support, the generation of treatment planning and dosimetric index reporting templates, and the development of better radiobiological models through preclinical studies and through conducting multi-institution clinical trials.

Planning and Treatment Recommendations for Breast Proton Therapy From a Single Center's Experience.

Purpose: Proton therapy use for breast cancer has grown due to advantages in coverage and potentially reduced late toxicities compared with conventional radiation therapy. We aimed to provide recommendations for robustness criteria, daily imaging, and quality assurance computed tomography (QA CT) frequency for these patients. Methods and Materials: All patients treated for localized breast cancer at the Johns Hopkins Proton Center between November 2019 and February 2022 were eligible for inclusion. Daily shift information was extracted and examined through control charts. If an adaptive plan was used, the time to replan was recorded. Three and 5 mm setup uncertainty was used to calculate robustness. Robust evaluation of QA CTs was compared with initial robustness range for breast/chest wall and lymph node target coverage. Results: Sixty-six patients were included: 19 with intact breast, 25 with non-reconstructed chest wall, and 22 with chest wall plus expanders or implants. Sixteen percent, 13%, and 41% of breast, chest wall, and expander/implant patients had a replan. Only patients with expanders or implants required 2 adaptive plans. Daily shift data showed large variation and did not correlate with plan adaptation. Patients without adaptive plans had QA CTs with dose-volume histogram metrics within robustness more frequently than those with adaptive plans. Using 3 mm robustness for patients who did not require an adaptive plan, 91% to 100% of patients had QA CTs within robustness, while 55% to 60% of patients with an adaptive plan had QA CTs within robustness for the axilla, internal mammary nodes, and supraclavicular nodes. Five millimeter setup uncertainty did not significantly improve this. Conclusions: We recommend using daily cone beam CT because of the large variation in daily setup with 3 mm setup uncertainty in robustness analysis. If daily cone beam CT imaging is not available, then larger setup uncertainty should be used. Two QA CTs should be conducted during treatment if the patient has expanders or implants; otherwise, one QA CT is sufficient.

Clinical Characterization of a Table Mounted Range Shifter Board for Synchrotron-Based Intensity Modulated Proton Therapy for Pediatric Craniospinal Irradiation.

Purpose: To report our design, manufacturing, commissioning and initial clinical experience with a table-mounted range shifter board (RSB) intended to replace the machine-mounted range shifter (MRS) in a synchrotron-based pencil beam scanning (PBS) system to reduce penumbra and normal tissue dose for image-guided pediatric craniospinal irradiation (CSI). Methods: A custom RSB was designed and manufactured from a 3.5 cm thick slab of polymethyl methacrylate (PMMA) to be placed directly under patients, on top of our existing couch top. The relative linear stopping power (RLSP) of the RSB was measured using a multi-layer ionization chamber, and output constancy was measured using an ion chamber. End-to-end tests were performed using the MRS and RSB approaches using an anthropomorphic phantom and radiochromic film measurements. Cone beam CT (CBCT) and 2D planar kV X-ray image quality were compared with and without the RSB present using image quality phantoms. CSI plans were produced using MRS and RSB approaches for two retrospective pediatric patients, and the resultant normal tissue doses were compared. Results: The RLSP of the RSB was found to be 1.163 and provided computed penumbra of 6.9 mm in the phantom compared to 11.8 mm using the MRS. Phantom measurements using the RSB demonstrated errors in output constancy, range, and penumbra of 0.3%, -0.8%, and 0.6 mm, respectively. The RSB reduced mean kidney and lung dose compared to the MRS by 57.7% and 46.3%, respectively. The RSB decreased mean CBCT image intensities by 86.8 HU but did not significantly impact CBCT or kV spatial resolution providing acceptable image quality for patient setup. Conclusions: A custom RSB for pediatric proton CSI was designed, manufactured, modeled in our TPS, and found to significantly reduce lateral proton beam penumbra compared to a standard MRS while maintaining CBCT and kV image-quality and is in routine use at our center.

Treatment Planning of Bulky Tumors Using Pencil Beam Scanning Proton GRID Therapy.

Purpose: To compare spatially fractionated radiation therapy (GRID) treatment planning techniques using proton pencil-beam-scanning (PBS) and photon therapy. Materials and Methods: PBS and volumetric modulated arc therapy (VMAT) GRID plans were retrospectively generated for 5 patients with bulky tumors. GRID targets were arranged along the long axis of the gross tumor, spaced 2 and 3 cm apart, and treated with a prescription of 18 Gy. PBS plans used 2- to 3-beam multiple-field optimization with robustness evaluation. Dosimetric parameters including peak-to-edge ratio (PEDR), ratio of dose to 90% of the valley to dose to 10% of the peak VPDR(D90/D10), and volume of normal tissue receiving at least 5 Gy (V5) and 10 Gy (V10) were calculated. The peak-to-valley dose ratio (PVDR), VPDR(D90/D10), and organ-at-risk doses were prospectively assessed in 2 patients undergoing PBS-GRID with pretreatment quality assurance computed tomography (QACT) scans. Results: PBS and VMAT GRID plans were generated for 5 patients with bulky tumors. Gross tumor volume values ranged from 826 to 1468 cm3. Peak-to-edge ratio for PBS was higher than for VMAT for both spacing scenarios (2-cm spacing, P = .02; 3-cm spacing, P = .01). VPDR(D90/D10) for PBS was higher than for VMAT (2-cm spacing, P = .004; 3-cm spacing, P = .002). Normal tissue V5 was lower for PBS than for VMAT (2-cm spacing, P = .03; 3-cm spacing, P = .02). Normal tissue mean dose was lower with PBS than with VMAT (2-cm spacing, P = .03; 3-cm spacing, P = .02). Two patients treated using PBS GRID and assessed with pretreatment QACT scans demonstrated robust PVDR, VPDR(D90/D10), and organs-at-risk doses. Conclusions: The PEDR was significantly higher for PBS than VMAT plans, indicating lower target edge dose. Normal tissue mean dose was significantly lower with PBS than VMAT. PBS GRID may result in lower normal tissue dose compared with VMAT plans, allowing for further dose escalation in patients with bulky disease.

Pathogen identification with laser-induced breakdown spectroscopy: the effect of bacterial and biofluid specimen contamination.

In this paper, the potential use of laser-induced breakdown spectroscopy (LIBS) for the rapid discrimination and identification of bacterial pathogens in realistic clinical specimens is investigated. Specifically, the common problem of sample contamination was studied by creating mixed samples to investigate the effect that the presence of a second contaminant bacterium in the specimen had on the LIBS-based identification of the primary pathogen. Two closely related bacterial specimens, Escherichia coli strain ATCC 25922 and Enterobacter cloacae strain ATCC 13047, were mixed together in mixing fractions of 10:1, 100:1, and 1000:1. LIBS spectra from the three mixtures were reliably classified as the correct E. coli strain with 98.5% accuracy when all the mixtures were withheld from the training model and classified against spectra from pure specimens. To simulate a rapid test for the presence of urinary tract infection pathogens, LIBS spectra were obtained from specimens of Staphylococcus epidermidis obtained from distilled water and sterile urine. LIBS spectra from the urine-harvested bacteria were classified as S. epidermidis with 100% accuracy when classified using a model containing only spectra from other Staphylococci species and with 88.5% accuracy when a model containing five genera of bacteria was utilized. Bacterial specimens comprising five different genera and 13 classifiable taxonomic groups of species and strains were compiled in a library that was tested using external validation techniques. The importance of utilizing external validation techniques where the library is tested with data withheld from all previous testing and training of the model was revealed by comparing the results against "leave-one-out" cross-validation results. Last, the effect of using sequential models for the classification of a single unknown spectrum was investigated by comparing the misclassification of two closely related bacteria, E. coli and E. cloacae, when the classification was first performed using the five-genus bacterial library and then with a smaller model consisting only of E. coli and E. cloacae specimens. This result shows the utility of using successively more targeted analyses and models that use preliminary classifications from more general models as input.

Evaluating Proton Dose and Associated Range Uncertainty Using Daily Cone-Beam CT.

Purpose: This study aimed to quantitatively evaluate the range uncertainties that arise from daily cone-beam CT (CBCT) images for proton dose calculation compared to CT using a measurement-based technique. Methods: For head and thorax phantoms, wedge-shaped intensity-modulated proton therapy (IMPT) treatment plans were created such that the gradient of the wedge intersected and was measured with a 2D ion chamber array. The measured 2D dose distributions were compared with 2D dose planes extracted from the dose distributions using the IMPT plan calculated on CT and CBCT. Treatment plans of a thymoma cancer patient treated with breath-hold (BH) IMPT were recalculated on 28 CBCTs and 9 CTs, and the resulting dose distributions were compared. Results: The range uncertainties for the head phantom were determined to be 1.2% with CBCT, compared to 0.5% for CT, whereas the range uncertainties for the thorax phantom were 2.1% with CBCT, compared to 0.8% for CT. The doses calculated on CBCT and CT were similar with similar anatomy changes. For the thymoma patient, the primary source of anatomy change was the BH uncertainty, which could be up to 8 mm in the superior-inferior (SI) direction. Conclusion: We developed a measurement-based range uncertainty evaluation method with high sensitivity and used it to validate the accuracy of CBCT-based range and dose calculation. Our study demonstrated that the CBCT-based dose calculation could be used for daily dose validation in selected proton patients.

Functional Lung Avoidance for Individualized Radiation Therapy: Results of a Double-Masked, Randomized Controlled Trial.

PURPOSE: To determine whether functional lung avoidance based on 3He magnetic resonance imaging (MRI) improves quality of life (QOL) for patients undergoing concurrent chemoradiotherapy (CCRT) for advanced non-small cell lung cancer. METHODS AND MATERIALS: Patients with stage III non-small cell lung cancer (or oligometastatic disease treated with curative intent) undergoing CCRT with at least a 10 pack-year smoking history were eligible. Patients underwent pretreatment 3He MRI to measure lung ventilation and had 2 radiation therapy (RT) plans created before randomization: a standard plan, which did not make use of the 3He MRI, and an avoidance plan, preferentially sparing well-ventilated lung. All participants were masked to assignment except the physicist responsible for exporting the selected plan. The primary end point was patient-reported QOL measured at 3-months post-RT by the FACT-L lung cancer subscale (LCS); secondary end points included other QOL metrics, toxicity, and survival outcomes. Target accrual was 64. RESULTS: Twenty-seven patients were randomized before the trial was closed due to slower-than-expected accrual, with 11 randomized to the standard arm and 16 to the avoidance arm. Baseline patient characteristics were well-balanced. At 3 months post-RT, the mean ± SD LCS scores were 17.4 ± 2.8 versus 17.3 ± 6.1 for the standard and avoidance arms, respectively (P = .485). A clinically meaningful, prespecified decline of ≥3 points in the LCS score was observed in 50% (4/8) in the standard arm and 33% (4/12) in the avoidance arm (P = .648). Two patients in each arm developed grade ≥2 radiation pneumonitis, with no grade ≥4 toxicities. CONCLUSIONS: Although this trial did not reach full accrual, QOL scores were very similar between arms. Due to the scarcity of 3He MRI, other, more commonly available methods to measure functional lung, such as 4-dimensional computed tomography ventilation mapping, may be considered in the assessment of functional lung avoidance RT, and a larger, multicenter approach would be needed to accrue sufficient patients to test such approaches.

Radiomic modeling to predict risk of vertebral compression fracture after stereotactic body radiation therapy for spinal metastases.

OBJECTIVE: In the treatment of spinal metastases with stereotactic body radiation therapy (SBRT), vertebral compression fracture (VCF) is a common and potentially morbid complication. Better methods to identify patients at high risk of radiation-induced VCF are needed to evaluate prophylactic measures. Radiomic features from pretreatment imaging may be employed to more accurately predict VCF. The objective of this study was to develop and evaluate a machine learning model based on clinical characteristics and radiomic features from pretreatment imaging to predict the risk of VCF after SBRT for spinal metastases. METHODS: Vertebral levels C2 through L5 containing metastases treated with SBRT were included if they were naive to prior surgery or radiation therapy, target delineation was based on consensus guidelines, and 1-year follow-up data were available. Clinical features, including characteristics of the patient, disease, and treatment, were obtained from chart review. Radiomic features were extracted from the planning target volume (PTV) on pretreatment CT and T1-weighted MRI. Clinical and radiomic features selected by least absolute shrinkage and selection operator (LASSO) regression were included in random forest classification models, which were trained to predict VCF within 1 year after SBRT. Model performance was assessed with leave-one-out cross-validation. RESULTS: Within 1 year after SBRT, 15 of 95 vertebral levels included in the analysis demonstrated new or progressive VCF. Selected clinical features included BMI, performance status, total prescription dose, dose to 99% of the PTV, lumbar location, and 2 components of the Spine Instability Neoplastic Score (SINS): lytic tumor character and spinal misalignment. Selected radiomic features included 5 features from CT and 3 features from MRI. The best-performing classification model, derived from a combination of selected clinical and radiomic features, demonstrated a sensitivity of 0.844, specificity of 0.800, and area under the receiver operating characteristic (ROC) curve (AUC) of 0.878. This model was significantly more accurate than alternative models derived from only selected clinical features (AUC = 0.795, p = 0.048) or only components of the SINS (AUC = 0.579, p < 0.0001). CONCLUSIONS: In the treatment of spinal metastases with SBRT, a machine learning model incorporating both clinical features and radiomic features from pretreatment imaging predicted VCF at 1 year after SBRT with excellent sensitivity and specificity, outperforming models developed from clinical features or components of the SINS alone. If validated, these findings may allow more judicious selection of patients for prophylactic interventions.