Lung Irradiation Research Articles

The Role of Coronary Artery Calcium Score to Assess Risk of Cardiovascular Disease in Irradiated Esophageal Cancer Patients

Coronary artery calcium (CAC) score is an important predictive imaging marker of cardiovascular disease (CVD). While studies have found positive association between CAC score and cardiac toxicity in irradiated lung and breast cancer patients, there are no studies assessing CAC scores in esophageal cancer (EC). While a cardiac-gated CT is required for standard Agatston CAC score, visual assessment of CAC via ordinal scoring on non-gated CT has shown good concordance with Agatston score. In this study, we sought to examine whether visual assessment of CAC, measured on standard of care, non-contrast chest CT, predicts the development of adverse cardiovascular events (ACVE) in irradiated EC patients. This is a single institution retrospective study of EC patients treated with RT from 2010-2021. We included patients with available PET/CT at diagnosis or chest CT simulation scan without contrast, and excluded those with history of percutaneous coronary intervention, coronary bypass surgery, or prior thoracic RT. Pre-treatment characteristics, clinical factors, and grade ≥ 3 (G3+) adverse cardiovascular events (ACVE) (CTCAEv5.0) were evaluated. Visual assessment of CAC was performed using ordinal method (CAC scored from 0 to 12), by a thoracic radiologist. Fine and Gray regression was used to compute hazard ratios for time to first ACVE. Univariate analyses using Cox proportional hazards were used for overall survival (OS). ACVEs were recorded from start of oncologic treatment and OS calculated after completion of RT. A total of 118 patients were analyzed with a median follow-up of 16 months. Median age was 67 years, 65% male, 43% white, 59% with EC of distal esophagus, and 59% had squamous cell carcinoma. Median mean heart dose was 21.93 Gy (range 0.15-36.94). 24% developed G3+ ACVEs: atrial fibrillation 9%, stroke 6%, heart failure 4%, pulmonary embolism 4%, pericardial effusion 3%, myocardial infarction 2%, heart block 2%, and cardiac death 1%. On univariate analyses, CAC >1 vs. CAC ≤ 1 trended towards increased risk of ACVE (HR = 1.95, 95% CI = 0.89-4.26; p = 0.094), however it is not predictive of OS (HR = 1.31, 95% CI = 0.75-2.30; p = 0.343). Proportion of patients with ACVEs was greater in CAC>1 group (Table). When compared to patients with CAC ≤ 1, those with CAC >1 were older (median age 62 vs 72 years, p = 0.0015), less likely to be never smokers (38% vs 30%, p = 0.0437), and more likely to have hypertension (43% vs 64%, p = 0.0197), and hyperlipidemia (30% vs 47%, p = 0.0557). This is the first study to investigate the relationship between CAC score and ACVEs in EC. While the study was underpowered (likely due to low rates of recorded ACVEs), to detect a significant association between CAC score and ACVEs, there was a trend towards increased risk of ACVEs in patients with a CAC score >1 by visual ordinal scoring. Further prospective evaluation with a larger cohort is warranted.

Analysis of the Measured FDG Uptake from the First-in-Human Clinical Trial of Biology-Guided Radiotherapy

The RefleXion X1 system is a novel linear accelerator equipped with dual 90° PET arcs incorporated into its architecture to capture emissions from tumors and designed to respond by directing the radiation beam towards target. This study reports on the measured FDG uptake from the first in human multi-institutional clinical trial (BIOGUIDE-X) evaluating the performance and safety of the RefleXion X1 PET-LINAC. A total of nine patients treated with stereotactic body radiotherapy (SBRT) for lung (5) and bone (4) tumors were enrolled in the Cohort II of this study after screening their pre-study diagnostic PET/CT, acquired up to 60 days prior to enrollment, to ensure their tumor size between 2 to 5 cm and SUVmax >6. After CT simulation, the tumor and OARs were delineated, and patients had a 4-pass Imaging-only (BgRT Modeling) PET/CT acquisition on the X1 system to generate biology-guided radiotherapy (BgRT) plans. Before the patients' first and last SBRT fractions, they were injected with FDG, and short PET pre-scan (1-pass) was performed on the X1 followed by a long-PET acquisition (4-pass) to emulate the expected BgRT dose distribution without firing beam. Patients were also imaged on a third-party diagnostic PET/CT scanner after the last-fraction X1 scan. This study compares the SUVmax from the screening PET/CT, X1 Imaging-only scan, X1 PET pre-scan and long scan before the first and last-fractions, and final diagnostic PET/CT. The median time from injection to PET imaging was 84 ± 15.4 mins for X1 Imaging-only (used for generating BgRT plans), 77 ± 21.6 mins for X1 pre-scan (safety check before treatment start), 108+/- 22 mins for X1 long-PET (used to emulate treatment delivery), and 161 ± 23 mins for final diagnostic PET. For a nominal 10 mCi injection, the mean SUVmax for screening imaging performed on the diagnostic PET/CT was 10.8 ± 4.3. For a 15 mCi nominal injection, the mean SUVmax calculated on the X1 was 5.3 ± 2.6, 5.4 ± 2.0, 5.5 ± 2.6, 5.2 ± 1.8 and 5.4 ± 2.2 for the Imaging-only, first-fraction PET pre-scan, first-fraction long PET scan, last-fraction PET pre-scan, and last-fraction long PET scan, respectively. The overall median SUVmax for all patients across all timepoints and scans with X1 was calculated to be 4.8 with a range of 2.4 to 9.8. The median SUVmax for the diagnostic PET/CT scan after the last fraction X1 scan was 15.8 with a range of 8.5 to 27.7. The dual PET arcs and limited axial extent of the X1 PET subsystem results in lower system sensitivity in comparison to diagnostic PET scanners equipped with full ring and larger axial extent, as expected. With the same FDG injection, the RefleXion X1 produced SUVmax values that were 30.4 % of the diagnostic PET/CT scanners' values. Nevertheless, the X1 collected sufficient emission data to enable successful completion of emulated BgRT deliveries that met dose accuracy criteria in a clinical setting.

Vertebral Dose Sparing during Lung and Esophageal Radiation Therapy

The vertebral bodies contain approximately 20-25% of all bone marrow in the body. Lymphopenia is a known negative prognostic factor in thoracic malignancies. Studies have previously demonstrated that patients receiving radiation to the lumbar spine and/or pelvis have shown increased fat deposition/bone marrow scarring following therapy, which leads to long term immunosuppressive effects. In anticipation for an open clinical trial, and based on previously published work, we explored whether retrospectively constraining the thoracic bone marrow is practically feasible and leads to minimal increase in dose to the remaining OARs (Organs at Risk). Patients with previously treated thoracic cancer were included in this study. The thoracic bone marrow was contoured using PET scan to verify avid areas and a new plan was created. Guideline constraints for the thoracic bone marrow were V10 (<300cc), V20 (<200 cc), and V30 (<150cc). If bone marrow optimization caused a violation of standard OAR guidelines, then the bone marrow constraints were not met. The median changes in thoracic bone marrow and OARs (lung, heart, spinal cord) were compared with the Wilcoxon sign rank test for non-parametric paired samples. We included 20 patients, 10 with esophageal cancer and 10 with NSCLC (Non-Small Cell Lung Cancer). Only three cases were able to meet the prespecified bone marrow constraints after optimization (15%). Bone marrow median V10 was reduced by 20cc (-8.16%). Larger changes were seen in V20 and V30 dose-volume reductions, with decreases of 35.3 and 32.3 cc (-16.4% and -21.3%), respectively. There was a significant reduction (p<0.001) for V30, V20, and V10. Though most experienced a decrease in mean heart dose, there was an overall median increase of 21.00 cGy, attributable to a single outlier (P = 1). Median cord dose was decreased by 418.5 cGy. There was a minimal non-significant increase in median Lung V20 of 0.76% as well as minimal median increase in the mean lung dose (7 cGy). This retrospective dosimetric analysis reveals that bone marrow can be optimized. While not able to meet thresholds predictive of minimizing Grade 4 lymphopenia, dose reduction can safely be done with minimal increase in values known to cause toxicity in the heart, lungs, and cord. Though radiation dosage to the thoracic vertebrae was not eliminated entirely, significant decreases in median dosages were achieved without compromising OAR dose. Bone marrow sparing should be considered when feasible and this planning technique is currently being used in an open prospective trial.

Observed and Predicted Toxicity in Daily Cone-Beam CT-Based Online Adaptive Stereotactic Partial Breast Irradiation with Decreased PTV Margins

Accelerated partial breast irradiation (APBI) delivers smaller radiation volumes over less time compared to whole breast irradiation (WBI), but the organ-at-risk (OAR) sparing allowed by its large (up to 1 cm) planning target volume (PTV) can be improved. PTV can be decreased with daily online adaptive planning, which we hypothesized yields low rates of adverse events observed and predicted by normal tissue complication probability (NTCP) models. Intensity-modulated (IMRT) cone-beam CT (CBCT)-based daily online adaptive stereotactic PBI (A-SPBI) plans with 3-mm PTV from 8 patients were recreated with 1-cm PTV per the Florence APBI IMRT trial planning guideline. Dose statistics with evidence for association with toxicity were compared. Documented toxicities were collected for patients treated with A-SPBI with a minimum follow-up of 3.5 months and Common Terminology Criteria for Adverse Events (CTCAE) v.5.0 grade was assigned. Using α/β = 3 for breast and lung, dose statistics were converted to equivalent doses in 2-Gy fractions (EQD2) for use in NTCP models and for comparison using paired t tests, with differences considered significant if p≤0.05. The table details EQD2 dose statistics for breast, lung, and cosmetic toxicity for A-SPBI plans with 3-mm PTV and their 1-cm PTV re-plans in 8 patients. PTV volume, mean lung dose (MLD), and lung V5, V20, and V30 were significantly lower in 1-cm plans. Acute, subacute (3-6 months), and late toxicities were collected for 30 patients followed for a median of 8 months (range 4-13 months). Radiation dermatitis was the most common acute toxicity (n = 16, 53%), followed by hyperpigmentation (n = 12, 40%), fibrosis (n = 9, 30%), and fatigue (n = 9, 30%). One grade 3 radiation dermatitis was the only grade ≥3 toxicity. Six patients (20%) acutely developed breast or axillary edema: 4 (13.3%) resolved, and 2 (6.7%) developed acutely and persist at last follow-up, >6 months after RT. No patient had a lung V20, V30, or MLD meeting thresholds for radiation-induced lung injury, radiation pneumonitis, or symptomatic or imaging-based pneumonitis models, respectively. The breast V55 model predicted a median risk of unfavorable cosmesis of 33% (range 26-44%) for A-SBPI plans and 35% (range 28-51) for 1-cm PTV plans (p = 0.28). Observed acute toxicities are tolerable and rarely persist in patients treated with A-SPBI with 3-mm PTV margins with daily CBCT-based online adaptation. NTCP modeling predicts similar cosmetic outcome to 1-cm margins. The significant reduction in ipsilateral lung dose with a 3-mm PTV in our first 8 patients especially supports daily adaptation in low-risk breast cancer patients with smoking history and/or lung comorbidity.

Toxicity of Patients with Ultra-Central Thoracic Tumors Treated with Stereotactic Body Radiotherapy (SBRT) with Dose of 50 Gy in 5 Fractions

The ideal regimen for stereotactic body radiotherapy (SBRT) in ultra-central lung tumors is still to be defined, mostly due to the risk of unacceptable or fatal toxicity. There is not much information on outcomes after SBRT for this group of patients. We summarize here our experience with ultra-central lung cancer patients treated with the dose of 50 Gy delivered in 5 fractions. This study is a retrospective review of all cases of ultra-central thoracic tumors treated with SBRT with the dose of 50 Gy in 5 fractions, delivered every other day, at our institution. In all cases, as we defined ultra-central lung tumor, the PTV overlapped or touched one or more of the following structures: bronchial tree, trachea, great vessels, heart, and esophagus. Metastatic and primary lung lesions were included. The volumes of treatment were defined by 4D-CT to consider breathing motion. Normal organs constraints followed the recommendations of the RTO 0813 trial as follows: Spinal cord: max 30 Gy. Lung right or lung left: V13 Gy[cc] < 1500. Esophagus: max 52 Gy and nonadjacent esophagus: V27.5 Gy[cc] < 5. Heart: V32 Gy[cc] < 15; max 52 Gy. Great vessels: max 52 Gy and non-adjacent great vessels V47 Gy[cc] < 10. Trachea plus bronchus: max 52 Gy and non-adjacent V18 Gy[cc] < 4. Follow-up, at the discretion of the treating MD, included periodic CT scans of the thorax after SBRT and assessment of radiation-induced toxicity scored with CTCv3.0. Between December 2015 and February 2022, 86 patients were eligible for this review. Median follow-up was 17 months (range: 1-76 months); the median age was 74 years (range: 37-98 years). Histology was as follows: 50 patients had biopsy proved NSCLC, 16 had no biopsy, and 20 had metastatic non-lung primaries. Overlapped structures were as follows: with great vessels in 46 cases, heart in 20 cases, trachea/branchial tree in 18 cases, and esophagus in 2 cases. In 16 patients the overlap was present in more than one structure. Overall, 68.6% did not report acute toxicity. The most common acute side effects were fatigue (15.1%), coughing (8.1%), shortness of breath (6.9%), esophagitis (2.3%), and dysphagia (1.1%). No grade 3 or more significant toxicity was described. As acute side effects, many patients had exacerbations of the previous condition, such as shortness of breath (16 pts) or coughing (4 pts) during follow-up. Pneumonitis was found as a late side effect in four cases. One patient had empyema associated with a fistula in the non-irradiated lung, where the patient had previous surgery, but in the irradiated lung no severe complication was detected. There were no deaths attributed to the SBRT treatment. 67.5% of 86 patients were alive at the time of the review; 87.2% had local control, and 65.1% had metastases-free survival. In this cohort of patients, no death or even severe acute or chronic toxicity was attributed to SBRT. SBRT seems safe for ultra-central lesions using the regimen of 50 Gy in 5 fractions with the constraints of the RTOG 0813 trial.

Molecular Imaging of Radiation-Induced Lung Injury Using [18F]AlF Labeled Polypeptide Targeting C-X-C-Chemokine-Receptor-Type-4

Radiation-induced lung injury (RILI) is a severe side effect of radiotherapy (RT) for thoracic malignancies and we currently lack established means for the early detection of RILI. In this study, we synthesized a new tracer, [18F]AlF-NOTA-QHY-04, targeting C-X-C-chemokine-receptor-type-4 (CXCR4) and investigated the feasibility of using this tracer in positron emission tomography combined with computed tomography (PET/CT) for detecting RILI. An RILI model was established using a high-dose single RT (50 Gy/Fraction) to the right lung of female Wistar rats. Experimental animals were scanned with [18F]AlF-NOTA-QHY-04 PET/CT and [18F]FDG PET/CT at various time-points post-RT. MicroCT imaging was conducted weekly till 11 weeks post-RT. Dynamic, competition, autoradiography and histopathological studies were performed on day 14 post-RT. Biodistribution study was further performed on day 18 post-RT. Lung QHY-04 uptake was analyzed in twelve patients with radiation pneumonia, developed during or after thoracic RT. The yield of [18F]AlF-NOTA-QHY-04 was 28.5-43.2%, and the specific activity was 27-33 GBq/μmol. Significantly increased [18F]AlF-NOTA-QHY-04 uptake in the damaged lung compared with that in the normal lung was observed in the experimental animal model on 6 post-RT and peaked on day 14 post-RT (0.96 ± 0.06 vs. 0.50 ± 0.05 %ID/mL, P<0.05), whereas no apparent uptake of [18F]FDG was shown on day 7 and 15 post-RT. Significant intense [18F]AlF-NOTA-QHY-04 uptake was confirmed by autoradiography. No significant difference in CT density was observed between the damaged and normal lung tissues until six weeks post-RT. Immunofluorescence staining demonstrated expression of CXCR4 was significantly increased in the damaged lung tissue, which correlated with results obtained from hematoxylin-eosin and Masson's trichrome staining. Maximum standardized uptake values (SUVmax) were significantly higher in the irradiated lung compared with that in the normal lung in 12 patients with radiation pneumonia (3.07 ± 0.86 vs. 0.585 ± 0.17, P<0.001). SUVmax of patients with grade 2 RILI was significantly higher than that of patients with grade 1 RILI (3.30 ± 0.65 vs. 1.64 ± 0.08, P<0.05). This study indicated that [18F]AlF-NOTA-QHY-04 PET/CT imaging can detect RILI noninvasively and earlier than [18F]FDG PET/CT in a rat model. Clinical studies verified its' feasibility, suggesting the clinical potential of [18F]AlF-NOTA-QHY-04 as a PET/CT tracer for early monitoring of RILI.

Daily Adaptive vs. Non-Adaptive External Beam Radiation Therapy with Concurrent Chemotherapy for Locally Advanced Non-Small Cell Lung Cancer (NSCLC): A Prospective Randomized Trial of an Individualized Approach for Toxicity Reduction (ARTIA-Lung)

Radiotherapy (RT) with concurrent chemotherapy is a standard treatment for Stage III NSCLC. However, radiation pneumonitis incidence increases rapidly with volume of lung irradiated, and esophagitis increases with dose to the esophagus. Both conditions can have adverse impacts on patients' quality of life. Daily online adaptive RT (ART) may allow for reduced normal tissue doses due to smaller margins around the target, as well as target size reduction with tumor response. This prospective, randomized controlled trial tests the hypothesis that the proportion of study participants who experience score ≥3 PRO-CTCAE cough, dyspnea, or dysphagia will be at least 20% lower with daily ART than with non-adapted RT. Enrollment goals are 244 subjects at up to 10 cancer centers worldwide. Eligibility criteria include stage IIIA-IIIC (AJCC v8) NSCLC; baseline grade 0-2 dyspnea, cough, and dysphagia; and no contralateral hilar or supraclavicular/cervical lymph node involvement. Subjects will be randomized (1:1) to CBCT-based daily ART or non-adapted RT using IMRT or VMAT delivering 60-66 Gy in 30-33 fractions with concurrent platinum doublet chemotherapy. Adjuvant immunotherapy with durvalumab is permitted. Follow-up for study participants will be for 1-year post-completion of chemoRT. Study endpoints include: frequency of PRO-CTCAE score ≥3 cough, dyspnea, or dysphagia from randomization to 30 days post-chemoRT; patient-reported quality of life (FACT-L and EQ-5D-5L questionnaires); percentage of lung receiving ≥20 Gy; mean doses to lung, heart, and esophagus; primary tumor response on CT or PET-CT (RECIST v1.1); local disease progression; and incidence of grade ≥2 pneumonitis within 1 year. Stratification factors are the treating institution and the presence of contralateral mediastinal lymph node metastases (associated with increased volume of irradiated lung). Interim analyses for futility and superiority will be performed when the primary endpoint data have been collected for 50% of evaluable participants. This study opened to enrollment on 20 October 2022 and is expected to be completed in approximately 3 years. This prospective, randomized clinical trial rigorously evaluates the impacts of daily online ART on radiation pneumonitis, esophagitis, and quality of life in patients with advanced NSCLC. It will collect standard tumor response and disease progression metrics to assure that reduced margins do not have an adverse impact on outcomes. Online ART is emerging as an innovative approach enabling increased sparing of normal tissues. The results of this clinical study will support evidence-based clinical decisions around ART technologies.

Unplanned Hospitalization and Subsequent Mortality in Lung Cancer Patients Undergoing Concomitant Chemo-/Immuno-Therapy and Radiotherapy: An Analysis of Over 10,000 Patients in a Nationwide Database

Radiotherapy (RT) and concomitant chemotherapy (CHT) is a major modality for treating many malignancies including lung cancer and is associated with toxicity-related unplanned hospitalization (UPH). Previous investigations of factors associated with UPH have been single institutional retrospective studies and none assessed the role of concurrent immunotherapy (IO). Here, we aimed to identify factors associated with UPH and in-hospital mortality by leveraging a multi-institutional nationwide database. The Vizient® Clinical Data Base which includes data from 98% of the AAMC hospitals and 110 cancer hospitals, was queried for lung cancer patients (any histology) treated in 2019-2021 with RT+CHT/IO. Endpoints were UPH and mortality during or within 30 days of completion of RT. The variables included age, sex, race, ethnicity, income level (quartile), an education level (quartile), any concomitant CHT or IO drugs, RT technique (3D vs. IMRT vs. SBRT), obesity, prior hospitalization within 3 months, prior oncologic surgery within 3 months, prior CHT and/or IO within 3 months, insurance types, hospital types (Rural vs. Urban, AAMC vs. non-AAMC, NCCN vs. non-NCCN, bed size tertile). Logistic regression was performed to identify variables associated with UPH and in-hospital mortality. Data from the Vizient Clinical Data Base used with permission of Vizient, Inc. All rights reserved. A total of 10,337 patients were included. The rate of UPH and mortality among UPH was 24.5% and 3.2%, respectively. Factors associated with UPH included other races (vs. White, OR 1.44; 95% CI 1.11-1.88; p<0.001), living in a low income zip code (OR 1.7; 95% CI 1.39-2.09; p = 0.0006), living in a zip code with lower education attainment (OR 0.71; 95% CI 0.58-0.86; p = 0.0007), CHT/IO types (cis-etoposide vs. carbo-Taxol, OR 1.33; 95% CI 1.13-1.57; p<0.0001), obesity (OR 1.71; 95% CI 1.53-1.92; p<0.0001), prior hospitalization (OR 2.0; 95% CI 1.80-2.22; p<0.0001), prior oncologic surgery (OR 0.34; 95% CI 0.22-0.52; p<0.0001), other primary payers (vs. commercial; OR 1.75; 95% CI 1.37-2.23; p<0.0001), rural hospital (OR 1.3; 95% CI 1.07-1.62, p<0.01), small bed size (OR 0.59; 95% CI 0.5-0.71; p<0.0001). Factors associated with in-hospital mortality included CHT/IO type (p<0.0001, but cis-etoposide vs. carbo-taxol no difference), prior hospitalization (OR 0.34; 95% CI 0.2-0.56; p<0.0001), AAMC (OR 2.12; 95% CI 1.23-3.67; p = 0.007), bed size (OR 0.58; 95% CI 0.38-0.88; p<0.01). In the largest study to date regarding UPH and in-hospital mortality related to lung RT, we identified factors contributing to these endpoints. Future prospective studies are warranted to develop strategies to prevent these complications in high-risk populations.

Analysis of Skin Dose and Position Stability for a New Personalized Device for Breast Radiotherapy

Whole breast irradiation is the standard treatment for patients with early-stage breast cancer. We previously developed a personalized breast support device (PERSBRA) that reduced heart and lung radiation exposure. However, the skin dose was concerned for the device due to its thickness. In this study, we designed the new honeycomb structures to reduce the dose to the skin and maintain stable breast position with this device. Three different structures of PERSBRA were designed. They were solid structure, honeycomb structures with 3.5 mm wall thickness and honeycomb structures with 4.5 mm wall thickness respectively. Those patients who scheduled to receive whole breast irradiation were enrolled for anthropometric breast position analysis. Stability of breast position in supine with PERSBRA were analyzed by scanning with a 3D infrared scanner. The distances between the nipples, between the nipple and the xiphoid process, and between the nipple and the inframammary fold were used to be the index. 32 patients were enrolled for anthropometric breast position analysis. The skin dose was simulated using the thermoluminescent dosimeter (TLD) positioned on the phantom with PERSBRA in the treatment scenario. The displacements between two nipples, the nipple and the infra mammary point, and the nipple and the xiphoid process were 1.4%, 1.2%, and 0.4% for 3.5 mm honeycomb structure. Meanwhile, these displacements were 0.8%, 0.7% and 0.2% for solid 10% structure. Compared to these results, there were no significant difference for the two designations. The surface dose simulating the treatment scenario were 78.27%, 89.39% and 91.9% of prescribed dose for the 3.5mm, 4.5 mm honeycomb structure and the solid 10% filled structure, respectively. The 3.5 mm honeycomb structure reduce the surface dose significantly compared to another two designations. The honeycomb structures do not jeopardize mechanical properties of PERSBRA or the breast positional stability support. Moreover, honeycomb structure with 3.5 mm thickness effectively reduces skin surface dose on a breast phantom. These data encourage further clinical studies to investigate the effects of such design on radiation dermatitis during whole breast irradiation.

Chinese clinical practice guidelines for the prevention and treatment of radiation‐induced esophagitis

AbstractAcute radiation‐induced esophagitis is a common complication of radiotherapy for esophageal, lung, and other malignancies. Therefore, understanding the diagnosis, grading, risk factors, prevention, and treatment of radiation‐induced esophagitis is essential. Currently, there are few consensuses and guidelines on radiation‐induced esophagitis worldwide, mainly the American College of Gastroenterology (ACG) clinical guideline: evidenced based approach to the diagnosis and management of esophageal eosinophilia and eosinophilic esophagitis (EoE) and the Digestive Endoscopy Society of Chinese Medical Association's “Guidelines for the Diagnosis and Treatment of Reflux Esophagitis.” However, no consensus or guidelines specifically addressing radiation‐induced esophagitis have been established. Efforts have been made to organize experts to draft Chinese consensus or guidelines, but the recommendations in these guidelines also vary owing to differences in expert backgrounds. The clinical practice guidelines presented herein were developed for the first time with the joint participation of Chinese radiotherapy experts. Drugs and methods with clinical significance were selected by reviewing and summarizing the prevention and treatment of radiation‐induced esophagitis and combining them with China's national conditions. After multiple rounds of discussion and revision, clinical practice guidelines were established in line with the needs of Chinese clinicians, providing useful clinical guidance for the prevention and treatment of radiation‐induced esophagitis.

Nicaraven partially attenuates radiation-induced expression of adhesion molecules in the murine lung

Thoracic irradiation has been found to promote cancer metastasis in the lungs, but the relevant mechanism remains unclear. Adhesion and extracellular matrix (ECM) molecules, major components of the tissue microenvironment, play a critical role in cancer metastasis. We have found that nicaraven, a small chemical compound, effectively protects normal tissue (stem) cells against radiation-induced injuries and attenuates cancer metastasis. In this study, we tried to investigate whether nicaraven regulates adhesion and ECM molecules expressions in the irradiated lungs. To find the potential adhesion and ECM molecules are regulated by nicaraven in the irradiated lungs, we collected the lungs from mice 24 h after thorax irradiation with a single dose of 5 Gy X-rays, and then widely evaluated the expression of adhesion and ECM molecules by RT-PCR assay. Our data showed that several adhesion and ECM molecules were up- or down-regulated in the irradiated murine lungs. Interestingly, nicaraven effectively attenuated radiation-enhanced expressions of Itga2 and Pecam1 in the murine lungs. Our study demonstrated that nicaraven suppresses the adhesion and ECM remodeling in the irradiated lungs, which may contribute to attenuate the radiation-induced enhancement of lung metastasis. Further study is warranted to determine how nicaraven regulates the expression of adhesion and ECM molecules and prevents cancer metastasis after irradiation.

Estimating surgery, radiotherapy and systemic anti-cancer therapy treatment costs for cancer patients by stage at diagnosis

BackgroundThe increasing burden of cancer has economic implications for the healthcare system in England. However, there is limited evidence on the cost of cancer treatment. We calculated the costs of initial cancer treatment (resection, radiotherapy, systemic anti-cancer therapy [SACT]) based on stage at diagnosis.MethodsData from England’s National Cancer Registration Dataset were matched to English Hospital, Radiotherapy and SACT data for breast, lung, prostate, colon and rectal cancers diagnosed between 2016 and 2018. Treatment data were matched to National Schedule of Reference Costs data to calculate the cost of each treatment event.ResultsBreast, colon and rectal cancers treated with resection, radiotherapy or SACT had increasing costs with later stage at diagnosis; costs for lung and prostate cancers were lower at stages 1 and 4 compared to stages 2 and 3. In general, surgery and SACT were the most expensive treatments. Radiotherapy and SACT costs showed little change across stages 1–3; radiotherapy costs decreased in stage 4, while SACT costs increased.ConclusionsThis analysis estimates initial treatment costs by stage based on observed data. Future research can build on this to provide more comprehensive costings associated with cancer; this is important for future planning of cancer services.

Analysis of clinical and physical dosimetric factors that determine the outcome of severe acute radiation pneumonitis in lung cancer patients

ObjectiveWe conducted a retrospective statistical analysis of clinical and physical dosimetric factors of lung cancer patients who had previously undergone lung and/or mediastinal radiotherapy and died of or survived severe acute radiation pneumonitis (SARP). Our study was the first to reveal the heterogeneity in clinical factors, physical dosimetric factors, and SARP onset time that determined the clinical outcomes of lung cancer patients who developed SARP.Materials and methodsThe clinical characteristics, physical dosimetry factors, and SARP onset time of deceased and surviving patients were retrospectively analyzed. SPSS 20.0 was used for data analysis. Student’s t-test was used for intergroup comparison, and a Mann–Whitney U test was used for data with skewed distribution. Qualitative data were represented using frequencies (%), and Fisher’s exact test or χ2 test was used for intergroup comparison of nonparametric data. Binary logistic analysis was used for univariate and multivariate analyses. Differences with a P < 0.05 were considered statistically significant.ResultsUnivariate analysis revealed that the potential predictors of SARP death were as follows: ipsilateral lung V5 and V30, contralateral lung V5, V10, and V30, total lung V5, V10, and V30, mean lung dose, mean heart dose, and maximum spinal cord dose. Multivariate analysis showed that ipsilateral lung V5 and total lung V5 were predictors that determined the final outcome of SARP patients. In addition, we analyzed the time from the completion of radiotherapy to SARP onset, and found significant difference between the two groups.ConclusionsThere was no decisive correlation between clinical characteristics and SARP outcome (i.e., death or survival) in lung radiotherapy patients. Ipsilateral lung V5 and total lung V5 were independent predictors of death in SARP patients.

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

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. 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. 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). 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.

Impact of varying the number of irradiation fields on dose distribution: A four-dimensional scanned carbon-ion lung radiotherapy

To shorten the treatment procedure and increase the treatment efficiency, we performed planning studies to evaluate the 4D dose (4DD) distributions of different number of irradiation fields with the fixed treatment ports of scanning carbon-ion beam delivery. We enrolled 10 lung cancer patients treated with respiratory-gated scanning carbon-ion therapy. 4-field, 3-field, and 2-field plans were generated with fixed treatment ports by rotating the beam angle with a 20∼40-degree difference. For each field, the range-adapted internal target volume (raITV) was calculated. The prescription dose of 50 Gy (RBE)-weighted dose with 1 fraction was optimized on the reference phase (T50). The 4DD distributions were calculated for each patient, and dose metrics of CTV dose coverage and OARs sparing were evaluated. p < 0.05 was considered to be statistically significant by Wilcoxon signed-rank test. The sufficient CTV-D95 > 97.8% could be achieved for all the three types of treatment plan. The Dmax of skin was increased (= 19.1 ± 5.7 Gy (RBE)) for the 2-field plans as compared to 4-field plans (= 14.2 ± 6.6 Gy (RBE), p = 0.006), which is still acceptable for clinical use (<35 Gy (RBE)). And there were no differences (p > 0.076) of V20 of lung (= 15.5 ± 6.6%, 16.2 ± 7.0%, 15.6 ± 6.3%) and Dmax of spinal cord (= 3.0 ± 2.9, 3.4 ± 3.9, 3.3 ± 4.3 Gy (RBE)) among the three types of plans. Lung treatment plans under the fixed orthogonal beam ports with zero-degree couch pitch angle is feasible for clinical use to further increase the treatment efficiency and throughput.

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

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

Adaptive Lung Radiation Therapy in the Era of Immunotherapy: A Single-Center Retrospective Study

Treatment for locally advanced non-small cell lung cancer consists of concurrent chemoradiation followed by immunotherapy. Though this combination has been shown to have a benefit in both progression-free survival and overall survival, treatment is often limited by the development of pneumonitis. One way to mitigate toxicity is through adaptive radiation therapy, which does not currently have a standardized implementation in clinical practice. A single-center retrospective review of patients with locally advanced stage III or oligometastatic stage IV non-small cell lung cancer who were treated with chemoradiation with concurrent or subsequent immunotherapy from 2015 to 2020 was performed. Patients were stratified based on having 1 or more offline adapted plan. The aim of this study was to evaluate the association between dose-volume histogram values and common toxicities experienced during this treatment, including pneumonitis and esophagitis. Twenty-five patients were included in the final analysis: 10 with adapted plans (AP), and 15 with nonadapted plans (NAP). Mean age at onset was 74 years. The most common histology was adenocarcinoma (N=13). Five patients experienced pneumonitis: 2 in AP and 3 in NAP. Mann-Whitney U test of gross tumor volume sizes between AP (346.2 ± 269.7 cm3) and NAP (153.1 ± 99.6 cm3) was significant (P=.019). Multiple linear regression analysis with adjustment for covariates of pneumonitis versus plan adaptation (P=.106) and esophagitis versus plan adaptation (P=.59) did not demonstrate a significant difference in toxicity between the adapted and nonadaptive patients. Despite similar toxicities in both groups, the gross tumor volume size in the AP was more than double compared with NAP, suggesting that adaptive techniques provide a method for patients with larger target volumes to be treated without an observed difference in pneumonitis rates. These results suggest adaptive radiation therapy may have a role in mitigating toxicity experience from chemoradiation and immunotherapy and warrants further investigation.

Retraction Note: Cellular immunotherapy using irradiated lung cancer cell vaccine co-expressing GM-CSF and IL-18 can induce significant antitumor effects

Retraction Note: Cellular immunotherapy using irradiated lung cancer cell vaccine co-expressing GM-CSF and IL-18 can induce significant antitumor effects

Outcomes in lung-only metastatic rhabdomyosarcoma: An analysis of data from the European paediatric Soft tissue sarcoma Study Group MTS 2008 study

PurposePatients with metastatic rhabdomyosarcoma (MTS RMS) and lung as the only metastatic site have better reported outcomes than other patients with MTS RMS. We analysed patients with lung-only MTS RMS receiving standard treatment within the EpSSG MTS 2008 protocol. Patients and methodsPreviously untreated patients aged< 21 years with MTS RMS received standard induction chemotherapy with radiotherapy (RT) and/or surgery to the primary site and RT recommended to all metastatic sites. Clinical characteristics, treatment and outcomes of patients with lung-only MTS RMS were compared to lung + other site and other site MTS RMS. ResultsAmong 270 patients with MTS RMS, 59 (22%) had lung-only metastatic disease, 68 (25%) in lung + other and 143 (53%) in other sites. 3-yr Event Free Survival (EFS) and Overall Survival (OS) for lung-only MTS RMS were 40% (95%CI 27–53%) and 60% (95%CI 46–71%). Although 3-yr OS for lung-only MTS RMS was significantly better than lung + other (35%; 95% CI 24–47%) and other (49%; 95% CI 40–57%) sites (p = 0.0382), EFS and OS adjusted for known clinical (Oberlin) risk factors, did not differ between the groups. 3-year EFS was significantly higher in patients with lung-only MTS who received RT to the lungs (RT, n = 26, EFS 56%, 95% CI 35–73%; no RT, n = 24, EFS 33%, 95% CI 16–52%, p = 0.0435). ConclusionsBetter outcomes for lung-only MTS RMS seem to be determined by the presence of fewer clinical risk factors. Whole lung radiotherapy continues to be recommended in patients with lung-only MTS RMS.

Benchmarking Automated Machine Learning-Enhanced Planning With Ethos Against Manual and Knowledge-Based Planning for Locally Advanced Lung Cancer

Currently, there is insufficient guidance for standard fractionation lung planning using the Varian Ethos adaptive treatment planning system and its unique intelligent optimization engine. Here, we address this gap in knowledge by developing a methodology to automatically generate high-quality Ethos treatment plans for locally advanced lung cancer. Fifty patients previously treated with manually generated Eclipse plans for inoperable stage IIIA-IIIC non-small cell lung cancer were included in this institutional review board-approved retrospective study. Fifteen patient plans were used to iteratively optimize a planning template for the Daily Adaptive vs Non-Adaptive External Beam Radiation Therapy With Concurrent Chemotherapy for Locally Advanced Non-Small Cell Lung Cancer: A Prospective Randomized Trial of an Individualized Approach for Toxicity Reduction (ARTIA-Lung); the remaining 35 patients were automatically replanned without intervention. Ethos plan quality was benchmarked against clinical plans and reoptimized knowledge-based RapidPlan (RP) plans, then judged using standard dose-volume histogram metrics, adherence to clinical trial objectives, and qualitative review. Given equal prescription target coverage, Ethos-generated plans showed improved primary and nodal planning target volume V95% coverage (P < .001) and reduced lung gross tumor volume V5 Gy and esophagus D0.03 cc metrics (P ≤ .003) but increased mean esophagus and brachial plexus D0.03 cc metrics (P < .001) compared with RP plans. Eighty percent, 49%, and 51% of Ethos, clinical, and RP plans, respectively, were "per protocol" or met "variation acceptable" ARTIA-Lung planning metrics. Three radiation oncologists qualitatively scored Ethos plans, and 78% of plans were clinically acceptable to all reviewing physicians, with no plans receiving scores requiring major changes. A standard Ethos template produced lung radiation therapy plans with similar quality to RP plans, elucidating a viable approach for automated plan generation in the Ethos adaptive workspace.