Introduction: As immunotherapy has improved distant metastasis-free survival (DMFS) in Non-Small Cell Lung Cancer (NSCLC), isolated locoregional recurrences have increased. However, management of locoregional recurrences can be challenging. We report our institutional experience with definitive intent re-irradiation using Intensity Modulated Proton Therapy (IMPT). Method: Retrospective cohort study of recurrent or second primary NSCLC or LS-SCLC treated with IMPT. Kaplan-Meier method and log-rank test were used for time-to-event analyses. Results: 22 patients were treated from 2019 to 2021. After first course of radiation (median 60 Gy, range 45-70 Gy), 45% received adjuvant immunotherapy. IMPT re-irradiation began a median of 28.2 months (8.8-172.9 months) after initial radiotherapy. The median IMPT dose was 60 GyE (44-60 GyE). 36% received concurrent chemotherapy with IMPT and 18% received immunotherapy after IMPT. The median patient’s IMPT lung mean dose was 5.3 GyE (0.9-13.9 GyE) and 5 patients had cumulative esophagus max dose >100 GyE with 1-year overall survival (OS) 68%, 1-year local control 80%, 1-year progression free survival 45%, and 1-year DMFS 60%. Higher IMPT (HR 1.4; 95% CI 1.1-1.7, p=0.01) and initial radiotherapy mean lung doses (HR 1.3; 95% CI 1.0-1.6, p=0.04) were associated with worse OS. Two patients developed Grade 3 pneumonitis or dermatitis, one patient developed Grade 2 pneumonitis, and seven patients developed Grade 1 toxicity. There were no Grade 4 or 5 toxicities. Discussion: Definitive IMPT re-irradiation for lung cancer can prolong disease control with limited toxicity, particularly in the immunotherapy era.
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.
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.
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.
PURPOSE/OBJECTIVE(S): Low-dose radiotherapy (LD-RT) is a well-established treatment for multiple human inflammatory conditions. Whole-lung LD-RT may be effective in COVID-19-related pneumonia. MATERIALS/METHODS: Patients hospitalized with COVID-19-related pneumonia receiving supportive care, glucocorticosteroids, and/or remdesivir were administered LD-RT treatment of 0.5 or 1.5 Gy to the bilateral lungs on a prospective, combined phase I/II, multi-site, single-institution trial. Patients were followed for 28 days or until discharge and compared to controls blindly matched by age, comorbidity, duration of symptoms, and disease severity. Eligible patients were confirmed by SARS-CoV-2 positive PCR, unable to wean from oxygen at enrollment, and had radiographic consolidations. Patients were enrolled into 5 cohorts stratified by treatment variables and severity of illness: LD-RT alone vs. LD-RT with concurrent drug therapies, non-intubated vs. intubated status, and low (1.5 Gy) vs. lower (0.5 Gy) radiation dose. Qualitative aims were to establish safety and explore efficacy. Quantitative endpoints were continuous, categorical, and time-to-event, and included clinical recovery, intubation, radiographic changes, and biomarker responses. Intubation endpoints are reported for all cohorts using the log-rank test and Kaplan-Meier method. RESULTS: Outcomes of 80 patients were available for analysis at study closure. In total, 40 of 70 planned patients (57% trial enrollment) received whole-lung LD-RT between April 24 and December 7, 2020 and were compared to 40 matched controls. Cohorts 1&2: Ten non-intubated patients received 1.5 Gy without concurrent COVID-directed drug therapies (10 of 10 planned, 100% cohort enrollment) and were compared to matched controls. Intubation rates were 40% in controls compared to 10% following LD-RT (P = 0.11). Cohort 3: One intubated patient received 1.5 Gy (1 of 20 planned, 5% cohort enrollment). Cohort 4: Twenty separate non-intubated patients received 1.5 Gy with concurrent dexamethasone/remdesivir (20 of 20 planned, 100% cohort enrollment) and were compared to matched controls. Intubation rates were 32% in controls compared to 14% following LD-RT (P = 0.09). Cohort 5: Nine patients received 0.5 Gy with concurrent drug therapies (9 of 20 planned, 45% cohort enrollment) and were compared to matched controls. Zero controls required intubation compared to 11% following LD-RT (P = 0.32). Among all non-intubated patients and matched controls combined (n = 78), mechanical ventilation was required in 28% of controls compared to 12% following LD-RT (reduced 57%, P = 0.05). The trial was prematurely closed due to observed reproducibility of efficacy. A randomized trial is now ongoing. CONCLUSION: In the first, prospective, phase I/II trial of radiotherapy for COVID-19-related pneumonia, a single treatment of whole-lung LD-RT reduced intubation rates by 57% compared to controls in patients receiving supportive care with or without drug therapies (P = 0.05).
Background: Low-dose radiotherapy (LD-RT) has produced anti-inflammatory effects in both animal models and early human trials of COVID-19-related pneumonia. The role of whole-lung LD-RT within existing treatment paradigms merits further study. Methods: A phase II prospective trial studied the addition of LD-RT to standard drug treatments. Hospitalized and oxygen-dependent patients receiving dexamethasone and/or remdesevir were treated with 1.5 Gy whole-lung LD-RT and compared to a blindly-matched contemporaneous control cohort. Results: Of 40 patients evaluated, 20 received drug therapy combined with whole-lung LD-RT and 20 without LD-RT. Intubation rates were 14% with LD-RT compared to 32% without (p = 0.09). Intubation-free survival was 77% vs. 68% (p = 0.17). Biomarkers of inflammation (C-reactive protein, p = 0.02) and cardiac injury (creatine kinase, p < 0.01) declined following LD-RT compared to controls. Mean time febrile was 1.4 vs 3.3 days, respectively (p = 0.14). Significant differences in clinical recovery (7.5 vs. 7 days, p = 0.37) and radiographic improvement (p = 0.72) were not detected. On subset analysis, CRP decline following LD-RT was predictive of recovery without intubation compared to controls (0% vs. 31%, p = 0.04), freedom from prolonged hospitalizations (21+ days) (0% vs. 31%, p = 0.04), and decline in oxygenation burden (56% reduction, p = 0.06). CRP decline following 1st drug therapy was not similarly predictive of outcome in controls (p = 0.36). Conclusions: Adding LD-RT to standard drug treatments reduced biomarkers of inflammation and cardiac injury in COVID-19 patients and may have reduced intubation. Durable CRP decline following LD-RT predicted especially favorable recovery, freedom from intubation, reduction in prolonged hospitalization, and reduced oxygenation burden. A confirmatory randomized trial is now ongoing. Clinical Trial Registration: NCT04366791.
Purpose: High radiation doses to the heart have been correlated with poor overall survival in patients receiving radiation therapy for stage III non-small cell lung cancer (NSCLC). We built a knowledge-based planning (KBP) tool to limit the dose to the heart during creation of volumetric modulated arc therapy (VMAT) treatment plans for patients being treated to 60 Gy in 30 fractions for stage III NSCLC. Methods and Materials: A previous study at our institution retrospectively delineated intracardiac volumes and optimized VMAT treatment plans to reduce dose to these substructures and to the whole heart. Two RapidPlan (RP) KBP models were built from this cohort, 1 model using the clinical plans and a separate model using the cardiac-optimized plans. Using target volumes and 6 organs at risk (OARs), models were trained to generate treatment plans in a semiautomated process. The cardiac-sparing KBP model was tested in the same cohort used for training, and both models were tested on an external validation cohort of 30 patients. Results: Both RP models produced clinically acceptable plans in terms of target coverage, dose uniformity, and dose to OARs. Compared with the previously created cardiac-optimized plans, cardiac-sparing RPs showed significant reductions in the mean dose to the esophagus and lungs while performing similarly or better in all evaluated heart dose metrics. When comparing the 2 models, the cardiac-sparing RP showed reduced (P < .05) heart mean and maximum doses as well as volumes receiving 60 Gy, 50 Gy, and 30 Gy. Conclusions: By using a set of cardiac-optimized treatment plans for training, the proposed KBP model provided a means to reduce the dose to the heart and its substructures without the need to explicitly delineate cardiac substructures. This tool may offer reduced planning time and improved plan quality and might be used to improve patient outcomes.
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.
OBJECTIVE: Here, we report musculoskeletal outcomes and the impact of radiotherapy dose on vertebral body growth for an institutional series of long-term survivors of high-risk neuroblastoma. METHODS: We conducted a retrospective study of 23 patients who were disease-free and at least 36 months from the end of treatment. The patients were initially treated from July 2003 to May 2012. Patient records were reviewed for growth percentiles (obtained at approximately 6-month intervals from onset of treatment to the last follow-up) and musculoskeletal comorbidities. RT plans and most recent surveillance CT scans were reviewed for locations of in-field vertebral bodies and corresponding vertebral growth patterns. RESULTS: The median follow-up was 7.93 years. The median prescribed radiation dose was 21.6 Gy. Musculoskeletal abnormalities included scoliosis (5 patients), muscular hypoplasia (3), and hypodontia (1). The median growth percentile at treatment onset was 35.5 (range, 4.7-100) versus 10 (0-94.1) at the last follow-up. The median numbers of vertebral bodies encompassed (by at least half of their volume) by the 5-, 10-, 15-, and 20-Gy isodose lines were 7 (mean, 6.78), 7 (6.56), 6 (6.17), and 6 (5.52), respectively. Sixteen patients (70.0%) had in-field abnormalities in vertebral body growth, manifesting as stretches of successive vertebral bodies at the same height, while normally there is a gradual vertebral body height increase progressing caudally down the spinal column. CONCLUSIONS: Musculoskeletal abnormalities, below average height, and stunted in-field vertebral body growth are routine in long-term survivors of high-risk neuroblastoma. Sparing vertebral bodies when feasible may lead to improvement in patient growth trajectories.
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.