iBCS: 3. A Biopharmaceutics Classification System for Orally Inhaled Drug Products.

In this article, we specify for the first time a quantitative biopharmaceutics classification system for orally inhaled drugs. To date, orally inhaled drug product developers have lacked a biopharmaceutics classification system like the one developed to navigate the development of immediate release of oral medicines. Guideposts for respiratory drug discovery chemists and inhalation product formulators have been elusive and difficult to identify due to the complexity of pulmonary physiology, the intricacies of drug deposition and disposition in the lungs, and the influence of the inhalation delivery device used to deliver the drug as a respirable aerosol. The development of an inhalation biopharmaceutics classification system (iBCS) was an initiative supported by the Product Quality Research Institute (PQRI). The goal of the PQRI iBCS working group was to generate a qualitative biopharmaceutics classification system that can be utilized by inhalation scientists as a "rule of thumb" to identify desirable molecular properties and recognize and manage CMC product development risks based on physicochemical properties of the drug and the deposited lung dose. Herein, we define the iBCS classes quantitatively according to the dose number and permeability. The proposed iBCS was evaluated for its ability to categorize marketed inhaled drugs using data from the literature. The appropriateness of the classification of each drug was assessed based on published development, clinical and nonclinical data, and mechanistic physiologically based biopharmaceutics modeling. The inhaled drug product development challenges for each iBCS classification are discussed and illustrated for different classes of marketed inhaled drugs. Finally, it is recognized that discriminatory laboratory methods to characterize regional lung deposition, dissolution, and permeability will be key to fully realizing the benefits of an iBCS to streamline and derisk inhaled drug development.

Modelled lung deposition and retention of welding fume particles in occupational scenarios: a comparison to doses used in vitro.

Translating particle dose from in vitro systems to relevant human exposure remains a major challenge for the use of in vitro studies in assessing occupational hazard and risk of particle exposure. This study aimed to model the lung deposition and retention of welding fume particles following occupational scenarios and subsequently compare the lung doses to those used in vitro. We reviewed published welding fume concentrations and size distributions to identify input values simulating real-life exposure scenarios in the multiple path particle dosimetry (MPPD) model. The majority of the particles were reported to be below 0.1 µm and mass concentrations ranged between 0.05 and 45 mg/m3. Following 6-h exposure to 5 mg/m3 with a count median diameter of 50 nm, the tracheobronchial lung dose (0.89 µg/cm2) was found to exceed the in vitro cytotoxic cell dose (0.125 µg/cm2) previously assessed by us in human bronchial epithelial cells (HBEC-3kt). However, the tracheobronchial retention decreased rapidly when no exposure occurred, in contrast to the alveolar retention which builds-up over time and exceeded the in vitro cytotoxic cell dose after 1.5 working week. After 1 year, the tracheobronchial and alveolar retention was estimated to be 1.15 and 2.85 µg/cm2, respectively. Exposure to low-end aerosol concentrations resulted in alveolar retention comparable to cytotoxic in vitro dose in HBEC-3kt after 15-20 years of welding. This study demonstrates the potential of combining real-life exposure data with particle deposition modelling to improve the understanding of in vitro concentrations in the context of human occupational exposure.

Effect of total body irradiation lung block parameters on lung doses using three-dimensional dosimetry.

PURPOSE: Total body irradiation (TBI) is an integral part of stem cell transplant. However, patients are at risk of treatment-related toxicities, including radiation pneumonitis. While lung dose is one of the most crucial aspects of TBI dosimetry, currently available data are based on point doses. As volumetric dose distribution could be substantially altered by lung block parameters, we used 3D dosimetry in our treatment planning system to estimate volumetric lung dose and measure the impact of various lung block designs. MATERIALS AND METHODS: We commissioned a TBI beam model in RayStation that matches the measured tissue-phantom ratio under our clinical TBI setup. Cerrobend blocks were automatically generated in RayStation on thoracic Computed Tomography (CT) scans from three anonymized patients using the lung, clavicle, spine, and diaphragmatic contours. The margin for block edge was varied to 0, 1, or 2 cm from the superior, lateral, and inferior thoracic borders, with a uniform margin 2.5 cm lateral to the vertebral bodies. The lung dose was calculated and compared with a prescription dose of 1200 cGy in six fractions (three with blocks and three without). RESULT: The point dose at midplane under the block and the average lung dose are at the range of 73%-76% and 80%-88% of prescription dose respectively regardless of the block margins. In contrast, the percent lung volume receiving 10 Gy increased by nearly two-fold, from 31% to 60% over the margins from 0 to 2 cm. CONCLUSIONS: The TPS-derived 3D lung dose is substantially different from the nominal dose assumed with HVL lung blocks. Point doses under the block are insufficient to accurately gauge the relationship between dose and pneumonitis, and TBI dosimetry could be highly variable between patients and institutions as more descriptive parameters are not included in protocols. Much progress remains to be made to optimize and standardize technical aspects of TBI, and better dosimetry could provide more precise dosimetric predictors for pneumonitis risk.

Seasonal variation of indoor radon, thoron and their progeny in Belagavi district of Karnataka, India.

Systematic investigations on the seasonal variation of indoor radon, thoron and their progeny levels have been carried out in Belagavi district of Karnataka, India. The radon and thoron levels were measured using LR-115 type II dosimeter in cups with single-entry pinhole. The measurements were carried out in all the four season, viz, monsoon, autumn, winter and summer, in selected houses of the region. The higher indoor radon levels were observed during autumn with an average concentration of 56.45 Bq m-3. The minimum in radon levels was observed in summer with an average concentration of 21.8 Bq m-3. The indoor thoron concentration was also maximum during autumn with an average value of 36.44 Bq m-3 and minimum in summer with an average value of 15.9 Bq m-3. The radon and thoron levels were also found to depend on the nature of walls and floorings of dwellings. The lung dose rate to the population due to radon ranged from 1.195 to 9.557 mSv year-1, with an average of 4.572 mSv year-1. Risk levels were found to be significant during autumn and winter due to the inhalation of indoor radon and thoron. The study forms the first comprehensive report on the indoor radon and thoron levels and the resulting population dose in the Belagavi region. The studies reveal that the major contributor to the population is radon and its progeny. However, a sizable dose also comes from indoor thoron and its progeny. The study emphasises the need to provide better ventilation system to future dwellings to reduce the risk from indoor radon and thoron.

A comparison of breast and lung doses from chest CT scans using organ-based tube current modulation (OBTCM) vs. Automatic tube current modulation (ATCM).

PURPOSE: The purpose of this work was to estimate and compare breast and lung doses of chest CT scans using organ-based tube current modulation (OBTCM) to those from conventional, attenuation-based automatic tube current modulation (ATCM) across a range of patient sizes. METHODS: Thirty-four patients (17 females, 17 males) who underwent clinically indicated CT chest/abdomen/pelvis (CAP) examinations employing OBTCM were collected from two multi-detector row CT scanners. Patient size metric was assessed as water equivalent diameter (Dw ) taken at the center of the scan volume. Breast and lung tissues were segmented from patient image data to create voxelized models for use in a Monte Carlo transport code. The OBTCM schemes for the chest portion were extracted from the raw projection data. ATCM schemes were estimated using a recently developed method. Breast and lung doses for each TCM scenario were estimated for each patient model. CTDIvol -normalized breast (nDbreast ) and lung (nDlung ) doses were subsequently calculated. The differences between OBTCM and ATCM normalized organ dose estimates were tested using linear regression models that included CT scanner and Dw as covariates. RESULTS: Mean dose reduction from OBTCM in nDbreast was significant after adjusting for the scanner models and patient size (P = 0.047). When pooled with females and male patient, mean dose reduction from OBTCM in nDlung was observed to be trending after adjusting for the scanner model and patient size (P = 0.085). CONCLUSIONS: One specific manufacturer's OBTCM was analyzed. OBTCM was observed to significantly decrease normalized breast relative to a modeled version of that same manufacturer's ATCM scheme. However, significant dose savings were not observed in lung dose over all. Results from this study support the use of OBTCM chest protocols for females only.

Correlation between gastric volume and organs at risk dose in adjuvant radiotherapy for left breast cancer.

BACKGROUND: The role of the gastric volume on the dose-effect relationship for these organs has not been investigated. The aim of the study was to evaluate the correlation between gastric volume and dose-volume histogram (DVH) parameters of the heart, left lung and stomach during left breast cancer radiotherapy (RT). MATERIALS AND METHODS: Ninety-nine left breast cancer patients who got adjuvant radiotherapy were included. Study was classified into two groups based on treatment field arrangements: 1) breast tangential fields only (T) and 2) breast tangential and supraclavicular fields (TS). Organs DVHs were extracted. Descriptive statistics, Pearson correlation, linear regression analyses, and receiver operating characteristic (ROC) analyses were performed. RESULTS: There is a direct but not significant correlation between the gastric volume and doses to the stomach and left lung. For a 100-cc increase in the gastric volume, the stomach maximum dose and the V50 increased by 3 Gy and 4%, respectively. For the left lung, V4 and V5 increased by 1% for TS cases. Considering ROC analysis results, one can make a decision for about 74% of patients due to their left lung DVH parameters, using gastric volume as a known input data. The correlation between gastric volume and heart dose was not significant. CONCLUSIONS: The gastric volume of about 170 cc or less can result in lower dose to the stomach and ipsilateral lung during left breast cancer radiotherapy, especially for TS cases. To reach this gastric volume threshold, patients should be fast for 2 hours before the procedure of CT simulation and treatment.

Acute severe radiation pneumonitis among non-small cell lung cancer (NSCLC) patients with moderate pulmonary dysfunction receiving definitive concurrent chemoradiotherapy: Impact of pre-treatment pulmonary function parameters.

PURPOSE: Severe acute radiation pneumonitis (SARP) is a life-threatening complication of thoracic radiotherapy. Pre-treatment pulmonary function (PF) may influence its incidence. We have previously reported on the incidence of SARP among patients with moderate pulmonary dysfunction who received definitive concurrent chemoradiotherapy (dCCRT) for non-small cell lung cancer (NSCLC). METHODS: The clinical outcomes, dose-volume histograms (DVH), and PF parameters of 122 patients (forced expiratory volume in 1 s [FEV1%]: 60-69%) receiving dCCRT between 2013 and 2019 were recorded. SARP was defined as grade ≥3 RP occurring during or within 3 months after CCRT. Logistic regression, receiver operating characteristics curves (ROC), and hazard ratio (HR) analyses were performed to evaluate the predictive value of each factor for SARP. RESULTS: Univariate and multivariate analysis indicated that the ratio of carbon monoxide diffusing capacity (DLCO%; odds ratio [OR]: 0.934, 95% confidence interval [CI] 0.896-0.974, p = 0.001) and mean lung dose (MLD; OR: 1.002, 95% CI 1.001-1.003, p = 0.002) were independent predictors of SARP. The ROC AUC of combined DLCO%/MLD was 0.775 (95% confidence interval [CI]: 0.688-0.861, p = 0.001), with a sensitivity and specificity of 0.871 and 0.637, respectively; this was superior to DLCO% (0.656) or MLD (0.667) alone. Compared to the MLD-low/DLCO%-high group, the MLD-high/DLCO%-low group had the highest risk for SARP, with an HR of 9.346 (95% CI: 2.133-40.941, p = 0.003). CONCLUSION: The DLCO% and MLD may predict the risk for SARP among patients with pre-treatment moderate pulmonary dysfunction who receive dCCRT for NSCLC. Prospective studies are needed to validate our findings.

Dose-volume parameters predict radiation pneumonitis after induction chemoradiotherapy followed by surgery for non-small cell lung cancer: a retrospective analysis.

BACKGROUND: The relationship between lung dose-volume histogram (DVH) parameters and radiation pneumonitis (RP) associated with induction concurrent chemoradiotherapy (CCRT) followed by surgery in patients with non-small cell lung cancer (NSCLC) is unclear, particularly when concerning irradiation of the whole lung prior to resection. We performed this study to identify factors associated with grade ≥ 2 RP in such patients. METHODS: Patients who received induction CCRT (chemotherapy: cisplatin and docetaxel; radiotherapy: 46 Gy/23 fractions) between May 2003 and May 2017 were reviewed. The mean lung dose (MLD) and the percentage of the lung volume that received ≥5 Gy (V5) and ≥ 20 Gy (V20) were calculated. Factors associated with the development of grade ≥ 2 RP were analyzed. RESULTS: One hundred and eight patients were included in this study, 34 (31.5%) of whom experienced grade ≥ 2 RP. A V20 ≥ 21%, an MLD ≥10 Gy, and a lower lobe tumor location were significant predictors of grade ≥ 2 RP on univariate analysis (p = 0.007, 0.002, and 0.004, respectively). Moreover, an MLD ≥10 Gy and lower lobe location were significant predictors of grade ≥ 2 RP on multivariate analysis (p = 0.026 and 0.0043, respectively). The cumulative incidence rates of grade ≥ 2 RP at 6 months were 15.7 and 45.6% in patients with MLDs < 10 Gy and ≥ 10 Gy, respectively, and were 23.5 and 55.6% in patients with upper/middle lobe- vs. lower lobe-located tumors, respectively. CONCLUSIONS: MLD and lower lobe location were predictors of grade ≥ 2 RP in patients who received induction CCRT. It is necessary to reduce the MLD to the greatest extent possible to prevent the occurrence of this adverse event.

Dose-Volume Parameters Predict Radiation Pneumonitis after Surgery with Induction Concurrent Chemoradiotherapy for Non-small Cell Lung Cancer.

To clarify the relationship between dose-volume histogram (DVH) parameters and radiation pneumonitis (RP) after surgery in cases of non-small cell lung cancer (NSCLC) treated with induction concurrent chemoradiotherapy (CCRT). Patients with NSCLC treated with induction CCRT (chemotherapy: cisplatin and docetaxel; radiotherapy: 2.0 Gy fractions once daily for a total of 46 Gy) before surgery were reviewed. We calculated the percentage of lung volume receiving at least 20 Gy (V20) and the mean lung dose (MLD) for the total lung volume and the lung remaining after resection. Factors affecting the incidence of RP at grade 2 or higher (≥ G2 RP) were analyzed. Eighteen of 49 patients (37%) experienced ≥G2 RP. The V20 and MLD for the lung remaining after resection (V20r and MLDr) were significant predictors according to the multivariate analysis (p=0.007 and 0.041, respectively). The incidence of ≥G2 RP was 8% in patients with V20r<10%, and 13% in patients with MLDr<5.6 Gy, respectively. The optimal approach to reduce the rate of postoperative RP in patients with induction CCRT for NSCLC is to keep the V20r below 10% and/or the MLDr below 5.6 Gy in the radiotherapy planning.

Evaluation of sparing organs at risk (OARs) in left-breast irradiation in the supine and prone positions and with deep inspiration breath-hold.

PURPOSE: To compare doses to organs at risk (OARs) for left-sided whole-breast radiation therapy with comparable planning target volume (PTV) coverage using three techniques: free breathing in a supine position (SFB), deep inspirational breath-hold in a supine position (SDIBH), and free breathing in prone position (PFB). MATERIALS AND METHODS: Thirty-three patients with left-sided early-stage breast cancer underwent CT simulation following SFB, SDIBH, and PFB protocols for whole-breast radiation therapy. One radiation oncologist contoured the breast PTV, heart, left ventricle (LV), and left anterior descending artery (LAD). Treatment plans were optimized using field-in-field technique with the AAA algorithm. Each plan was optimized to provide identical coverage to the PTV such that a reasonable comparison for OAR dosimetry could be evaluated. All plans were prescribed 42.56 Gy in 16 fractions to the left-breast PTV. RESULTS: The mean dose in SFB for the heart, LV, and LAD was 1.92, 3.19, and 21.73 Gy, respectively, which were significantly higher than the mean dose in SDIBH for the heart (1.08 Gy, P ≤ 0.0001), LV (1.50 Gy, P ≤ 0.0001), and LAD (6.3 Gy, P ≤ 0.0001) and in PFB for the heart (0.98 Gy, P ≤ 0.0001), LV (1.34 Gy, P ≤ 0.0001), and LAD (6.57 Gy, P ≤ 0.0001). Similar findings were noted for the cardiac components in SFB for V2.5, V5, V10, V20, and V30 compared with values in SDIBH and PFB. The mean dose for the left lung in PFB was 0.61 Gy that was significantly lower than in SFB (5.63 Gy, P ≤ 0.0001) and SDIBH (5.54 Gy, P ≤ 0.0001). Mean dose and dosimetric values for each OAR increased in SFB and SDIBH for patients with a large breast volume compared with values for patients with a small breast volume. CONCLUSIONS: SFB results in higher heart, LAD, and LV doses than the other techniques. Both PFB and SDIBH are more advantageous for these OARs irrespective of breast volume. PFB results in significantly lower lung doses than SFB and SDIBH. PFB always provided better results than SFB for the heart, LV, LAD, and lung. This conclusion contrasts with some published studies concluding that the prone position has no benefit for heart sparing.

The Impact of Inspiratory Flow Rate on Drug Delivery to the Lungs with Dry Powder Inhalers.

Current marketed dry powder inhalers utilize the energy from patient inspiration to fluidize and disperse bulk powder agglomerates into respirable particles. Variations in patient inspiratory flow profiles can lead to marked differences in total lung dose (TLD), and ultimately patient outcomes for an inhaled therapeutic. The present review aims to quantitate the flow rate dependence in TLD observed for a number of drug/device combinations using a new metric termed the Q index. With this data in hand, the review explores key attributes in the design of the formulation and device that impact flow rate dependence. The review also proposes alternative in vitro methods to assess flow rate dependence that more closely align with in vivo observations. Finally, the impact of variations in flow rate on lung function for inhaled bronchodilators is summarized.

Deposition efficiency of inhaled particles (15-5000 nm) related to breathing pattern and lung function: an experimental study in healthy children and adults.

BACKGROUND: Exposure to airborne particles has a major impact on global health. The probability of these particles to deposit in the respiratory tract during breathing is essential for their toxic effects. Observations have shown that there is a substantial variability in deposition between subjects, not only due to respiratory diseases, but also among individuals with healthy lungs. The factors determining this variability are, however, not fully understood. METHOD: In this study we experimentally investigate factors that determine individual differences in the respiratory tract depositions of inhaled particles for healthy subjects at relaxed breathing. The study covers particles of diameters 15-5000 nm and includes 67 subjects aged 7-70 years. A comprehensive examination of lung function was performed for all subjects. Principal component analyses and multiple regression analyses were used to explore the relationships between subject characteristics and particle deposition. RESULTS: A large individual variability in respiratory tract deposition efficiency was found. Individuals with high deposition of a certain particle size generally had high deposition for all particles <3500 nm. The individual variability was explained by two factors: breathing pattern, and lung structural and functional properties. The most important predictors were found to be breathing frequency and anatomical airway dead space. We also present a linear regression model describing the deposition based on four variables: tidal volume, breathing frequency, anatomical dead space and resistance of the respiratory system (the latter measured with impulse oscillometry). CONCLUSIONS: To understand why some individuals are more susceptible to airborne particles we must understand, and take into account, the individual variability in the probability of particles to deposit in the respiratory tract by considering not only breathing patterns but also adequate measures of relevant structural and functional properties.

DIBH reduces right coronary artery and lung radiation dose in right breast cancer loco-regional radiotherapy.

To determine whether deep inspiratory breath-hold (DIBH) reduces dose to organs-at-risk (OAR), in particular the right coronary artery (RCA), in women with breast cancer requiring right-sided post-mastectomy radiotherapy (PMRT) including internal mammary chain (+IMC) radiotherapy (RT). Fourteen consecutive women requiring right-sided PMRT + IMC were retrospectively identified. Nodal delineation was in accordance with European Society for Radiology and Oncology (ESTRO) guidelines and tangential chest wall fields marked. Patients were planned with Anisotropic Analytical Algorithm using free-breathing (FB) and DIBH datasets. Dose was calculated using Acuros External Beam algorithm. FB and DIBH dose comparisons were analyzed for heart, RCA and right lung, as were chest wall and IMC planning target volumes (PTVs). DIBH vs FB resulted in median decreases of: the RCA mean dose by 0.6Gray (Gy) (interquartile range (IQR) 0.1, 1.9) (p = 0.002), RCA max dose by 1.8Gy (IQR 0.8, 6.1) (p = 0.002), and V5Gy by 2.9% (IQR 0.0, 37.2) (p = 0.016). RCA data indicated no statistically significant dosimetric reduction ≥10Gy. A median reduction of 1.7Gy (c -0.0, 7.1) (p = 0.019) in maximum heart dose was recorded with DIBH vs FB; no significant difference was observed in other heart and left anterior descending coronary artery parameters. The median reduction in right lung mean dose was 2.8Gy for DIBH vs FB plans (IQR 1.6, 3.6) (p = 0.001); significant median reductions of V5Gy, V20Gy, and V30Gy were all achieved with DIBH. Chest wall PTV coverage did not significantly differ between DIBH and FB plans; IMC dosimetric coverage improved with use of DIBH (V47.5Gy, V45Gy, V42Gy). DIBH reduced OAR dose in right-sided PMRT + IMC patients. A novel finding was that DIBH decreased RCA dose. Heart and right lung dose were also decreased with DIBH, whilst optimally dosed PTVs were maintained.

Deep Learning-based Lung dose Prediction Using Chest X-ray Images in Non-small Cell Lung Cancer Radiotherapy.

Purpose: This study aimed to develop a deep learning model for the prediction of V20 (the volume of the lung parenchyma that received ≥20 Gy) during intensity-modulated radiation therapy using chest X-ray images. Methods: The study utilized 91 chest X-ray images of patients with lung cancer acquired routinely during the admission workup. The prescription dose for the planning target volume was 60 Gy in 30 fractions. A convolutional neural network-based regression model was developed to predict V20. To evaluate model performance, the coefficient of determination (R2), root mean square error (RMSE), and mean absolute error (MAE) were calculated with conducting a four-fold cross-validation method. The patient characteristics of the eligible data were treatment period (2018-2022) and V20 (19.3%; 4.9%-30.7%). Results: The predictive results of the developed model for V20 were 0.16, 5.4%, and 4.5% for the R2, RMSE, and MAE, respectively. The median error was -1.8% (range, -13.0% to 9.2%). The Pearson correlation coefficient between the calculated and predicted V20 values was 0.40. As a binary classifier with V20 <20%, the model showed a sensitivity of 75.0%, specificity of 82.6%, diagnostic accuracy of 80.6%, and area under the receiver operator characteristic curve of 0.79. Conclusions: The proposed deep learning chest X-ray model can predict V20 and play an important role in the early determination of patient treatment strategies.

Aerosol Delivery Efficiency With High-Flow Nasal Cannula Therapy in Neonatal, Pediatric, and Adult Nasal Upper-Airway and Lung Models.

BACKGROUND: High-flow nasal cannula (HFNC) systems employ different methods to provide aerosol to patients. This study compared delivery efficiency, particle size, and regional deposition of aerosolized bronchodilators during HFNC in neonatal, pediatric, and adult upper-airway and lung models between a proximal aerosol adapter and distal aerosol circuit chamber. METHODS: A filter was connected to the upper airway to a spontaneously breathing lung model. Albuterol was nebulized using the aerosol adapter and circuit at different clinical flow settings. The aerosol mass deposited in the upper airway and lung was quantified. Particle size was measured with a laser diffractometer. Regional deposition was assessed with a gamma camera at each nebulizer location and patient model with minimum flow settings. RESULTS: Inhaled lung doses ranged from 0.2-0.8% for neonates, 0.2-2.2% for the small child, and 0.5-5.2% for the adult models. Neonatal inhaled lung doses were not different between the aerosol circuit and adapter, but the aerosol circuit showed marginally greater lung doses in the pediatric and adult patient models. Impacted aerosols and condensation in the non-heated HFNC and aerosol delivery components contributed to the dispersion of coarse liquid droplets, high deposition (11-44%), and occlusion of the supine neonatal upper airway. In contrast, the upright pediatric and adult upper-airway models had minimal deposition (0.3-7.0%) and high fugitive losses (∼24%) from liquid droplets leaking out of the nose. The high impactive losses in the aerosol adapter (56%) were better contained than in the aerosol circuit, resulting in less cannula sputter (5% vs 22%), fewer fugitive losses (18% vs 24%), and smaller inhaled aerosols (5 µm vs 13 µm). CONCLUSIONS: The inhaled lung dose was low (1-5%) during HFNC. Approaches that streamline aerosol delivery are needed to provide safe and effective therapy to patients receiving aerosolized medications with this HFNC system.

Heart and Lung Dose as Predictors of Overall Survival in Patients With Locally Advanced Lung Cancer. A National Multicenter Study.

Introduction: It is an ongoing debate how much lung and heart irradiation impact overall survival (OS) after definitive radiotherapy for lung cancer. This study uses a large national cohort of patients with locally advanced NSCLC to investigate the association between OS and irradiation of lung and heart. Methods: Treatment plans were acquired from six Danish radiotherapy centers, and patient characteristics were obtained from national registries. A hybrid segmentation tool automatically delineated the heart and substructures. Dose-volume histograms for all structures were extracted and analyzed using principal component analyses (PCAs). Parameter selection for a multivariable Cox model for OS prediction was performed using cross-validation based on bootstrapping. Results: The population consisted of 644 patients with a median survival of 26 months (95% confidence interval [CI]: 24-29). The cross-validation selected two PCA variables to be included in the multivariable model. PCA1 represented irradiation of the heart and affected OS negatively (hazard ratio, 1.14; 95% CI: 1.04-1.26). PCA2 characterized the left-right balance (right atrium and left ventricle) irradiation, showing better survival for tumors near the right side (hazard ratio, 0.92; 95% CI: 0.84-1.00). Besides the two PCA variables, the multivariable model included age, sex, body-mass index, performance status, tumor dose, and tumor volume. Conclusions: Besides the classic noncardiac risk factors, lung and heart doses had a negative impact on survival, while it is suggested that the left side of the heart is a more radiation dose-sensitive region. The data indicate that overall heart irradiation should be reduced to improve the OS if possible.

Design of dry powder inhalers to improve patient outcomes: it's not just about the device.

INTRODUCTION: Up to 50% of asthma/COPD patients make critical errors in dose preparation and dose inhalation with current marketed DPIs which negatively impact clinical outcomes. Others fail to adhere to their chronic treatment regimen. AREAS COVERED: For this review, we describe how a human-factors approach to design of a dry powder inhaler can be used to improve usability, proficiency, and functionality of DPIs, while effectively mitigating critical errors associated with DPIs. The review highlights the critical importance of utilizing improved formulations with monomodal aerodynamic particle size distributions to reduce variability associated with oropharyngeal filtering of particles, flow rate dependence, and co-formulation effects. EXPERT OPINION: Much of the variability in dose delivery with DPIs is associated with limitations of the bimodal APSDs inherent in current lactose blend formulations. Evidence supports that improved lung targeting and dose consistency can be achieved with drug-device combination products comprising spray-dried powders. Unfortunately, no data exists to assess whether these advances observed in in vitro and in vivo dose delivery studies will translate into improved clinical outcomes. Given the significant percentage of patients that receive suboptimal drug delivery with current DPIs it would behoove the industry to assess the efficacy of new approaches.

Estimated Doses to the Heart, Lungs and Oesophagus and Risks From Typical UK Radiotherapy for Early Breast Cancer During 2015-2023.

PURPOSE: Breast cancer radiotherapy can increase the risks of heart disease, lung cancer and oesophageal cancer. At present, the best dosimetric predictors of these risks are mean doses to the whole heart, lungs and oesophagus, respectively. We aimed to estimate typical doses to these organs and resulting risks from UK breast cancer radiotherapy. METHODS: A systematic review and meta-analysis was conducted of planned or delivered mean doses to the whole heart, lungs or oesophagus from UK breast cancer radiotherapy in studies published during 2015-2023. Average mean doses were summarised for combinations of laterality and clinical targets. Heart disease and lung cancer mortality risks were then estimated using established models. RESULTS: For whole heart, thirteen studies reported 2893 doses. Average mean doses were higher in left than in right-sided radiotherapy and increased with extent of clinical targets. For left-sided radiotherapy, average mean heart doses were: 2.0 Gy (range 1.2-8.0 Gy) breast/chest wall, 2.7 Gy (range 0.6-5.6 Gy) breast/chest wall with either axilla or supraclavicular nodes and 2.9 Gy (range 1.3-4.7 Gy) breast/chest wall with nodes including internal mammary. For right-sided radiotherapy, average mean heart doses were: 1.0 Gy (range 0.3-1.0 Gy) breast/chest wall and 1.2 Gy (range 1.0-1.4 Gy) breast/chest wall with either axilla or supraclavicular nodes. There were no whole heart dose estimates from right internal mammary radiotherapy. For whole lung, six studies reported 2230 doses. Average mean lung doses increased with extent of targets irradiated: 2.6 Gy (range 1.4-3.0 Gy) breast/chest wall, 3.0 Gy (range 0.9-5.1 Gy) breast/chest wall with either axilla or supraclavicular nodes and 7.1 Gy (range 6.7-10.0 Gy) breast/chest wall with nodes including internal mammary. For whole oesophagus, two studies reported 76 doses. Average mean oesophagus doses increased with extent of targets irradiated: 1.4 Gy (range 1.0-2.0 Gy) breast/chest wall with either axilla or supraclavicular nodes and 5.8 Gy (range 1.9-10.0 Gy) breast/chest wall with nodes including internal mammary. CONCLUSIONS: The typical doses to these organs may be combined with dose-response relationships to estimate radiation risks. Estimated 30-year absolute lung cancer mortality risks from modern UK breast cancer radiotherapy for patients irradiated when aged 50 years were 2-6% for long-term continuing smokers, and <1% for non-smokers. Estimated 30-year mortality risks for heart disease were <1%.

Learning curve of lung dose optimization in intensity-modulated radiotherapy for locally advanced non-small cell lung cancer.

BACKGROUND: Intensity-modulated radiotherapy (IMRT) has been increasingly used for patients with locally advanced non-small cell lung cancer (LA-NSCLC). However, there are some barriers to implementing IMRT for LA-NSCLC, including the complexity of treatment plan optimization. This study aimed to evaluate the learning curve of lung dose optimization in IMRT for LA-NSCLC and identify the factors that affect the degree of achievement of lung dose optimization. METHODS: We retrospectively evaluated 40 consecutive patients with LA-NSCLC who received concurrent chemoradiotherapy at our institution. These 40 patients were divided into two groups: 20 initially treated patients (earlier group) and 20 subsequently treated patients (later group). Patient and tumor characteristics were compared between the two groups. The dose-volume parameter ratio between the actually delivered IMRT plan and the simulated three-dimensional conformal radiotherapy plan was also compared between the two groups to determine the learning curve of lung dose optimization. RESULTS: The dose-volume parameter ratio for lung volume to receive more than 5 Gy (lung V5) and mean lung dose (MLD) significantly decreased in later groups. The spread of the beam path and insufficient optimization of dose coverage of planning target volume (PTV) might cause poor control of lung V5, MLD. CONCLUSIONS: A learning curve for lung dose optimization was observed with the accumulation of experience. Appropriate techniques, such as restricting the beam path and ensuring dose coverage of PTV during the optimization process, are essential to control lung dose in IMRT for LA-NSCLC.

Ipsilateral lung dose as a correlative measure for radiation pneumonitis in patients treated with definitive concurrent radiochemotherapy.

Objective: Mean lung dose (MLD) and percent of total lung (TL) volume that receive a dose greater than 20 Gy (V20) have been the most validated parameters in the prediction of radiation pneumonitis (RP). However, these parameters present mean values of TL parenchyma and predict the right and the left lung as a unique functional organ unit, not take into account the difference in function and dose density between the lungs. Furthermore, there have been very limited data evaluating ipsilateral lung dosimetric constraints in addition to TL parameters to predict RP in non-small cell lung cancer (NSCLC) patients treated with radiochemotherapy (RCT). Methods: Between 2010 and 2017, clinical-radiological findings of NSCLC patients treated with RCT were evaluated in terms of RP, retrospectively. MLD, V20, and V30 values of ipsilateral lung were assessed from dose-volume histogram and registered. The primary endpoint was to assess the relation between ipsilateral lung dose constraints and RP risk. Results: There were 75 patients. There was ≥Grade 2 RP in 33 cases (%44). In univariate analysis, ipsilateral MLD, ipsilateral V20, ipsilateral V30, and TL V30 were found to be significant. Ipsilateral MLD and PTV were found to be the independent risk factors for RP. Cutoff values for RP risk were determined as 18Gy, 35%, and 28% for ipsilateral MLD, ipsilateral V20, and ipsilateral V30, respectively. Predictive values for ipsilateral MLD and ipsilateral V20 were higher than TL. Conclusions: In NSCLC patients treated with RCT, MLD, V20, and V30 values of ipsilateral lung parameters might increase the predictability of RP risk in addition to TL parameters. Advances in Knowledge: Cutoff values for RP risk were determined as 18Gy, 35%, and 28% for ipsilateral MLD, ipsilateral V20, and ipsilateral V30, respectively. Predictive values for ipsilateral MLD and ipsilateral V20 were higher than TL.