DNA methylation profiles of cancer-related fatigue associated with markers of inflammation and immunometabolism.

Cancer patients are commonly affected by fatigue. Herein, we sought to examine epigenetic modifications (i.e., DNA methylation) related to fatigue in peripheral blood among patients during and after treatment for head and neck cancer (HNC). Further, we determined whether these modifications were associated with gene expression and inflammatory protein markers, which we have previously linked to fatigue in HNC. This prospective, longitudinal study enrolled eligible patients with data collected at pre-radiotherapy, end of radiotherapy, and six months and one-year post-radiotherapy. Fatigue data were reported by patients using the Multidimensional Fatigue Inventory (MFI)-20. DNA methylation (Illumina MethylationEPIC) and gene expression (Applied Biosystems Clariom S) arrays and assays for seven inflammatory markers (R&D Systems multiplex) were performed. Mixed models and enrichment analyses were applied to establish the associations. A total of 386 methylation loci were associated with fatigue among 145 patients (False Discovery Rate [FDR] < 0.05). Enrichment analyses showed the involvement of genes related to immune and inflammatory responses, insulin and lipid metabolism, neuropsychological disorders, and tumors. We further identified 16 methylation-gene expression pairs (FDR < 0.05), which were linked to immune and inflammatory responses and lipid metabolism. Ninety-one percent (351) of the 386 methylation loci were also significantly associated with inflammatory markers (e.g., interleukin 6, c-reactive protein; FDR < 0.05), which further mediated the association between methylation and fatigue (FDR < 0.05). These data suggest that epigenetic modifications associated with inflammation and immunometabolism, in conjunction with relevant gene expression and protein markers, are potential targets for treating fatigue in HNC patients. The findings also merit future prospective studies in other cancer populations as well as interventional investigations.

Neoadjuvant and Adjuvant Treatment for Early-Stage Resectable Non-small Cell Lung Cancer (NSCLC): Consensus Recommendations from the International Association for the Study of Lung Cancer (IASLC).

Advances in the multidisciplinary care of early-stage resectable non-small cell lung cancer (rNSCLC) are emerging at an unprecedented pace. Numerous phase 3 trials produced results that have transformed patient outcomes for the better, yet these findings also require important modifications to the patient treatment journey trajectory and re-organization of care pathways. Perhaps most notably, the need for multispecialty collaboration for this patient population has never been greater. These rapid advances have inevitably left us with important gaps in knowledge for which definitive answers will only become available in several years. To this end, the IASLC commissioned a diverse multidisciplinary international expert panel to evaluate the current landscape and provide diagnostic, staging, and therapeutic recommendations for patients with rNSCLC, with particular emphasis on patients with AJCC/UICC TNM 8th edition stage II and III disease. Using a team-based approach, we generated 19 recommendations, of which all but one achieved greater than 85% consensus amongst panel members. A public voting process was initiated, which successfully validated and provided qualitative nuance to our recommendations. Highlights include: 1) the critical importance of a multidisciplinary approach to the evaluation of patients with rNSCLC driven by shared clinical decision making of a multispecialty team of expert providers; 2) biomarker testing for rNSCLC; 3) a preference for neoadjuvant chemoimmunotherapy for stage III rNSCLC; 4) equipoise regarding the optimal management of patients with stage II between up-front surgery followed by adjuvant therapy and neoadjuvant/perioperative strategies; and 5) the robust preference for adjuvant targeted therapy for patients with rNSCLC and sensitizing EGFR and ALK tumor alterations. Our primary goals were to provide practical recommendations sensitive to the global differences in biology and resources for patients with rNSCLC, and to provide expert consensus guidance tailored to the individualized patient needs, goals, and preferences in their cancer care journey as these are areas where physicians must make daily clinical decisions in the absence of definitive data. These recommendations will continue to evolve as the treatment landscape for rNSCLC expands and more knowledge is acquired on the best therapeutic approach in specific patient and disease subgroups.

Immune System Dose With Proton Versus Photon Radiotherapy for Treatment of Locally Advanced NSCLC.

Purpose: Emerging data have illuminated the impact of effective radiation dose to immune cells (EDIC) on outcomes in patients with locally advanced, unresectable non-small cell lung cancer (NSCLC) treated with intensity-modulated radiotherapy (IMRT). Hypothesizing that intensity-modulated proton therapy (IMPT) may reduce EDIC versus IMRT, we conducted a dosimetric analysis of patients treated at our institution. Materials and Methods: Data were retrospectively collected for 12 patients with locally advanced, unresectable NSCLC diagnosed between 2019 and 2021 who had physician-approved IMRT and IMPT plans. Data to calculate EDIC from both Jin et al (PMID: 34944813) and Ladbury et al's (PMID: 31175902) models were abstracted. Paired t tests were utilized to compare the difference in mean EDIC between IMPT and IMRT plans. Results: IMPT decreased EDIC for 11 of 12 patients (91.7%). The mean EDIC per the Jin model was significantly lower with IMPT than IMRT (3.04 GyE vs 4.99 Gy, P < .001). Similarly, the mean EDIC per the Ladbury model was significantly lower with IMPT than IMRT (4.50 GyE vs 7.60 Gy, P < .002). Modeled 2-year overall survival was significantly longer with IMPT than IMRT (median 71% vs 63%; P = .03). Conclusion: IMPT offers a statistically significant reduction in EDIC compared to IMRT. Given the emergence of EDIC as a modifiable prognostic factor in treatment planning, our dosimetric study highlights a potential role for IMPT to address an unmet need in improving oncologic outcomes in patients with locoregionally advanced NSCLC.

Intensity-Modulated Reirradiation Therapy With Nivolumab in Recurrent or Second Primary Head and Neck Squamous Cell Carcinoma: A Nonrandomized Controlled Trial.

Importance: Intensity-modulated radiation therapy (IMRT) reirradiation of nonmetastatic recurrent or second primary head and neck squamous cell carcinoma (HNSCC) results in poor progression-free survival (PFS) and overall survival (OS). Objective: To investigate the tolerability, PFS, OS, and patient-reported outcomes with nivolumab (approved standard of care for patients with HNSCC) during and after IMRT reirradiation. Design, Setting, and Participants: In this multicenter nonrandomized phase 2 single-arm trial, the treatment outcomes of patients with recurrent or second primary HNSCC who satisfied recursive partitioning analysis class 1 and 2 definitions were evaluated. Between July 11, 2018, and August 12, 2021, 62 patients were consented and screened. Data were evaluated between June and December 2023. Intervention: Sixty- to 66-Gy IMRT in 30 to 33 daily fractions over 6 to 6.5 weeks with nivolumab, 240 mg, intravenously 2 weeks prior and every 2 weeks for 5 cycles during IMRT, then nivolumab, 480 mg, intravenously every 4 weeks for a total nivolumab duration of 52 weeks. Main Outcomes and Measures: The primary end point was PFS. Secondary end points included OS, incidence, and types of toxic effects, including long-term treatment-related toxic effects, patient-reported outcomes, and correlatives of tissue and blood biomarkers. Results: A total of 62 patients were screened, and 51 were evaluable (median [range] age was 62 [56-67] years; 42 [82%] were male; 6 [12%] had p16+ disease; 38 [75%] had salvage surgery; and 36 [71%.] had neck dissection). With a median follow-up of 24.5 months (95% CI, 19.0-25.0), the estimated 1-year PFS was 61.7% (95% CI, 49.2%-77.4%), rejecting the null hypothesis of 1-year PFS rate of less than 43.8% with 1-arm log-rank test P = .002 within a 1-year timeframe. The most common treatment-related grade 3 or higher adverse event (6 [12%]) was lymphopenia with 2 patients (4%) and 1 patient each (2%) exhibiting colitis, diarrhea, myositis, nausea, mucositis, and myasthenia gravis. Functional Assessment of Cancer Therapy-General and Functional Assessment of Cancer Therapy-Head and Neck Questionnaire quality of life scores remained stable and consistent across all time points. A hypothesis-generating trend favoring worsening PFS and OS in patients with an increase in blood PD1+, KI67+, and CD4+ T cells was observed. Conclusions and Relevance: This multicenter nonrandomized phase 2 trial of IMRT reirradiation therapy and nivolumab suggested a promising improvement in PFS over historical controls. The treatment was well tolerated and deserves further evaluation. Trial Registration: ClinicalTrials.gov Identifier: NCT03521570.

American Radium Society Appropriate Use Criteria for Unresectable Locally Advanced Non-Small Cell Lung Cancer.

Importance: The treatment of locally advanced non-small cell lung cancer (LA-NSCLC) has been informed by more than 5 decades of clinical trials and other relevant literature. However, controversies remain regarding the application of various radiation and systemic therapies in commonly encountered clinical scenarios. Objective: To develop case-referenced consensus and evidence-based guidelines to inform clinical practice in unresectable LA-NSCLC. Evidence Review: The American Radium Society (ARS) Appropriate Use Criteria (AUC) Thoracic Committee guideline is an evidence-based consensus document assessing various clinical scenarios associated with LA-NSCLC. A systematic review of the literature with evidence ratings was conducted to inform the appropriateness of treatment recommendations by the ARS AUC Thoracic Committee for the management of unresectable LA-NSCLC. Findings: Treatment appropriateness of a variety of LA-NSCLC scenarios was assessed by a consensus-based modified Delphi approach using a range of 3 points to 9 points to denote consensus agreement. Committee recommendations were vetted by the ARS AUC Executive Committee and a 2-week public comment period before official approval and adoption. Standard of care management of good prognosis LA-NSCLC consists of combined concurrent radical (60-70 Gy) platinum-based chemoradiation followed by consolidation durvalumab immunotherapy (for patients without progression). Planning and delivery of locally advanced lung cancer radiotherapy usually should be performed using intensity-modulated radiotherapy techniques. A variety of palliative and radical fractionation schedules are available to treat patients with poor performance and/or pulmonary status. The salvage therapy for a local recurrence after successful primary management is complex and likely requires both multidisciplinary input and shared decision-making with the patient. Conclusions and Relevance: Evidence-based guidance on the management of various unresectable LA-NSCLC scenarios is provided by the ARS AUC to optimize multidisciplinary patient care for this challenging patient population.

Implementation of a Novel Chart Rounds Application to Facilitate Peer Review in a Virtual Academic Environment.

Purpose: Peer review in the form of chart rounds is a critical component of quality assurance and safety in radiation therapy treatments. Radiation therapy departments have undergone significant changes that impose challenges to meaningful review, including institutional growth and increasing use of virtual environment. We discuss the implementation of a novel chart rounds (NCR) format and application adapted to modern peer review needs at a single high-volume multisite National Cancer Institute designated cancer center. Methods and Materials: A working group was created to improve upon the prior institutional chart rounds format (standard chart rounds or SCR). Using a novel in-house application and format redesign, an NCR was created and implemented to accomplish stated goals. Data regarding the SCR and NCR system were then extracted for review. Results: SCR consisted of 2- 90-minute weekly sessions held to review plans across all disease sites, review of 49 plans per hour on average. NCR uses 1-hour long sessions divided by disease site, enabling additional time to be spent per patient (11 plans per hour on average) and more robust discussion. The NCR application is able to automate a list of plans requiring peer review from the institutional treatment planning system. The novel application incorporates features that enable efficient and accurate review of plans in the virtual setting across multiple sites. A systematic scoring system is integrated into the application to record feedback. Over 5 months of use of the NCR, 1160 plans have been reviewed with 143 scored as requiring minor changes, 32 requiring major changes and 307 with comments. Major changes triggered treatment replan. Feedback from scoring is incorporated into physician workflow to ensure changes are addressed. Conclusion: The presented NCR format and application enables standardized and highly reliable peer review of radiation therapy plans that is robust across a variety of complex planning scenarios and could be implemented globally.

Deformable lung 4DCT image registration via landmark-driven cycle network.

BACKGROUND: An automated, accurate, and efficient lung four-dimensional computed tomography (4DCT) image registration method is clinically important to quantify respiratory motion for optimal motion management. PURPOSE: The purpose of this work is to develop a weakly supervised deep learning method for 4DCT lung deformable image registration (DIR). METHODS: The landmark-driven cycle network is proposed as a deep learning platform that performs DIR of individual phase datasets in a simulation 4DCT. This proposed network comprises a generator and a discriminator. The generator accepts moving and target CTs as input and outputs the deformation vector fields (DVFs) to match the two CTs. It is optimized during both forward and backward paths to enhance the bi-directionality of DVF generation. Further, the landmarks are used to weakly supervise the generator network. Landmark-driven loss is used to guide the generator's training. The discriminator then judges the realism of the deformed CT to provide extra DVF regularization. RESULTS: We performed four-fold cross-validation on 10 4DCT datasets from the public DIR-Lab dataset and a hold-out test on our clinic dataset, which included 50 4DCT datasets. The DIR-Lab dataset was used to evaluate the performance of the proposed method against other methods in the literature by calculating the DIR-Lab Target Registration Error (TRE). The proposed method outperformed other deep learning-based methods on the DIR-Lab datasets in terms of TRE. Bi-directional and landmark-driven loss were shown to be effective for obtaining high registration accuracy. The mean and standard deviation of TRE for the DIR-Lab datasets was 1.20 ± 0.72 mm and the mean absolute error (MAE) and structural similarity index (SSIM) for our datasets were 32.1 ± 11.6 HU and 0.979 ± 0.011, respectively. CONCLUSION: The landmark-driven cycle network has been validated and tested for automatic deformable image registration of patients' lung 4DCTs with results comparable to or better than competing methods.

Cardiac stereotactic radiation therapy for refractory ventricular arrhythmias in patients with left ventricular assist devices.

Left ventricular assist device (LVAD) implantation is an established treatment for patients with advanced heart failure refractory to medical therapy. However, the incidence of ventricular arrhythmias (VAs) is high in this population, both in the acute and delayed phases after implantation. About one-third of patients implanted with an LVAD will experience sustained VAs, predisposing these patients to worse outcomes and complicating patient management. The combination of pre-existing myocardial substrate and complex electrical remodeling after LVAD implantation account for the high incidence of VAs observed in this population. LVAD patients presenting VAs refractory to antiarrhythmic therapy and catheter ablation procedures are not rare. In such patients, treatment options are extremely limited. Stereotactic body radiation therapy (SBRT) is a technique that delivers precise and high doses of radiation to highly defined targets, reducing exposure to adjacent normal tissue. Cardiac SBRT has recently emerged as a promising alternative with a growing number of case series reporting the effectiveness of the technique in reducing the VA burden in patients with arrhythmias refractory to conventional therapies. The safety profile of cardiac SBRT also appears favorable, even though the current clinical experience remains limited. The use of cardiac SBRT for the treatment of refractory VAs in patients implanted with an LVAD are even more scarce. This review summarizes the clinical experience of cardiac SBRT in LVAD patients and describes technical considerations related to the implementation of the SBRT procedure in the presence of an LVAD.

A Novel Inverse Algorithm To Solve the Integrated Optimization of Dose, Dose Rate, and Linear Energy Transfer of Proton FLASH Therapy With Sparse Filters.

PURPOSE: The recently proposed Integrated Physical Optimization Intensity Modulated Proton Therapy (IPO-IMPT) framework allows simultaneous optimization of dose, dose rate, and linear energy transfer (LET) for ultra-high dose rate (FLASH) treatment planning. Finding solutions to IPO-IMPT is difficult because of computational intensiveness. Nevertheless, an inverse solution that simultaneously specifies the geometry of a sparse filter and weights of a proton intensity map is desirable for both clinical and preclinical applications. Such solutions can reduce effective biologic dose to organs at risk in patients with cancer as well as reduce the number of animal irradiations needed to derive extra biologic dose models in preclinical studies. METHODS AND MATERIALS: Unlike the initial forward heuristic, this inverse IPO-IMPT solution includes simultaneous optimization of sparse range compensation, sparse range modulation, and spot intensity. The daunting computational tasks vital to this endeavor were resolved iteratively with a distributed computing framework to enable Simultaneous Intensity and Energy Modulation and Compensation (SIEMAC). SIEMAC was demonstrated on a human patient with central lung cancer and a minipig. RESULTS: SIEMAC simultaneously improves maps of spot intensities and patient-field-specific sparse range compensators and range modulators. For the patient with lung cancer, at our maximum nozzle current of 300 nA, dose rate coverage above 100 Gy/s increased from 57% to 96% in the lung and from 93% to 100% in the heart, and LET coverage above 4 keV/µm dropped from 68% to 9% in the lung and from 26% to <1% in the heart. For a simple minipig plan, the full-width half-maximum of the dose, dose rate, and LET distributions decreased by 30%, 1.6%, and 57%, respectively, again with similar target dose coverage, thus reducing uncertainty in these quantities for preclinical studies. CONCLUSIONS: The inverse solution to IPO-IMPT demonstrated the capability to simultaneously modulate subspot proton energy and intensity distributions for clinical and preclinical studies.

Proton liver stereotactic body radiation therapy: Treatment techniques and dosimetry feasibility from a single institution.

Purpose: To assess the resulting dosimetry characteristics of simulation and planning techniques for proton stereotactic body radiation therapy (SBRT) of primary and secondary liver tumors. Methods: Consecutive patients treated under volumetric daily image guidance with liver proton SBRT between September 2019 and March 2022 at Emory Proton Therapy Center were included in this study. Prescriptions ranged from 40 Gy to 60 Gy in 3- or 5-fraction regimens, and motion management techniques were used when target motion exceeded 5 mm. 4D robust optimization was used when necessary. Dosimetry evaluation was conducted for ITV V100, D99, Dmax, and liver-ITV mean dose and D700cc. Statistical analysis was performed using independent-samples Mann-Whitney U tests. Results: Thirty-six tumors from 29 patients were treated. Proton therapy for primary and secondary liver tumors using motion management techniques and robust optimization resulted in high target coverage and low doses to critical organs. The median ITV V100% was 100.0%, and the median ITV D99% was 111.3%. The median liver-ITV mean dose and D700cc were 499 cGy and 5.7 cGy, respectively. The median conformity index (CI) was 1.03, and the median R50 was 2.56. Except for ITV D99% (primary 118.1% vs. secondary 107.2%, p = 0.005), there were no significant differences in age, ITV volume, ITV V100%, ITV maximum dose, liver-ITV mean dose, or D700cc between primary and secondary tumor groups. Conclusion: The study demonstrated that proton therapy with motion management techniques and robust optimization achieves excellent target coverage with low normal liver doses for primary and secondary liver tumors. The results showed high target coverage, high conformality, and low doses to the liver.

Associations of differentially expressed genes with psychoneurological symptoms in patients with head and neck cancer: A longitudinal study.

OBJECTIVE: Patients with head and neck cancer (HNC) experience psychoneurological symptoms (PNS, i.e., depression, fatigue, sleep disturbance, pain, and cognitive dysfunction) during intensity-modulated radiotherapy (IMRT) that negatively impact their functional status, quality of life, and overall survival. The underlying mechanisms for PNS are still not fully understood. This study aimed to examine differentially expressed genes and pathways related to PNS for patients undergoing IMRT (i.e., before, end of, 6 months, and 12 months after IMRT). METHODS: Participants included 142 patients with HNC (mean age 58.9 ± 10.3 years, 72.5% male, 83.1% White). Total RNA extracted from blood leukocytes were used for genome-wide gene expression assays. Linear mixed effects model was used to examine the association between PNS and gene expression across time. Gene Ontology (GO) enrichment analysis was employed to identify pathways related to PNS. RESULTS: A total of 1352 genes (162 upregulated, 1190 downregulated) were significantly associated with PNS across time (false discovery rate (FDR) < 0.05). Among these genes, 112 GO terms were identified (FDR < 0.05). The top 20 GO terms among the significant upregulated genes were related to immune and inflammatory responses, while the top 20 GO terms among the significant downregulated genes were associated with telomere maintenance. CONCLUSION: This study is the first to identify genes and pathways linked to immune and inflammatory responses and telomere maintenance that are associated with PNS in patients with HNC receiving IMRT. Inflammation and aging markers may be candidate biomarkers for PNS. Understanding biological markers may produce targets for novel interventions.

Circulating short chain fatty acids and fatigue in patients with head and neck cancer: A longitudinal prospective study.

Fatigue among patients with head and neck cancer (HNC) has been associated with higher inflammation. Short-chain fatty acids (SCFAs) have been shown to have anti-inflammatory and immunoregulatory effects. Therefore, this study aimed to examine the association between SCFAs and fatigue among patients with HNC undergoing treatment with radiotherapy with or without concurrent chemotherapy. Plasma SCFAs and the Multidimensional Fatigue Inventory-20 were collected prior to and one month after the completion of treatment in 59 HNC patients. The genome-wide gene expression profile was obtained from blood leukocytes prior to treatment. Lower butyrate concentrations were significantly associated with higher fatigue (p = 0.013) independent of time of assessment, controlling for covariates. A similar relationship was observed for iso/valerate (p = 0.025). Comparison of gene expression in individuals with the top and bottom 33% of butyrate or iso/valerate concentrations prior to radiotherapy revealed 1,088 and 881 significantly differentially expressed genes, respectively (raw p < 0.05). The top 10 Gene Ontology terms from the enrichment analyses revealed the involvement of pathways related to cytokines and lipid and fatty acid biosynthesis. These findings suggest that SCFAs may regulate inflammatory and immunometabolic responses and, thereby, reduce inflammatory-related symptoms, such as fatigue.

Associations of inflammation with neuropsychological symptom cluster in patients with Head and neck cancer: A longitudinal study.

Purpose: Head and neck cancer (HNC) patients may experience multiple co-occurring neuropsychological symptoms (NPS) cluster, including fatigue, depression, pain, sleep disturbance, and cognitive impairment. While inflammation has been attributed as a key mechanism for some of these symptoms, its association with the NPS as a cluster of symptoms is unknown. Thus, the aim of this study was to examine the association between peripheral inflammation and NPS cluster among HNC patients over cancer treatment (radiotherapy with or without chemotherapy). Methods: HNC patients were recruited and followed at pre-treatment, end of treatment, three months and one-year post-treatment. Plasma inflammatory markers, including C-reactive protein (CRP), tumor necrosis factor-alpha (TNFA), soluble tumor necrosis factor receptor-2 (sTNFR2), interleukin-1 beta (IL1-ß), interleukin-6 (IL-6), interleukin-10 (IL-10), monocyte chemotactic protein-1 (MCP-1), and interleukin-1 receptor antagonist (IL-1RA) and patient-reported NPS cluster were collected at the 4 time points. Associations between inflammatory markers and the NPS cluster were analyzed using linear mixed-effects models and generalized estimating equations (GEE) models controlling covariates. Results: 147 HNC patients were eligible for analysis. 56% of the patients received chemoradiotherapy as treatment. The highest NPS cluster score was reported at the end of treatment, which gradually decreased over time. An increase in inflammatory markers including CRP, sTNFR2, IL-6 and IL-1RA was associated with higher continuous NPS cluster scores (p<0.001, p = 0.003, p<0.001, p<0.001; respectively). GEE further confirmed that patients with at least two moderate symptoms had elevated sTNFR2, IL-6, and IL-1RA (p = 0.017, p = 0.038, p = 0.008; respectively). Notably, this positive association between NPS cluster and inflammatory markers was still significant at one-year post-treatment for CRP (p = 0.001), sTNFR2 (p = 0.006), and IL-1RA (p = 0.043). Conclusions: Most HNC patients experienced NPS clusters over time, especially immediately after the end of treatment. Elevated inflammation, as represented by inflammatory markers, was strongly associated with worse NPS cluster over time; this trend was also notable at one-year post-treatment. Our findings suggest that peripheral inflammation plays a pivotal role in the NPS cluster over cancer treatment, including long-term follow-ups. Interventions on reducing peripheral inflammation may contribute to alleviating the NPS cluster in cancer patients.

Longitudinal associations among physical activity, inflammatory markers, and quality of life in patients with head and neck cancer.

INTRODUCTION: The aim of this study was to explore the associations among physical activity (PA), inflammatory markers, and quality of life (QoL) from preradiotherapy to 1-year postradiotherapy for patients with head and neck cancer (HNC). METHODS: This was an observational longitudinal study. Mixed-effect models incorporating within-subject correlation were used to examine the relationship among the three key variables. RESULTS: Aerobically active patients had significantly lower levels of sTNFR2 (but not other inflammatory markers) than aerobically inactive patients. Being aerobically active and lower inflammation were independently associated with better total QoL scores after adjusting covariates. The trend was similar for patients engaged in strength exercises. CONCLUSIONS: Being aerobically active was associated with lower inflammation as represented by sTNFR2 but not with other inflammatory markers. Higher PA (aerobic and strength) and lower inflammation were linked to better QoL. More research is warranted to validate the association among PA, inflammation, and QoL.

Safety and efficacy of durvalumab after concurrent chemoradiation in Black patients with locally advanced non-small cell lung cancer.

BACKGROUND: The PACIFIC trial established consolidative durvalumab after concurrent chemoradiation as standard-of-care in patients with stage III or unresectable non-small cell lung cancer (NSCLC). Black patients, however, comprised just 2% (n = 14) of randomized patients in this trial, warranting real-world evaluation of the PACIFIC regimen in these patients. METHODS: This single-institution, multi-site study included 105 patients with unresectable stage II/III NSCLC treated with concurrent chemoradiation followed by durvalumab between 2017 and 2021. Overall survival (OS), progression-free survival (PFS), and grade ≥3 pneumonitis-free survival (PNFS) were compared between Black and non-Black patients using Kaplan-Meier and Cox regression analyses. RESULTS: A total of 105 patients with a median follow-up of 22.8 months (interquartile range, 11.3-37.3 months) were identified for analysis, including 57 Black (54.3%) and 48 (45.7%) non-Black patients. The mean radiation prescription dose was higher among Black patients (61.5 ± 2.9 Gy vs. 60.5 ± 1.9 Gy; p = .031), but other treatment characteristics were balanced between groups. The median OS (not-reached vs. 39.7 months; p = .379) and PFS (31.6 months vs. 19.3 months; p = .332) were not statistically different between groups. Eight (14.0%) Black patients discontinued durvalumab due to toxicity compared to 13 (27.1%) non-Black patients (p = .096). The grade ≥3 pneumonitis rate was similar between Black and non-Black patients (12.3% vs. 12.5%; p = .973), and there was no significant difference in time to grade ≥3 PNFS (p = .904). Three (5.3%) Black patients and one (2.1%) non-Black patient developed grade 5 pneumonitis. CONCLUSIONS: The efficacy and tolerability of consolidative durvalumab after chemoradiation appears to be comparable between Black and non-Black patients.

American Radium Society Appropriate Use Criteria for Radiation Therapy in the Multidisciplinary Management of Thymic Carcinoma.

Importance: Thymic carcinoma is rare, and its oncologic management is controversial due to a paucity of prospective data. For this reason, multidisciplinary consensus guidelines are crucial to guide oncologic management. Objective: To develop expert multidisciplinary consensus guidelines on the management of common presentations of thymic carcinoma. Evidence Review: Case variants spanning the spectrum of stage I to IV thymic carcinoma were developed by the 15-member multidisciplinary American Radium Society (ARS) Thoracic Appropriate Use Criteria (AUC) expert panel to address management controversies. A comprehensive review of the English-language medical literature from 1980 to 2021 was performed to inform consensus guidelines. Variants and procedures were evaluated by the panel using modified Delphi methodology. Agreement/consensus was defined as less than or equal to 3 rating points from median. Consensus recommendations were then approved by the ARS Executive Committee and subject to public comment per established ARS procedures. Findings: The ARS Thoracic AUC panel identified 89 relevant references and obtained consensus for all procedures evaluated for thymic carcinoma. Minimally invasive thymectomy was rated as usually inappropriate (regardless of stage) due to the infiltrative nature of thymic carcinomas. There was consensus that conventionally fractionated radiation (1.8-2 Gy daily) to a dose of 45 to 60 Gy adjuvantly and 60 to 66 Gy in the definitive setting is appropriate and that elective nodal irradiation is inappropriate. For radiation technique, the panel recommended use of intensity-modulated radiation therapy or proton therapy (rather than 3-dimensional conformal radiotherapy) to reduce radiation exposure to the heart and lungs. Conclusions and Relevance: The ARS Thoracic AUC panel has developed multidisciplinary consensus guidelines for various presentations of thymic carcinoma, perhaps the most well referenced on the topic.

Deep learning-based fast volumetric imaging using kV and MV projection images for lung cancer radiotherapy: A feasibility study.

PURPOSE: The long acquisition time of CBCT discourages repeat verification imaging, therefore increasing treatment uncertainty. In this study, we present a fast volumetric imaging method for lung cancer radiation therapy using an orthogonal 2D kV/MV image pair. METHODS: The proposed model is a combination of 2D and 3D networks. The proposed model consists of five major parts: (1) kV and MV feature extractors are used to extract deep features from the perpendicular kV and MV projections. (2) The feature-matching step is used to re-align the feature maps to their projection angle in a Cartesian coordinate system. By using a residual module, the feature map can focus more on the difference between the estimated and ground truth images. (3) In addition, the feature map is downsized to include more global semantic information for the 3D estimation, which is useful to reduce inhomogeneity. By using convolution-based reweighting, the model is able to further increase the uniformity of image. (4) To reduce the blurry noise of generated 3D volume, the Laplacian latent space loss calculated via the feature map that is extracted via specifically-learned Gaussian kernel is used to supervise the network. (5) Finally, the 3D volume is derived from the trained model. We conducted a proof-of-concept study using 50 patients with lung cancer. An orthogonal kV/MV pair was generated by ray tracing through CT of each phase in a 4D CT scan. Orthogonal kV/MV pairs from nine respiratory phases were used to train this patient-specific model while the kV/MV pair of the remaining phase was held for model testing. RESULTS: The results are based on simulation data and phantom results from a real Linac system. The mean absolute error (MAE) values achieved by our method were 57.5 HU and 77.4 HU within body and tumor region-of-interest (ROI), respectively. The mean achieved peak-signal-to-noise ratios (PSNR) were 27.6 dB and 19.2 dB within the body and tumor ROI, respectively. The achieved mean normalized cross correlation (NCC) values were 0.97 and 0.94 within the body and tumor ROI, respectively. A phantom study demonstrated that the proposed method can accurately re-position the phantom after shift. It is also shown that the proposed method using both kV and MV is superior to current method using kV or MV only in image quality. CONCLUSION: These results demonstrate the feasibility and accuracy of our proposed fast volumetric imaging method from an orthogonal kV/MV pair, which provides a potential solution for daily treatment setup and verification of patients receiving radiation therapy for lung cancer.