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.

Streamlined pin-ridge-filter design for single-energy proton FLASH planning.

BACKGROUND: FLASH radiotherapy (FLASH-RT) with ultra-high dose rate has yielded promising results in reducing normal tissue toxicity while maintaining tumor control. Planning with single-energy proton beams modulated by ridge filters (RFs) has been demonstrated feasible for FLASH-RT. PURPOSE: This study explored the feasibility of a streamlined pin-shaped RF (pin-RF) design, characterized by coarse resolution and sparsely distributed ridge pins, for single-energy proton FLASH planning. METHODS: An inverse planning framework integrated within a treatment planning system was established to design streamlined pin RFs for single-energy FLASH planning. The framework involves generating a multi-energy proton beam plan using intensity-modulated proton therapy (IMPT) planning based on downstream energy modulation strategy (IMPT-DS), followed by a nested pencil-beam-direction-based (PBD-based) spot reduction process to iteratively reduce the total number of PBDs and energy layers along each PBD for the IMPT-DS plan. The IMPT-DS plan is then translated into the pin-RFs and the single-energy beam configurations for IMPT planning with pin-RFs (IMPT-RF). This framework was validated on three lung cases, quantifying the FLASH dose of the IMPT-RF plan using the FLASH effectiveness model. The FLASH dose was then compared to the reference dose of a conventional IMPT plan to measure the clinical benefit of the FLASH planning technique. RESULTS: The IMPT-RF plans closely matched the corresponding IMPT-DS plans in high dose conformity (conformity index of <1.2), with minimal changes in V7Gy and V7.4 Gy for the lung (<3%) and small increases in maximum doses (Dmax) for other normal structures (<3.4 Gy). Comparing the FLASH doses to the doses of corresponding IMPT-RF plans, drastic reductions of up to nearly 33% were observed in Dmax for the normal structures situated in the high-to-moderate-dose regions, while negligible changes were found in Dmax for normal structures in low-dose regions. Positive clinical benefits were seen in comparing the FLASH doses to the reference doses, with notable reductions of 21.4%-33.0% in Dmax for healthy tissues in the high-dose regions. However, in the moderate-to-low-dose regions, only marginal positive or even negative clinical benefit for normal tissues were observed, such as increased lung V7Gy and V7.4 Gy (up to 17.6%). CONCLUSIONS: A streamlined pin-RF design was developed and its effectiveness for single-energy proton FLASH planning was validated, revealing positive clinical benefits for the normal tissues in the high dose regions. The coarsened design of the pin-RF demonstrates potential advantages, including cost efficiency and ease of adjustability, making it a promising option for efficient production.

Streamlined Pin-Ridge-Filter Design for Single-energy Proton FLASH Planning.

PURPOSE: This study explored the feasibility of a streamlined pin-shaped ridge filter (pin-RF) design for single-energy proton FLASH planning. METHODS: An inverse planning framework integrated within a TPS was established for FLASH planning. The framework involves generating a IMPT plan based on downstream energy modulation strategy (IMPT-DS), followed by a nested spot reduction process to iteratively reduce the total number of pencil beam directions (PBDs) and energy layers along each PBD for the IMPT-DS plan. The IMPT-DS plan is then translated into the pin-RFs for a single-energy IMPT plan (IMPT-RF). The framework was validated on three lung cases, quantifying the FLASH dose of the IMPT-RF plan using the FLASH effectiveness model and comparing it with the reference dose of a conventional IMPT plan to assess the clinical benefit of the FLASH planning technique. RESULTS: The IMPT-RF plans closely matched the corresponding IMPT-DS plans in high dose conformity, with minimal changes in V7Gy and V7.4Gy for the lung (< 5%) and small increases in Dmax for other OARs (< 3.2 Gy). Comparing the FLASH doses to the doses of corresponding IMPT-RF plans, drastic reductions of up to ~33% were observed in Dmax for OARs in the high-to-moderate-dose regions with negligible changes in Dmax for OARs in low-dose regions. Positive clinical benefits were observed with notable reductions of 18.4-33.0% in Dmax for OARs in the high-dose regions. However, in the moderate-to-low-dose regions, only marginal positive or even negative clinical benefit for OARs were observed, such as increased lung V7Gy and V7.4Gy (16.4-38.9%). CONCLUSIONS: A streamlined pin-RF design for single-energy proton FLASH planning was validated, revealing positive clinical benefits for OARs in the high dose regions. The coarsened design of the pin-RF demonstrates potential cost efficiency and efficient production.

Deep learning-based Fast Volumetric Image Generation for Image-guided Proton FLASH Radiotherapy.

Objective: FLASH radiotherapy leverages ultra-high dose-rate radiation to enhance the sparing of organs at risk without compromising tumor control probability. This may allow dose escalation, toxicity mitigation, or both. To prepare for the ultra-high dose-rate delivery, we aim to develop a deep learning (DL)-based image-guide framework to enable fast volumetric image reconstruction for accurate target localization for proton FLASH beam delivery. Approach: The proposed framework comprises four modules, including orthogonal kV x-ray projection acquisition, DL-based volumetric image generation, image quality analyses, and water equivalent thickness (WET) evaluation. We investigated volumetric image reconstruction using kV projection pairs with four different source angles. Thirty patients with lung targets were identified from an institutional database, each patient having a four-dimensional computed tomography (CT) dataset with ten respiratory phases. Leave-phase-out cross-validation was performed to investigate the DL model's robustness for each patient. Main results: The proposed framework reconstructed patients' volumetric anatomy, including tumors and organs at risk from orthogonal x-ray projections. Considering all evaluation metrics, the kV projections with source angles of 135° and 225° yielded the optimal volumetric images. The patient-averaged mean absolute error, peak signal-to-noise ratio, structural similarity index measure, and WET error were 75±22 HU, 19±3.7 dB, 0.938±0.044, and -1.3%±4.1%. Significance: The proposed framework has been demonstrated to reconstruct volumetric images with a high degree of accuracy using two orthogonal x-ray projections. The embedded WET module can be used to detect potential proton beam-specific patient anatomy variations. This framework can rapidly deliver volumetric images to potentially guide proton FLASH therapy treatment delivery systems.

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.

Feasibility study of hybrid inverse planning with transmission beams and single-energy spread-out Bragg peaks for proton FLASH radiotherapy.

BACKGROUND: Ultra-high dose rate (FLASH) proton planning with only transmission beams (TBs) has limitations in normal tissue sparing. The single-energy spread-out Bragg peaks (SESOBPs) of the FLASH dose rate have been demonstrated feasible for proton FLASH planning. PURPOSE: To investigate the feasibility of combining TBs and SESOBPs for proton FLASH treatment. METHODS: A hybrid inverse optimization method was developed to combine the TBs and SESOBPs (TB-SESOBP) for FLASH planning. The SESOBPs were generated field-by-field from spreading out the BPs by pre-designed general bar ridge filters (RFs) and placed at the central target by range shifters (RSs) to obtain a uniform dose within the target. The SESOBPs and TBs were fully placed field-by-field allowing automatic spot selection and weighting in the optimization process. A spot reduction strategy was conducted in the optimization process to push up the minimum MU/spot assuring the plan deliverability at beam current of 165 nA. The TB-SESOBP plans were validated in comparison with the TB only (TB-only) plans and the plans with the combination of TBs and BPs (TB-BP plans) regarding 3D dose and dose rate (dose-averaged dose rate) distributions for five lung cases. The FLASH dose rate coverage (V40Gy/s ) was evaluated in the structure volume receiving > 10% of the prescription dose. RESULTS: Compared to the TB-only plans, the mean spinal cord D1.2cc drastically reduced by 41% (P < 0.05), the mean lung V7Gy and V7.4 Gy moderately reduced by up to 17% (P < 0.05), and the target dose homogeneity slightly increased in the TB-SESOBP plans. Comparable dose homogeneity was achieved in both TB-SESOBP and TB-BP plans. Besides, prominent improvements were achieved in lung sparing for the cases of relatively large targets by the TB-SESOBP plans compared to the TB-BP plans. The targets and the skin were fully covered with the FLASH dose rate in all three plans. For the OARs, V40Gy/s  = 100% was achieved by the TB-only plans while V40Gy/s  > 85% was obtained by the other two plans. CONCLUSION: We have demonstrated that the hybrid TB-SESOBP planning was feasible to achieve FLASH dose rate for proton therapy. With pre-designed general bar RFs, the hybrid TB-SESOBP planning could be implemented for proton adaptive FLASH radiotherapy. As an alternative FLASH planning approach to TB-only planning, the hybrid TB-SESOBP planning has great potential in dosimetrically improving OAR sparing while maintaining high target dose homogeneity.

Automatic segmentation of neurovascular bundle on mri using deep learning based topological modulated network.

PURPOSE: Radiation damage on neurovascular bundles (NVBs) may be the cause of sexual dysfunction after radiotherapy for prostate cancer. However, it is challenging to delineate NVBs as organ-at-risks from planning CTs during radiotherapy. Recently, the integration of MR into radiotherapy made NVBs contour delineating possible. In this study, we aim to develop an MRI-based deep learning method for automatic NVB segmentation. METHODS: The proposed method, named topological modulated network, consists of three subnetworks, that is, a focal modulation, a hierarchical block and a topological fully convolutional network (FCN). The focal modulation is used to derive the location and bounds of left and right NVBs', namely the candidate volume-of-interests (VOIs). The hierarchical block aims to highlight the NVB boundaries information on derived feature map. The topological FCN then segments the NVBs inside the VOIs by considering the topological consistency nature of the vascular delineating. Based on the location information of candidate VOIs, the segmentations of NVBs can then be brought back to the input MRI's coordinate system. RESULTS: A five-fold cross-validation study was performed on 60 patient cases to evaluate the performance of the proposed method. The segmented results were compared with manual contours. The Dice similarity coefficient (DSC) and 95th percentile Hausdorff distance (HD95 ) are (left NVB) 0.81 ± 0.10, 1.49 ± 0.88 mm, and (right NVB) 0.80 ± 0.15, 1.54 ± 1.22 mm, respectively. CONCLUSION: We proposed a novel deep learning-based segmentation method for NVBs on pelvic MR images. The good segmentation agreement of our method with the manually drawn ground truth contours supports the feasibility of the proposed method, which can be potentially used to spare NVBs during proton and photon radiotherapy and thereby improve the quality of life for prostate cancer patients.

Insurance Authorization and Access to Proton Therapy for Patients With Head and Neck Cancers.

PURPOSE: We evaluated our institutional experience to assess potential racial inequities in insurance coverage for proton therapy in patients with head and neck (HN) cancer. METHODS AND MATERIALS: We examined the demographics of 1519 patients with HN cancer seen in consultation at our HN multidisciplinary clinic (HN MDC) and 805 patients for whom a proton insurance authorization was sought (PAS) from January 2020 to June 2022. The prospects for proton therapy insurance authorization were prospectively noted based on each patient's ICD-10 (International Classification of Diseases, 10th Revision) diagnosis code and their specific insurance plan. Proton-unfavorable (PU) insurance were those plans whose policy describes proton beam therapy as "experimental" or "not medically necessary" for the given diagnosis. RESULTS: For patients seen in our HN MDC, Black, Indigenous, and people of color (BIPOC) were significantly more likely to have PU insurance than non-Hispanic White (NHW) patients (24.9% vs 18.4%, P = .005). In multivariable analysis including race, average income of residence ZIP code, and Medicare eligibility age, BIPOC patients had an odds ratio of 1.25 for PU insurance (P = .041). In the PAS cohort, while there was no difference in the percentage of patients receiving insurance approval for proton therapy between NHW and BIPOC populations (88% vs 88.2%, P = .80), for patients with PU insurance, the median time to determination was significantly longer (median, 15.5 days), and the median time to start any radiation of any modality was longer (46 vs 35 days, P = .08). Compared with NHW patients, the median time from consultation to start of radiation therapy was longer for BIPOC patients (37 vs 43 days, P = .01). CONCLUSIONS: BIPOC patients were significantly more likely to have insurance plans unfavorable to proton therapy coverage. These PU insurance plans were associated with a longer median time to determination, a lower approval rate for proton therapy, and a longer time to start radiation of any modality.

Factors Affecting Clinical Outcomes Among Patients Infected With HIV and Anal Cancer Treated With Modern Definitive Chemotherapy and Radiation Therapy.

Purpose: Anal cancer affects a disproportionate percentage of persons infected with human immunodeficiency virus (HIV). We analyzed a cohort of patients with HIV and anal cancer who received modern radiation therapy (RT) and concurrent chemotherapy to assess whether certain factors are associated with poor oncologic outcomes. Patients and Methods: We performed a retrospective chart review of 75 consecutive patients with HIV infection and anal cancer who received definitive chemotherapy and RT from 2008 to 2018 at a single academic institution. Local recurrence, overall survival, changes in CD4 counts, and toxicities were investigated. Results: Most patients were male (92%) with large representation from Black patients (77%). The median pretreatment CD4 count was 280 cells/mm3, which was persistently lower at 6 and 12 months' posttreatment, 87 cells/mm3 and 182 cells/mm3, respectively (P < .001). Most (92%) patients received intensity modulated RT; median dose was 54 Gy (Range, 46.8-59.4 Gy). At a median follow-up 5.4 years (Range, 4.37-6.21 years), 20 (27%) patients had disease recurrence and 10 (13%) had isolated local failures. Nine patients died due to progressive disease. In multivariable analysis, clinically node negative involvement was significantly associated with better overall survival (hazard ratio, 0.39; 95% confidence interval, 0.16-1.00, P = .049). Acute grade 2 and 3 skin toxicities were common, at 83% and 19%, respectively. Acute grade 2 and 3 gastrointestinal toxicities were 9% and 3%, respectively. Acute grade 3 hematologic toxicity was 20%, and one grade 5 toxicity was reported. Several late grade 3 toxicities persisted: gastrointestinal (24%), skin (17%), and hematologic (6%). Two late grade 5 toxicities were noted. Conclusions: Most patients with HIV and anal cancer did not experience local recurrence; however, acute and late toxicities were common. CD4 counts at 6 and 12 months' posttreatment remained lower than pretreatment CD4 counts. Further attention to treatment of the HIV-infected population is needed.

Early-Stage Primary Lung Neuroendocrine Tumors Treated With Stereotactic Body Radiation Therapy: A Multi-Institution Experience.

PURPOSE: Current guidelines recommend surgery as standard of care for primary lung neuroendocrine tumor (LNET). Given that LNET is a rare clinical entity, there is a lack of literature regarding treatment of LNET with stereotactic body radiation therapy (SBRT). We hypothesized that SBRT could lead to effective locoregional tumor control and long-term outcomes. METHODS AND MATERIALS: We retrospectively reviewed 48 tumors in 46 patients from 11 institutions with a histologically confirmed diagnosis of LNET, treated with primary radiation therapy. Data were collected for patients treated nonoperatively with primary radiation therapy between 2006 and 2020. Patient records were reviewed for lesion characteristics and clinical risk factors. Kaplan-Meier analysis, log-rank tests, and Cox multivariate models were used to compare outcomes. RESULTS: Median age at treatment was 71 years and mean tumor size was 2 cm. Thirty-two lesions were typical carcinoid histology, 7 were atypical, and 9 were indeterminate. The most common SBRT fractionation schedule was 50 to 60 Gy in 5 daily fractions. Overall survival at 3, 6, and 9 years was 64%, 43%, and 26%, respectively. Progression-free survival at 3, 6, and 9 years was 88%, 78%, and 78%, respectively. Local control at 3, 6, and 9 years was 97%, 91%, and 91%, respectively. There was 1 regional recurrence in a paraesophageal lymph node. No grade 3 or higher toxicity was identified. CONCLUSIONS: This is the largest series evaluating outcomes in patients with LNET treated with SBRT. This treatment is well tolerated, provides excellent locoregional control, and should be offered as an alternative to surgical resection for patients with early-stage LNET, particularly those who may not be ideal surgical candidates.

Ninety-day mortality following transoral robotic surgery or radiation at Commission on Cancer-accredited facilities.

BACKGROUND: Postoperative mortality for oropharynx squamous cell carcinoma (OPSCC) with transoral robotic surgery (TORS) varies from 0.2% to 6.5% on trials; the real-world rate is unknown. METHODS: NCDB study from 2010 to 2017 for patients with cT1-2N0-2M0 OPSCC with Charleson-Deyo score 0-1. Ninety-day mortality assessed from start and end of treatment at Commission on Cancer-accredited facilities. RESULTS: 3639 patients were treated with TORS and 1937 with radiotherapy. TORS cohort had more women and higher income, was younger, more often treated at academic centers, and more likely to have private insurance (all p < 0.05). Ninety-day mortality was 1.3% with TORS and 0.7% or 1.4% from start or end of radiotherapy, respectively. From end of therapy, there was no significant difference on MVA between treatment modality. CONCLUSIONS: There is minimal difference between 90-day mortality in patients treated with TORS or radiotherapy for early-stage OPSCC. While overall rates are low, for patients with expectation of cure, work is needed to identify optimal treatment.

Automated lung tumor delineation on positron emission tomography/computed tomography via a hybrid regional network.

BACKGROUND: Multimodality positron emission tomography/computed tomography (PET/CT) imaging combines the anatomical information of CT with the functional information of PET. In the diagnosis and treatment of many cancers, such as non-small cell lung cancer (NSCLC), PET/CT imaging allows more accurate delineation of tumor or involved lymph nodes for radiation planning. PURPOSE: In this paper, we propose a hybrid regional network method of automatically segmenting lung tumors from PET/CT images. METHODS: The hybrid regional network architecture synthesizes the functional and anatomical information from the two image modalities, whereas the mask regional convolutional neural network (R-CNN) and scoring fine-tune the regional location and quality of the output segmentation. This model consists of five major subnetworks, that is, a dual feature representation network (DFRN), a regional proposal network (RPN), a specific tumor-wise R-CNN, a mask-Net, and a score head. Given a PET/CT image as inputs, the DFRN extracts feature maps from the PET and CT images. Then, the RPN and R-CNN work together to localize lung tumors and reduce the image size and feature map size by removing irrelevant regions. The mask-Net is used to segment tumor within a volume-of-interest (VOI) with a score head evaluating the segmentation performed by the mask-Net. Finally, the segmented tumor within the VOI was mapped back to the volumetric coordinate system based on the location information derived via the RPN and R-CNN. We trained, validated, and tested the proposed neural network using 100 PET/CT images of patients with NSCLC. A fivefold cross-validation study was performed. The segmentation was evaluated with two indicators: (1) multiple metrics, including the Dice similarity coefficient, Jacard, 95th percentile Hausdorff distance, mean surface distance (MSD), residual mean square distance, and center-of-mass distance; (2) Bland-Altman analysis and volumetric Pearson correlation analysis. RESULTS: In fivefold cross-validation, this method achieved Dice and MSD of 0.84 ± 0.15 and 1.38 ± 2.2 mm, respectively. A new PET/CT can be segmented in 1 s by this model. External validation on The Cancer Imaging Archive dataset (63 PET/CT images) indicates that the proposed model has superior performance compared to other methods. CONCLUSION: The proposed method shows great promise to automatically delineate NSCLC tumors on PET/CT images, thereby allowing for a more streamlined clinical workflow that is faster and reduces physician effort.

Shared burden: the association between cancer diagnosis, financial toxicity, and healthcare cost-related coping mechanisms by family members of non-elderly patients in the USA.

PURPOSE: There has been little research on the healthcare cost-related coping mechanisms of families of patients with cancer. Therefore, we assessed the association between a cancer diagnosis and the healthcare cost-related coping mechanisms of participant family members through their decision to forego or delay seeking medical care, one of the manifestations of financial toxicity. METHODS: Using data from the National Health Interview Survey (NHIS) between 2000 and 2018, sample weight-adjusted prevalence was calculated and multivariable logistic regressions defined adjusted odds ratios (aORs) for participant family members who needed but did not get medical care or who delayed seeking medical care due to cost in the past 12 months, adjusting for relevant sociodemographic covariates, including participant history of cancer (yes vs. no) and participant age (18-45 vs. 46-64 years old). The analysis of family members foregoing or delaying medical care was repeated using a cancer diagnosis * age interaction term. RESULTS: Participants with cancer were more likely than those without a history of cancer to report family members delaying (19.63% vs. 16.31%, P < 0.001) or foregoing (14.53% vs. 12.35%, P = 0.001) medical care. Participants with cancer in the 18 to 45 years old age range were more likely to report family members delaying (pinteraction = 0.028) or foregoing (pinteraction < 0.001) medical care. Other factors associated with cost-related coping mechanisms undertaken by the participants' family members included female sex, non-married status, poorer health status, lack of health insurance coverage, and lower household income. CONCLUSION: A cancer diagnosis may be associated with familial healthcare cost-related coping mechanisms, one of the manifestations of financial toxicity. This is seen through delayed/omitted medical care of family members of people with a history of cancer, an association that may be stronger among young adult cancer survivors. These findings underscore the need to further explore how financial toxicity associated with a cancer diagnosis can affect patients' family members and to design interventions to mitigate healthcare cost-related coping mechanisms.

Impact of radiation dose to the immune cells in unresectable or stage III non-small cell lung cancer in the durvalumab era.

BACKGROUND/PURPOSE: Higher estimated radiation doses to immune cells (EDIC) have correlated with worse overall survival (OS) in patients with locally-advanced non-small cell lung cancer (NSCLC) prior to the PACIFIC trial, which established consolidative durvalumab as standard-of-care. Here, we examine the prognostic impact of EDIC in the durvalumab era. MATERIALS/METHODS: This single-institution, multi-center study included patients with unresectable stage II/III NSCLC treated with chemoradiation followed by durvalumab. Associations between EDIC [analyzed continuously and categorically (≤6 Gy vs > 6 Gy)] and OS, progression-free survival (PFS), and locoregional control (LRC) were evaluated by Kaplan-Meier and Cox proportional methods. RESULTS: 100 patients were included with median follow-up of 23.7 months. The EDIC > 6 Gy group had a significantly greater percentage of stage IIIB/IIIC disease (76.0 % vs 32.6 %; p < 0.001) and larger tumor volumes (170 cc vs 42 cc; p < 0.001). There were no differences in early durvalumab discontinuation from toxicity (24.1 % vs 15.2 %; p = 0.27). Median OS was shorter among the EDIC > 6 Gy group (29.6 months vs not reached; p < 0.001). On multivariate analysis, EDIC > 6 Gy correlated with worse OS (HR: 4.15, 95 %CI: 1.52-11.33; p = 0.006), PFS (HR: 3.79; 95 %CI: 1.80-8.0; p < 0.001), and LRC (HR: 2.66, 95 %CI: 1.15-6.18; p = 0.023). Analyzed as a continuous variable, higher EDIC was associated with worse OS (HR: 1.34; 95 %CI: 1.16-1.57; p < 0.001), PFS (HR: 1.52; 95 %CI: 1.29-1.79; p < 0.001), and LRC (HR: 1.34, 95 %CI: 1.13-1.60; p = 0.007). CONCLUSIONS: In the immunotherapy era, EDIC is an independent predictor of OS and disease control in locally advanced NSCLC, warranting investigation into techniques to reduce dose to the immune compartment.

Mutual enhancing learning-based automatic segmentation of CT cardiac substructure.

Objective.Current segmentation practice for thoracic cancer RT considers the whole heart as a single organ despite increased risks of cardiac toxicities from irradiation of specific cardiac substructures. Segmenting up to 15 different cardiac substructures can be a very time-intensive process, especially due to their different volume sizes and anatomical variations amongst different patients. In this work, a new deep learning (DL)-based mutual enhancing strategy is introduced for accurate and automatic segmentation, especially of smaller substructures such as coronary arteries.Approach.Our proposed method consists of three subnetworks: retina U-net, classification module, and segmentation module. Retina U-net is used as a backbone network architecture that aims to learn deep features from the whole heart. Whole heart feature maps from retina U-net are then transferred to four different sets of classification modules to generate classification localization maps of coronary arteries, great vessels, chambers of the heart, and valves of the heart. Each classification module is in sync with its corresponding subsequent segmentation module in a bootstrapping manner, allowing them to share their encoding paths to generate a mutual enhancing strategy. We evaluated our method on three different datasets: institutional CT datasets (55 subjects) 2) publicly available Multi-Modality Whole Heart Segmentation (MM-WHS) challenge datasets (120 subjects), and Automated Cardiac Diagnosis Challenge (ACDC) datasets (100 subjects). For institutional datasets, we performed five-fold cross-validation on training data (45 subjects) and performed inference on separate hold-out data (10 subjects). For each subject, 15 cardiac substructures were manually contoured by a resident physician and evaluated by an attending radiation oncologist. For the MM-WHS dataset, we trained the network on 100 datasets and performed an inference on a separate hold-out dataset with 20 subjects, each with 7 cardiac substructures. For ACDC datasets, we performed five-fold cross-validation on 100 datasets, each with 3 cardiac substructures. We compared the proposed method against four different network architectures: 3D U-net, mask R-CNN, mask scoring R-CNN, and proposed network without classification module. Segmentation accuracies were statistically compared through dice similarity coefficient, Jaccard, 95% Hausdorff distance, mean surface distance, root mean square distance, center of mass distance, and volume difference.Main results.The proposed method generated cardiac substructure segmentations with significantly higher accuracy (P < 0.05) for small substructures, especially for coronary arteries such as left anterior descending artery (CA-LADA) and right coronary artery (CA-RCA) in comparison to four competing methods. For large substructures (i.e. chambers of the heart), our method yielded comparable results to mask scoring R-CNN method, resulting in significantly (P < 0.05) improved segmentation accuracy in comparison to 3D U-net and mask R-CNN.Significance.A new DL-based mutual enhancing strategy was introduced for automatic segmentation of cardiac substructures. Overall results of this work demonstrate the ability of the proposed method to improve segmentation accuracies of smaller substructures such as coronary arteries without largely compromising the segmentation accuracies of larger substructures. Fast and accurate segmentations of up to 15 substructures can possibly be used as a tool to rapidly generate substructure segmentations followed by physicians' reviews to improve clinical workflow.

Bone Marrow Suppression during Postoperative Radiation for Bladder Cancer and Comparative Benefit of Proton Therapy-Phase 2 Trial Secondary Analysis.

PURPOSE: For patients with high-risk bladder cancer (pT3+ or N+), local regional failure remains a challenge after chemotherapy and cystectomy. An ongoing prospective phase 2 trial (NCT01954173) is examining the role of postoperative photon radiation therapy for high-risk patients using volumetric modulated arc therapy. Proton beam therapy (PBT) may be beneficial in this setting to reduce hematologic toxicity. We evaluated for dosimetric relationships with pelvic bone marrow (PBM) and changes in hematologic counts before and after pelvic radiation therapy and explored the potential of PBT treatment plans to achieve reductions in PBM dose. MATERIALS AND METHODS: All enrolled patients were retrospectively analyzed after pelvic radiation per protocol with 50.4 to 55.8 Gy in 28 to 31 fractions. Comparative PBT plans were generated using pencil-beam scanning and a 3-beam multifield optimization technique. Changes in hematologic nadirs were assessed using paired t test. Correlation of mean nadirs and relative PBM dose levels were assessed using the Pearson correlation coefficient (CC). RESULTS: Eighteen patients with a median age of 70 were analyzed. Mean cell count values after radiation therapy decreased compared with preradiation therapy values for white blood cells (WBCs), absolute neutrophil count (ANC), absolute lymphocyte count (all P < .001), and platelets (P = .03). Increased mean PBM dose was associated with lower nadirs in WBC (Pearson CC -0.593, P = .02), ANC (Pearson CC -0.597, P = .02), and hemoglobin (Pearson CC -0.506, P = .046), whereas the PBM V30 to V40 correlated with lower WBC (Pearson CC -0.512 to -0.618, P < .05), and V20 to V30 correlated with lower ANC (Pearson CC -0.569 to -0.598, P < .04). Comparative proton therapy plans decreased the mean PBM dose from 26.5 Gy to 16.1 Gy (P < .001) and had significant reductions in the volume of PBM receiving doses from 5 to 40 Gy (P < .001). CONCLUSION: Increased PBM mean dose and V20 to V40 were associated with lower hematologic nadirs. PBT plans reduced PBM dose and may be a valuable strategy to reduce the risk of hematologic toxicity in these patients.

Association of Operability With Post-Treatment Mortality in Early-Stage Non-Small Cell Lung Cancer.

BACKGROUND: Operability is both a crucial determinant in treatment selection and a potential confounder in analyses comparing surgery with non-surgical approaches such as stereotactic body radiotherapy (SBRT). We aimed to assess the association between operability status and intervention with post-treatment mortality in early-stage non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: We defined four groups of patients with cT1-T2N0M0 NSCLC diagnosed 2010 to 2014 from the National Cancer Database: SBRT patients deemed operable vs. inoperable and surgery patients receiving open vs. minimally-invasive approaches. Mortality rates at 30, 60, and 90 days post-treatment were calculated and compared. RESULTS: We abstracted 80,108 patients, 0.8% undergoing SBRT and operable, 13.2% undergoing SBRT and inoperable, 52.4% undergoing open surgery, and 33.7% undergoing minimally-invasive surgery. Mortality rates were highest among open surgery patients and lowest among operable SBRT patients (2.0% vs. 0.2% at 30 days and 3.7% vs. 0.7% at 90 days), with intermediate results in the other two groups. These findings persisted on multivariate Cox regression: compared to patients undergoing minimally-invasive surgery, mortality risk was highest among open surgery patients (30 days HR 1.32, 95%CI 1.16-1.51; 90 days HR 1.36, 95%CI 1.24-1.50; both P < .001) and lowest among operable SBRT patients (30 days HR 0.09, 95%CI 0.01-0.64; 90 days HR 0.15, 95%CI 0.05-0.46; both P ≤ .016). These associations were maintained in a propensity score-matched subset. CONCLUSION: Operable patients undergoing SBRT experience minimal post-treatment mortality compared to their inoperable counterparts. These findings illustrate the potential for confounding by operability to bias results in cohort studies that compare surgical vs. non-surgical approaches in early-stage NSCLC.

Impact of Metastasectomy and Aggressive Local Therapy in Newly Diagnosed Metastatic Soft Tissue Sarcoma: An Analysis of the NCDB.

BACKGROUND: The optimal management of patients with stage IV soft tissue sarcoma of the extremity (STSE) with distant metastases at diagnosis is unclear due to limited evidence and heterogeneity of current practice patterns. National guidelines have recommended surgical management of the primary site (SP) with or without radiotherapy (R), chemotherapy (C), and metastasectomy (M). METHODS: In the National Cancer Database (NCDB), patients with initially metastatic STSE who received definitive SP from 2004 to 2014 were identified. Survival distributions were estimated and compared using the Kaplan-Meier method and log-rank tests, and covariates were compared using Chi-square tests or analysis of variance (ANOVA). Propensity score analysis using inverse probability of treatment weighting was used. RESULTS: Overall, 1124 patients were included, with a median age of 55 years (range 18-90). Utilization of SP+M increased over time from 18.8% in 2004-2006, to 33.3% in 2007-2009, to 47.9% in 2010-2014 (p = 0.024). The addition of M to SP was associated with superior 5-year overall survival (OS) at 30.8% (SP+M+/-C+/-R) compared with 18.2% for those treated with non-surgical adjuvant therapies (SP+/-C+/-R) and 12.6% for SP alone (p < 0.0001). Positive surgical margins were noted in 24.1% of patients and was associated with worse OS (hazard ratio 1.44, p < 0.001) on multivariable analysis. CONCLUSIONS: This is the first known study utilizing a large database to explore practice patterns and outcomes for patients with metastatic STSE receiving definitive SP. Utilization of metastasectomy increased in the study period and was associated with longer survival compared with SP alone. These hypothesis-generating data warrant additional study.

The omission of intentional primary site radiation following transoral robotic surgery in 59 patients: No local-regional failures.

BACKGROUND: We assessed locoregional control with omission of intentional primary site radiation after transoral robotic surgery (TORS) and quantified nontargeted primary site dose. METHODS: Following Institutional Review Board (IRB) approval, patients treated with primary TORS resection for squamous cell carcinomas of the oropharynx were reviewed. Patients with cT1-2 tumors, >2 mm margins, in whom the surgeon resected the primary without revising specimen-driven margins, qualified for omission of primary site radiation. RESULTS: From 2014 to 2019, 112 patients met criteria. Fifty-nine (52%) patients did not receive radiation targeting the primary site; of whom, 22 received no radiation. In this group, there were no local failures; mean age was 58 years and median follow-up was 25 months. Thirty-seven patients received adjuvant radiation targeting the neck, mean bystander dose to the primary site was 28.8 Gy (range, 13.3-50.6 Gy). CONCLUSION: In a 59 patient population, omission of radiation to the primary site after TORS resulted in no locoregional failures.