Pneumonitis Rates Before and After Adoption of Immunotherapy Consolidation in Patients With Locally Advanced Non-Small Cell Lung Cancer Treated With Concurrent Chemoradiation.

PURPOSE: We hypothesized that after adoption of immune checkpoint inhibitor (ICI) consolidation for patients with locally advanced non-small cell lung cancer (LA-NSCLC) receiving concurrent chemoradiation therapy (cCRT), rates of symptomatic pneumonitis would increase, thereby supporting efforts to reduce lung radiation dose. METHODS AND MATERIALS: This single institution, multisite retrospective study included 783 patients with LA-NSCLC treated with definitive cCRT either before introduction of ICI consolidation (pre-ICI era cohort [January 2011-September 2017]; N = 448) or afterward (ICI era cohort [October 2017-December 2021]; N = 335). Primary endpoint was grade ≥2 pneumonitis (G2P) and secondary endpoint was grade ≥3 pneumonitis (G3P), per Common Terminology Criteria for Adverse Events v5.0. Pneumonitis was compared between pre-ICI era and ICI era cohorts using the cumulative incidence function and Gray's test. Inverse probability of treatment weighting (IPTW)-adjusted Fine-Gray models were generated. Logistic models were developed to predict the 1-year probability of G2P as a function of lung dosimetry. RESULTS: G2P was higher in the ICI era than in the pre-ICI era (1-year cumulative incidence 31.4% vs 20.1%; P < .001; IPTW-adjusted multivariable subdistribution hazard ratio, 2.03; 95% confidence interval, 1.53-2.70; P < .001). There was no significant interaction between ICI era treatment and either lung volume receiving ≥20 Gy (V20) or mean lung dose in Fine-Gray regression for G2P; however, the predicted probability of G2P was higher in the ICI era at clinically relevant values of lung V20 (≥24%) and mean lung dose (≥14 Gy). Cut-point analysis revealed a lung V20 threshold of 28% in the ICI era (1-year G2P rate 46.0% above vs 19.8% below; P < .001). Among patients receiving ICI consolidation, lung V5 was not associated with G2P. G3P was not higher in the ICI era (1-year cumulative incidence 7.5% vs 6.0%; P = .39; IPTW-adjusted multivariable subdistribution hazard ratio, 1.12; 95% confidence interval, 0.63-2.01; P = .70). CONCLUSIONS: In patients with LA-NSCLC treated with cCRT, the adoption of ICI consolidation was associated with an increase in G2P but not G3P. With ICI consolidation, stricter lung dose constraints may be warranted.

Phase 2 Trial of Consolidation Pembrolizumab After Proton Reirradiation for Thoracic Recurrences of Non-Small Cell Lung Cancer.

PURPOSE: Reirradiation (reRT) with proton beam therapy (PBT) may offer a chance of cure while minimizing toxicity for patients with isolated intrathoracic recurrences of non-small cell lung cancer (NSCLC). However, distant failure remains common, necessitating strategies to integrate more effective systemic therapy. METHODS AND MATERIALS: This was a phase 2, single-arm trial (NCT03087760) of consolidation pembrolizumab after PBT reRT for locoregional recurrences of NSCLC. Four to 12 weeks after completion of 60 to 70 Gy PBT reRT, patients without progressive disease received pembrolizumab for up to 12 months. Primary endpoint was progression-free survival (PFS), measured from the start of reRT. Secondary endpoints were overall survival (OS) and National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0 toxicity. RESULTS: Between 2017 and 2021, 22 patients received PBT reRT. Median interval from prior radiation end to reRT start was 20 months. Most recurrences (91%) were centrally located. Most patients received concurrent chemotherapy (95%) and pencil beam scanning PBT (77%), and 36% had received prior durvalumab. Fifteen patients (68%) initiated consolidation pembrolizumab on trial and received a median of 3 cycles (range, 2-17). Pembrolizumab was discontinued most commonly due to toxicity (n = 5; 2 were pembrolizumab-related), disease progression (n = 4), and completion of 1 year (n = 3). Median follow-up was 38.7 months. Median PFS and OS were 8.8 months (95% CI, 4.2-23.7) and 22.8 months (95% CI, 6.9-not reached), respectively. There was only one isolated in-field failure after reRT. Grade ≥3 toxicities occurred in 10 patients (45%); 2 were pembrolizumab-related. There were 2 grade 5 toxicities, an aorto-esophageal fistula at 6.9 months and hemoptysis at 46.8 months, both probably from reRT. The trial closed early due to widespread adoption of immunotherapy off-protocol. CONCLUSIONS: In the first-ever prospective trial combining PBT reRT with consolidation immunotherapy, PFS was acceptable and OS favorable. Late grade 5 toxicity occurred in 2 of 22 patients. This approach may be considered in selected patients with isolated thoracic recurrences of NSCLC.

Death without progression as an endpoint to describe cardiac radiation effects in locally advanced non-small cell lung cancer.

Background and purpose: Prior studies have examined associations of cardiovascular substructure dose with overall survival (OS) or cardiac events after chemoradiotherapy (CRT) for non-small cell lung cancer (NSCLC). Herein, we investigate an alternative endpoint, death without cancer progression (DWP), which is potentially more specific than OS and more sensitive than cardiac events for understanding CRT toxicity. Materials and methods: We retrospectively reviewed records of 187 patients with locally advanced or oligometastatic NSCLC treated with definitive CRT from 2008 to 2016 at a single institution. Dosimetric parameters to the heart, lung, and ten cardiovascular substructures were extracted. Charlson Comorbidity Index (CCI), excluding NSCLC diagnosis, was used to stratify patients into CCI low (0-2; n = 66), CCI intermediate (3-4; n = 78), and CCI high (≥5; n = 43) groups. Primary endpoint was DWP, modeled with competing risk regression. Secondary endpoints included OS. An external cohort consisted of 140 patients from another institution. Results: Median follow-up was 7.3 years for survivors. Death occurred in 143 patients (76.5 %), including death after progression in 118 (63.1 %) and DWP in 25 (13.4 %). On multivariable analysis, increasing CCI stratum and mean heart dose were associated with DWP. For mean heart dose ≥ 10 Gy vs < 10 Gy, DWP was higher (5-year rate, 16.9 % vs 6.7 %, p = 0.04) and OS worse (median, 22.9 vs 34.1 months, p < 0.001). Ventricle (left, right, and bilateral) and pericardial but not atrial substructure dose were associated with DWP, whereas all three were inversely associated with OS. Cutpoint analysis identified right ventricle mean dose ≥ 5.5 Gy as a predictor of DWP. In the external cohort, we confirmed an association of ventricle, but not atrial, dose with DWP. Conclusion: Cardiovascular substructure dose showed distinct associations with DWP. Future cardiotoxicity studies in NSCLC could consider DWP as an endpoint.

Higher Dose Volumes May Be Better for Evaluating Radiation Pneumonitis in Lung Proton Therapy Patients Compared With Traditional Photon-Based Dose Constraints.

PURPOSE: The dosimetric parameters used clinically to reduce the likelihood of radiation pneumonitis (RP) for lung cancer radiation therapy have traditionally been V20Gy ≤ 30% to 35% and mean lung dose ≤ 20 to 23 Gy; however, these parameters are derived based on studies from photon therapy. The purpose of this study is to evaluate whether such dosimetric predictors for RP are applicable for locally advanced non-small cell lung cancer (LA-NSCLC) patients treated with proton therapy. METHODS AND MATERIALS: In the study, 160 (78 photon, 82 proton) patients with LA-NSCLC treated with chemoradiotherapy between 2011 and 2016 were retrospectively identified. Forty (20 photon, 20 proton) patients exhibited grade ≥2 RP after therapy. Dose volume histograms for the uninvolved lung were extracted for each patient. The percent lung volumes receiving above various dose levels were obtained in addition to V20Gy and Dmean. These dosimetric parameters and patient characteristics were evaluated with univariate and multivariate logistic regression tests. Receiver operating characteristic curves were generated to obtain the optimal dosimetric constraints through analyzing RP and non-RP sensitivity and specificity values. RESULTS: The multivariate analysis showed V40Gy and Dmean to be statistically significant for proton and photon patients, respectively. V35Gy to V50Gy were strongly correlated to V40Gy for proton patients. Based on the receiver operating characteristic curves, V35Gy to V50Gy had the highest area under the curve compared with other dose levels for proton patients. A potential dosimetric constraint for RP predictor in proton patients is V40Gy ≤ 23%. CONCLUSIONS: In addition to V20Gy and Dmean, the lung volume receiving higher doses, such as V40Gy, may be used as an additional indicator for RP in LA-NSCLC patients treated with proton therapy.

Robust treatment planning in whole pelvis pencil beam scanning proton therapy for prostate cancer.

Whole-pelvis pencil beam scanning (PBS) proton therapy is utilized in both the intact and post-operative settings in patients with prostate cancer. As whole pelvis prostate radiotherapy has traditionally been delivered with standard photon beams, limited evidence and technical descriptions have been reported regarding the use of proton therapy. Here we present two robust three-field treatment planning approaches utilized to maximize target coverage in the presence of anatomic and delivery uncertainties. Both techniques, conventional optimization (CO) and robust optimization (RO), create treatment plans with acceptable target coverage and sparing of organs at risk (OAR). While the RO method is less time intensive and may theoretically allow for superior OAR sparing and improved robustness, the CO method can be implemented by institutions who do not have RO capabilities.

Re-evaluation of pediatric 18F-FDG dosimetry: Cristy-Eckerman versus UF/NCI hybrid computational phantoms.

Because of the concerns associated with radiation exposure at a young age, there is an increased interest in pediatric absorbed dose estimates for imaging agents. Almost all reported pediatric absorbed dose estimates, however, have been determined using adult pharmacokinetic data with radionuclide S values that take into account the anatomical differences between adults and children based upon the older Cristy-Eckerman (C-E) stylized phantoms. In this work, we use pediatric model-derived pharmacokinetics to compare absorbed dose and effective dose estimates for 18F-FDG in pediatric patients using S values generated from two different geometries of computational phantoms. Time-integrated activity coefficients of 18F-FDG in brain, lungs, heart wall, kidneys and liver, retrospectively, calculated from 35 pediatric patients at the Boston's Children Hospital were used. The absorbed dose calculation was performed in accordance with the Medical Internal Radiation Dose method using S values generated from the University of Florida/National Cancer Institute (UF/NCI) hybrid phantoms, as well as those from C-E stylized computational phantoms. The effective dose was computed using tissue-weighting factors from ICRP Publication 60 and ICRP Publication 103 for the C-E and UF/NCI, respectively. Substantial differences in the absorbed dose estimates between UF/NCI hybrid pediatric phantoms and the C-E stylized phantoms were found for the lungs, ovaries, red bone marrow and urinary bladder wall. Large discrepancies in the calculated dose values were observed in the bone marrow; ranging between -26% to +199%. The effective doses computed by the UF/NCI hybrid phantom S values were slightly different than those seen using the C-E stylized phantoms with percent differences of -0.7%, 2.9% and 2.5% for a newborn, 1 year old and 5 year old, respectively. Differences in anatomical modeling features among computational phantoms used to perform Monte Carlo-based photon and electron transport simulations for 18F, and very likely for other radionuclides, impact internal organ dosimetry computations for pediatric nuclear medicine studies.

Automated Information Extraction on Treatment and Prognosis for Non-Small Cell Lung Cancer Radiotherapy Patients: Clinical Study.

BACKGROUND: In outcome studies of oncology patients undergoing radiation, researchers extract valuable information from medical records generated before, during, and after radiotherapy visits, such as survival data, toxicities, and complications. Clinical studies rely heavily on these data to correlate the treatment regimen with the prognosis to develop evidence-based radiation therapy paradigms. These data are available mainly in forms of narrative texts or table formats with heterogeneous vocabularies. Manual extraction of the related information from these data can be time consuming and labor intensive, which is not ideal for large studies. OBJECTIVE: The objective of this study was to adapt the interactive information extraction platform Information and Data Extraction using Adaptive Learning (IDEAL-X) to extract treatment and prognosis data for patients with locally advanced or inoperable non-small cell lung cancer (NSCLC). METHODS: We transformed patient treatment and prognosis documents into normalized structured forms using the IDEAL-X system for easy data navigation. The adaptive learning and user-customized controlled toxicity vocabularies were applied to extract categorized treatment and prognosis data, so as to generate structured output. RESULTS: In total, we extracted data from 261 treatment and prognosis documents relating to 50 patients, with overall precision and recall more than 93% and 83%, respectively. For toxicity information extractions, which are important to study patient posttreatment side effects and quality of life, the precision and recall achieved 95.7% and 94.5% respectively. CONCLUSIONS: The IDEAL-X system is capable of extracting study data regarding NSCLC chemoradiation patients with significant accuracy and effectiveness, and therefore can be used in large-scale radiotherapy clinical data studies.

Dose Estimation in Pediatric Nuclear Medicine.

The practice of nuclear medicine in children is well established for imaging practically all physiologic systems but particularly in the fields of oncology, neurology, urology, and orthopedics. Pediatric nuclear medicine yields images of physiologic and molecular processes that can provide essential diagnostic information to the clinician. However, nuclear medicine involves the administration of radiopharmaceuticals that expose the patient to ionizing radiation and children are thought to be at a higher risk for adverse effects from radiation exposure than adults. Therefore it may be considered prudent to take extra care to optimize the radiation dose associated with pediatric nuclear medicine. This requires a solid understanding of the dosimetry associated with the administration of radiopharmaceuticals in children. Models for estimating the internal radiation dose from radiopharmaceuticals have been developed by the Medical Internal Radiation Dosimetry Committee of the Society of Nuclear Medicine and Molecular Imaging and other groups. But to use these models accurately in children, better pharmacokinetic data for the radiopharmaceuticals and anatomical models specifically for children need to be developed. The use of CT in the context of hybrid imaging has also increased significantly in the past 15 years, and thus CT dosimetry as it applies to children needs to be better understood. The concept of effective dose has been used to compare different practices involving radiation on a dosimetric level, but this approach may not be appropriate when applied to a population of children of different ages as the radiosensitivity weights utilized in the calculation of effective dose are not specific to children and may vary as a function of age on an organ-by-organ bias. As these gaps in knowledge of dosimetry and radiation risk as they apply to children are filled, more accurate models can be developed that allow for better approaches to dose optimization. In turn, this will lead to an overall improvement in the practice of pediatric nuclear medicine by providing excellent diagnostic image quality at the lowest radiation dose possible.

Depth-dependent concentrations of hematopoietic stem cells in the adult skeleton: Implications for active marrow dosimetry.

PURPOSE: The hematopoietically active (or red) bone marrow is the target tissue assigned in skeletal dosimetry models for assessment of stochastic effects (leukemia induction) as well as tissue reactions (marrow toxicity). Active marrow, however, is in reality a surrogate tissue region for specific cell populations, namely the hematopoietic stem and progenitor cells. Present models of active marrow dosimetry implicitly assume that these cells are uniformly localized throughout the marrow spaces of trabecular spongiosa. Data from Watchman et al. and Bourke et al., however, clearly indicate that there is a substantial spatial concentration gradient of these cells with the highest concentrations localized near the bone trabeculae surfaces. The purpose of the present study was thus to explore the dosimetric implications of these spatial gradients on active marrow dosimetry. METHODS: Images of several bone sites from a 45-yr female were retagged to group active marrow voxels into 50 µm increments of marrow depth, after which electron and alpha-particle depth-dependent specific absorbed fractions were computed for four source tissues - active marrow, inactive marrow, bone trabeculae volumes, and bone trabeculae surfaces. Corresponding depth-dependent S values (dose to a target tissue per decay in a source tissue) were computed and further weighted by the relative target cell concentration. These depth-weighted radionuclide S values were systematically compared to the more traditional volume-averaged radionuclide S values of the MIRD schema for both individual bones of the skeleton and their skeletal-averaged quantities. RESULTS: For both beta-emitters and alpha-emitters localized in the active and inactive marrow, depth-weighted S values were shown to differ from volume-averaged S values by only a few percent, as dose gradients across the marrow tissues are nonexistent. For bone volume and bone surface sources of alpha-emitters and lower energy beta-emitters, when marrow dose gradients are expected, explicit consideration of target cell spatial concentration gradients are shown to significantly impact marrow dosimetry. CONCLUSIONS: For medical isotopes currently utilized for treatment of skeletal metastases, namely 153 Sm and 223 Ra, accounting for hematopoietic stem and progenitor cell concentration gradients resulted in maximum percent differences to reference skeletal-averaged S values of ~21% and 55%, respectively.

Organ Doses to Airline Passengers Screened by X-Ray Backscatter Imaging Systems.

Advanced imaging technologies (AIT) are being developed for passenger airline transportation. They are designed to provide enhanced security benefits by identifying objects on passengers that would not be detected by methodologies now used for routine surveillance. X-ray backscatter imaging is one AIT system being considered. Since this technology is based on scanning passengers with ionizing radiation, concern has been raised relating to the health risks associated with these exposures. Recommendations for standards of radiation safety have been proposed by the American National Standards Institute published in ANSI/HPS N43.17-2009. A Monte Carlo based methodology for estimating organ doses received from an X-ray backscatter AIT system is presented. Radiological properties of a reference scanner including beam intensity, geometry and energy spectra were modeled based on previous studies and physical measurements. These parameters were incorporated into a Monte Carlo source subroutine and validated with comparison of simulated versus measured data. One extension of this study was to calculate organ and effective dose on a wide range of potential passengers. Computational phantoms with realistic morphologies were used including adults of 5th, 25th, 50th, 75th and 95th percentile weight, children of 5th, 50th and 95th percentile weight, and the developing fetus of 15, 25, and 38 weeks after conception. Additional sensitivity studies were performed to evaluate effects of passenger positioning within the scanner, energy spectrum and beam geometry, as well as failure mode analyses. Results for routine operations yielded a maximum effective dose to the adult and pediatric passengers of 15 and 25 nSv per screen, respectively. The developing fetus received a maximum organ dose and whole body dose of 16 nGy and 8.5 nGy per screen, respectively. The sensitivity analyses indicated that variations in positioning, energy spectra, and beam geometry yielded a range of effective doses per screen that were an order of magnitude below the ANSI recommendation.

An image-based skeletal dosimetry model for the ICRP reference adult female-internal electron sources.

An image-based skeletal dosimetry model for internal electron sources was created for the ICRP-defined reference adult female. Many previous skeletal dosimetry models, which are still employed in commonly used internal dosimetry software, do not properly account for electron escape from trabecular spongiosa, electron cross-fire from cortical bone, and the impact of marrow cellularity on active marrow self-irradiation. Furthermore, these existing models do not employ the current ICRP definition of a 50 µm bone endosteum (or shallow marrow). Each of these limitations was addressed in the present study. Electron transport was completed to determine specific absorbed fractions to both active and shallow marrow of the skeletal regions of the University of Florida reference adult female. The skeletal macrostructure and microstructure were modeled separately. The bone macrostructure was based on the whole-body hybrid computational phantom of the UF series of reference models, while the bone microstructure was derived from microCT images of skeletal region samples taken from a 45 years-old female cadaver. The active and shallow marrow are typically adopted as surrogate tissue regions for the hematopoietic stem cells and osteoprogenitor cells, respectively. Source tissues included active marrow, inactive marrow, trabecular bone volume, trabecular bone surfaces, cortical bone volume, and cortical bone surfaces. Marrow cellularity was varied from 10 to 100 percent for active marrow self-irradiation. All other sources were run at the defined ICRP Publication 70 cellularity for each bone site. A total of 33 discrete electron energies, ranging from 1 keV to 10 MeV, were either simulated or analytically modeled. The method of combining skeletal macrostructure and microstructure absorbed fractions assessed using MCNPX electron transport was found to yield results similar to those determined with the PIRT model applied to the UF adult male skeletal dosimetry model. Calculated skeletal averaged absorbed fractions for each source-target combination were found to follow similar trends of more recent dosimetry models (image-based models) but did not follow results from skeletal models based upon assumptions of an infinite expanse of trabecular spongiosa.

Pharmacokinetic modeling of [(18)F]fluorodeoxyglucose (FDG) for premature infants, and newborns through 5-year-olds.

BACKGROUND: Absorbed dose estimates for pediatric patients require pharmacokinetics that are, to the extent possible, age-specific. Such age-specific pharmacokinetic data are lacking for many of the diagnostic agents typically used in pediatric imaging. We have developed a pharmacokinetic model of [(18)F]fluorodeoxyglucose (FDG) applicable to premature infants and to 0- (newborns) to 5-year-old patients, which may be used to generate model-derived time-integrated activity coefficients and absorbed dose calculations for these patients. METHODS: The FDG compartmental model developed by Hays and Segall for adults was fitted to published data from infants and also to a retrospective data set collected at the Boston Children's Hospital (BCH). The BCH data set was also used to examine the relationship between uptake of FDG in different organs and patient weight or age. RESULTS: Substantial changes in the structure of the FDG model were required to fit the pediatric data. Fitted rate constants and fractional blood volumes were reduced relative to the adult values. CONCLUSIONS: The pharmacokinetic models developed differ substantially from adult pharmacokinetic (PK) models which can have considerable impact on the dosimetric models for pediatric patients. This approach may be used as a model for estimating dosimetry in children from other radiopharmaceuticals.

A risk index for pediatric patients undergoing diagnostic imaging with (99m)Tc-dimercaptosuccinic acid that accounts for body habitus.

Published guidelines for administered activity to pediatric patients undergoing diagnostic nuclear medicine imaging are currently obtained through expert consensus of the minimum values as a function of body weight as required to yield diagnostic quality images. We have previously shown that consideration of body habitus is also important in obtaining diagnostic quality images at the lowest administered activity. The objective of this study was to create a series of computational phantoms that realistically portray the anatomy of the pediatric patient population which can be used to develop and validate techniques to minimize radiation dose while maintaining adequate image quality. To achieve this objective, we have defined an imaging risk index that may be used in future studies to develop pediatric patient dosing guidelines. A population of 48 hybrid phantoms consisting of non-uniform B-spline surfaces and polygon meshes was generated. The representative ages included the newborn, 1 year, 5 year, 10 year and 15 year male and female. For each age, the phantoms were modeled at their 10th, 50th, and 90th height percentile each at a constant 50th weight percentile. To test the impact of kidney size, the newborn phantoms were modeled with the following three kidney volumes: -15%, average, and +15%. To illustrate the impact of different morphologies on dose optimization, we calculated the effective dose for each phantom using weight-based (99m)Tc-DMSA activity administration. For a given patient weight, body habitus had a considerable effect on effective dose. Substantial variations were observed in the risk index between the 10th and 90th percentile height phantoms from the 50th percentile phantoms for a given age, with the greatest difference being 18%. There was a dependence found between kidney size and risk of radiation induced kidney cancer, with the highest risk indices observed in newborns with the smallest kidneys. Overall, the phantoms and techniques in this study can be used to provide data to refine dosing guidelines for pediatric nuclear imaging studies while taking into account the effects on both radiation dose and image quality.