A process to reanalyze clinical DNA sequencing data for biomarker matching in the Lung-MAP Master Protocol.

For cancer clinical trials that require central confirmation of tumor genomic profiling, exhaustion of tissue from standard-of-care testing may prevent enrollment. For Lung-MAP, a master protocol that requires results from a defined centralized clinical trial assay to assign patients to a therapeutic substudy, we developed a process to repurpose existing commercial vendor raw genomic data for eligibility: genomic data reanalysis (GDR). Molecular results for substudy assignment were successfully generated for 369 of the first 374 patients (98.7%) using GDR for Lung-MAP, with a median time from request to result of 9 days. During the same period, 691 of 791 (87.4%) tissue samples received successfully yielded results, in a median of 14 days beyond sample acquisition. GDR is a scalable bioinformatic pipeline that expedites reanalysis of existing data for clinical trials in which validated integral biomarker testing is required for participation.

Edge roughness quantifies impact of physician variation on training and performance of deep learning auto-segmentation models for the esophagus.

Manual segmentation of tumors and organs-at-risk (OAR) in 3D imaging for radiation-therapy planning is time-consuming and subject to variation between different observers. Artificial intelligence (AI) can assist with segmentation, but challenges exist in ensuring high-quality segmentation, especially for small, variable structures, such as the esophagus. We investigated the effect of variation in segmentation quality and style of physicians for training deep-learning models for esophagus segmentation and proposed a new metric, edge roughness, for evaluating/quantifying slice-to-slice inconsistency. This study includes a real-world cohort of 394 patients who each received radiation therapy (mainly for lung cancer). Segmentation of the esophagus was performed by 8 physicians as part of routine clinical care. We evaluated manual segmentation by comparing the length and edge roughness of segmentations among physicians to analyze inconsistencies. We trained eight multiple- and individual-physician segmentation models in total, based on U-Net architectures and residual backbones. We used the volumetric Dice coefficient to measure the performance for each model. We proposed a metric, edge roughness, to quantify the shift of segmentation among adjacent slices by calculating the curvature of edges of the 2D sagittal- and coronal-view projections. The auto-segmentation model trained on multiple physicians (MD1-7) achieved the highest mean Dice of 73.7 ± 14.8%. The individual-physician model (MD7) with the highest edge roughness (mean ± SD: 0.106 ± 0.016) demonstrated significantly lower volumetric Dice for test cases compared with other individual models (MD7: 58.5 ± 15.8%, MD6: 67.1 ± 16.8%, p < 0.001). A multiple-physician model trained after removing the MD7 data resulted in fewer outliers (e.g., Dice ≤ 40%: 4 cases for MD1-6, 7 cases for MD1-7, Ntotal = 394). While we initially detected this pattern in a single clinician, we validated the edge roughness metric across the entire dataset. The model trained with the lowest-quantile edge roughness (MDER-Q1, Ntrain = 62) achieved significantly higher Dice (Ntest = 270) than the model trained with the highest-quantile ones (MDER-Q4, Ntrain = 62) (MDER-Q1: 67.8 ± 14.8%, MDER-Q4: 62.8 ± 15.7%, p < 0.001). This study demonstrates that there is significant variation in style and quality in manual segmentations in clinical care, and that training AI auto-segmentation algorithms from real-world, clinical datasets may result in unexpectedly under-performing algorithms with the inclusion of outliers. Importantly, this study provides a novel evaluation metric, edge roughness, to quantify physician variation in segmentation which will allow developers to filter clinical training data to optimize model performance.

Surgical management of non-small cell lung cancer with limited metastatic disease involving only the brain.

OBJECTIVE: The optimal primary site treatment modality for non-small cell lung cancer with brain oligometastases is not well established. This study sought to evaluate the long-term survival of patients with non-small cell lung cancer with isolated brain metastases undergoing multimodal therapy with or without thoracic surgery. METHODS: Patients with cT1-3, N0-1, M1b-c non-small cell lung cancer with synchronous limited metastatic disease involving only the brain treated with brain stereotactic radiosurgery or neurosurgical resection in the National Cancer Database (2010-2017) were included. Long-term overall survival of patients who underwent multimodal therapy including thoracic surgery ("Thoracic Surgery") versus systemic therapy with or without radiation to the lung ("No Thoracic Surgery") was evaluated using Kaplan-Meier analysis, Cox proportional hazards modeling, and propensity score matching. RESULTS: Of the 1240 patients with non-small cell lung cancer with brain-only metastases who received brain stereotactic radiosurgery or neurosurgery and met study inclusion criteria, 270 (21.8%) received primary site resection. The Thoracic Surgery group had improved overall survival compared with the No Thoracic Surgery group in Kaplan-Meier analysis (P < .001) and after multivariable-adjusted Cox proportional hazards modeling (P < .001). In a propensity score-matched analysis of 175 patients each in the Thoracic Surgery and No Thoracic Surgery groups, matching on 13 common prognostic variables, thoracic surgery was associated with better survival (P = .012). CONCLUSIONS: In this national analysis, patients with cT1-3, N0-1, M1b-c non-small cell lung cancer with isolated limited brain metastases had better overall survival after multimodal therapy including thoracic surgery compared with systemic therapy without surgery. Multimodal thoracic treatment including surgery can be considered for carefully selected patients with non-small cell lung cancer and limited brain metastases.

Pneumonitis in Patients Receiving Thoracic Radiotherapy and Osimertinib: A Multi-Institutional Study.

Introduction: Thoracic radiotherapy (TRT) is increasingly used in patients receiving osimertinib for advanced NSCLC, and the risk of pneumonitis is not established. We investigated the risk of pneumonitis and potential risk factors in this population. Methods: We performed a multi-institutional retrospective analysis of patients under active treatment with osimertinib who received TRT between April 2016 and July 2022 at two institutions. Clinical characteristics, including whether osimertinib was held during TRT and pneumonitis incidence and grade (Common Terminology Criteria for Adverse Events version 5.0) were documented. Logistic regression analysis was performed to identify risk factors associated with grade 2 or higher (2+) pneumonitis. Results: The median follow-up was 10.2 months (range: 1.9-53.2). Of 102 patients, 14 (13.7%) developed grade 2+ pneumonitis, with a median time to pneumonitis of 3.2 months (range: 1.5-6.3). Pneumonitis risk was not significantly increased in patients who continued osimertinib during TRT compared with patients who held osimertinib during TRT (9.1% versus 15.0%, p = 0.729). Three patients (2.9%) had grade 3 pneumonitis, none had grade 4, and two patients had grade 5 events (2.0%, diagnosed 3.2 mo and 4.4 mo post-TRT). Mean lung dose was associated with the development of grade 2+ pneumonitis in multivariate analysis (OR = 1.19, p = 0.021). Conclusions: Although the overall rate of pneumonitis in patients receiving TRT and osimertinib was relatively low, there was a small risk of severe toxicity. The mean lung dose was associated with an increased risk of developing pneumonitis. These findings inform decision-making for patients and providers.

Natural Language Processing Methods to Empirically Explore Social Contexts and Needs in Cancer Patient Notes.

PURPOSE: There is an unmet need to empirically explore and understand drivers of cancer disparities, particularly social determinants of health. We explored natural language processing methods to automatically and empirically extract clinical documentation of social contexts and needs that may underlie disparities. METHODS: This was a retrospective analysis of 230,325 clinical notes from 5,285 patients treated with radiotherapy from 2007 to 2019. We compared linguistic features among White versus non-White, low-income insurance versus other insurance, and male versus female patients' notes. Log odds ratios with an informative Dirichlet prior were calculated to compare words over-represented in each group. A variational autoencoder topic model was applied, and topic probability was compared between groups. The presence of machine-learnable bias was explored by developing statistical and neural demographic group classifiers. RESULTS: Terms associated with varied social contexts and needs were identified for all demographic group comparisons. For example, notes of non-White and low-income insurance patients were over-represented with terms associated with housing and transportation, whereas notes of White and other insurance patients were over-represented with terms related to physical activity. Topic models identified a social history topic, and topic probability varied significantly between the demographic group comparisons. Classification models performed poorly at classifying notes of non-White and low-income insurance patients (F1 of 0.30 and 0.23, respectively). CONCLUSION: Exploration of linguistic differences in clinical notes between patients of different race/ethnicity, insurance status, and sex identified social contexts and needs in patients with cancer and revealed high-level differences in notes. Future work is needed to validate whether these findings may play a role in cancer disparities.

Clinical validation of deep learning algorithms for radiotherapy targeting of non-small-cell lung cancer: an observational study.

BACKGROUND: Artificial intelligence (AI) and deep learning have shown great potential in streamlining clinical tasks. However, most studies remain confined to in silico validation in small internal cohorts, without external validation or data on real-world clinical utility. We developed a strategy for the clinical validation of deep learning models for segmenting primary non-small-cell lung cancer (NSCLC) tumours and involved lymph nodes in CT images, which is a time-intensive step in radiation treatment planning, with large variability among experts. METHODS: In this observational study, CT images and segmentations were collected from eight internal and external sources from the USA, the Netherlands, Canada, and China, with patients from the Maastro and Harvard-RT1 datasets used for model discovery (segmented by a single expert). Validation consisted of interobserver and intraobserver benchmarking, primary validation, functional validation, and end-user testing on the following datasets: multi-delineation, Harvard-RT1, Harvard-RT2, RTOG-0617, NSCLC-radiogenomics, Lung-PET-CT-Dx, RIDER, and thorax phantom. Primary validation consisted of stepwise testing on increasingly external datasets using measures of overlap including volumetric dice (VD) and surface dice (SD). Functional validation explored dosimetric effect, model failure modes, test-retest stability, and accuracy. End-user testing with eight experts assessed automated segmentations in a simulated clinical setting. FINDINGS: We included 2208 patients imaged between 2001 and 2015, with 787 patients used for model discovery and 1421 for model validation, including 28 patients for end-user testing. Models showed an improvement over the interobserver benchmark (multi-delineation dataset; VD 0·91 [IQR 0·83-0·92], p=0·0062; SD 0·86 [0·71-0·91], p=0·0005), and were within the intraobserver benchmark. For primary validation, AI performance on internal Harvard-RT1 data (segmented by the same expert who segmented the discovery data) was VD 0·83 (IQR 0·76-0·88) and SD 0·79 (0·68-0·88), within the interobserver benchmark. Performance on internal Harvard-RT2 data segmented by other experts was VD 0·70 (0·56-0·80) and SD 0·50 (0·34-0·71). Performance on RTOG-0617 clinical trial data was VD 0·71 (0·60-0·81) and SD 0·47 (0·35-0·59), with similar results on diagnostic radiology datasets NSCLC-radiogenomics and Lung-PET-CT-Dx. Despite these geometric overlap results, models yielded target volumes with equivalent radiation dose coverage to those of experts. We also found non-significant differences between de novo expert and AI-assisted segmentations. AI assistance led to a 65% reduction in segmentation time (5·4 min; p<0·0001) and a 32% reduction in interobserver variability (SD; p=0·013). INTERPRETATION: We present a clinical validation strategy for AI models. We found that in silico geometric segmentation metrics might not correlate with clinical utility of the models. Experts' segmentation style and preference might affect model performance. FUNDING: US National Institutes of Health and EU European Research Council.

Elevated Coronary Artery Calcium Quantified by a Validated Deep Learning Model From Lung Cancer Radiotherapy Planning Scans Predicts Mortality.

PURPOSE: Coronary artery calcium (CAC) quantified on computed tomography (CT) scans is a robust predictor of atherosclerotic coronary disease; however, the feasibility and relevance of quantitating CAC from lung cancer radiotherapy planning CT scans is unknown. We used a previously validated deep learning (DL) model to assess whether CAC is a predictor of all-cause mortality and major adverse cardiac events (MACEs). METHODS: Retrospective analysis of non-contrast-enhanced radiotherapy planning CT scans from 428 patients with locally advanced lung cancer is performed. The DL-CAC algorithm was previously trained on 1,636 cardiac-gated CT scans and tested on four clinical trial cohorts. Plaques ≥ 1 cubic millimeter were measured to generate an Agatston-like DL-CAC score and grouped as DL-CAC = 0 (very low risk) and DL-CAC ≥ 1 (elevated risk). Cox and Fine and Gray regressions were adjusted for lung cancer and cardiovascular factors. RESULTS: The median follow-up was 18.1 months. The majority (61.4%) had a DL-CAC ≥ 1. There was an increased risk of all-cause mortality with DL-CAC ≥ 1 versus DL-CAC = 0 (adjusted hazard ratio, 1.51; 95% CI, 1.01 to 2.26; P = .04), with 2-year estimates of 56.2% versus 45.4%, respectively. There was a trend toward increased risk of major adverse cardiac events with DL-CAC ≥ 1 versus DL-CAC = 0 (hazard ratio, 1.80; 95% CI, 0.87 to 3.74; P = .11), with 2-year estimates of 7.3% versus 1.2%, respectively. CONCLUSION: In this proof-of-concept study, CAC was effectively measured from routinely acquired radiotherapy planning CT scans using an automated model. Elevated CAC, as predicted by the DL model, was associated with an increased risk of mortality, suggesting a potential benefit for automated cardiac risk screening before cancer therapy begins.

Dosimetric Planning Tradeoffs to Reduce Heart Dose Using Machine Learning-Guided Decision Support Software in Patients with Lung Cancer.

PURPOSE: Cardiac toxicity is a well-recognized risk after radiation therapy (RT) in patients with non-small cell lung cancer (NSCLC). However, the extent to which treatment planning optimization can reduce mean heart dose (MHD) without untoward increases in lung dose is unknown. METHODS AND MATERIALS: Retrospective analysis of RT plans from 353 consecutive patients with locally advanced NSCLC treated with intensity modulated RT (IMRT) or 3-dimensional conformal RT. Commercially available machine learning-guided clinical decision support software was used to match RT plans. A leave-one-out predictive model was used to examine lung dosimetric tradeoffs necessary to achieve a MHD reduction. RESULTS: Of all 232 patients, 91 patients (39%) had RT plan matches showing potential MHD reductions of >4 to 8 Gy without violating the upper limit of lung dose constraints (lung volume [V] receiving 20 Gy (V20 Gy) <37%, V5 Gy <70%, and mean lung dose [MLD] <20 Gy). When switching to IMRT, 75 of 103 patients (72.8%) had plan matches demonstrating improved MHD (average 2.0 Gy reduction, P < .0001) without violating lung constraints. Examining specific lung dose tradeoffs, a mean ≥3.7 Gy MHD reduction was achieved with corresponding absolute increases in lung V20 Gy, V5 Gy, and MLD of 3.3%, 5.0%, and 1.0 Gy, respectively. CONCLUSIONS: Nearly 40% of RT plans overall, and 73% when switched to IMRT, were predicted to have reductions in MHD >4 Gy with potentially clinically acceptable tradeoffs in lung dose. These observations demonstrate that decision support software for optimizing heart-lung dosimetric tradeoffs is feasible and may identify patients who might benefit most from more advanced RT technologies.

Surgical complications and clinical outcomes after dose-escalated trimodality therapy for non-small cell lung cancer in the era of intensity-modulated radiotherapy.

BACKGROUND: Trimodality therapy (TMT) with preoperative chemoradiation followed by surgical resection is used for locally-advanced non-small-cell lung cancer (LA-NSCLC). Traditionally, preoperative radiation doses ≤54 Gy are used due to concerns regarding excess morbidity, but little is known about outcomes and toxicities after TMT with intensity-modulated radiotherapy (IMRT) to higher doses. METHODS: A retrospective analysis of patients who received planned TMT with IMRT for LA-NSCLC at Brigham and Women's Hospital/Dana-Farber Cancer Institute between 2008 and 2017 was performed. Clinical and treatment characteristics, pathologic response, and surgical toxicity were assessed. Kaplan-Meier method and log-rank test was used for survival outcomes. Cox proportional-hazards regression was used for multivariable analysis. RESULTS: Forty-six patients received less than definitive doses of <60 Gy and 30 patients received definitive doses ≥60 Gy. Surgical outcomes, pathologic complete response, and postoperative toxicity did not differ significantly between the groups. With median follow-up of 3.6 years (range: 0.4-11.4), three-year locoregional recurrence-free survival (78.0% vs. 68.3%, p = 0.51) and overall survival (OS) (61.0% vs. 69.4%, p = 0.32) was not significantly different between patients receiving <60 Gy and ≥60 Gy, respectively. On multivariable analysis, older age, clinical stage, and length of hospital stay (LOS) >7 days were associated with OS. CONCLUSIONS: With IMRT, there was no increased rate of surgical complications in patients receiving higher doses of radiation. Survival outcomes or LOS did not differ based on radiation dose, but increased LOS was associated with worse OS. Larger prospective studies are needed to further examine outcomes after IMRT in patients with LA-NSCLC receiving TMT.

Veliparib in combination with carboplatin/paclitaxel-based chemoradiotherapy in patients with stage III non-small cell lung cancer.

OBJECTIVES: Veliparib is a potent poly(ADP)-ribose polymerase (PARP) 1 and 2 inhibitor that impedes repair of DNA damage induced by cytotoxic and radiation therapies. This phase 1 study evaluated veliparib in combination with chemoradiotherapy in patients with unresectable stage III non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: Patients received veliparib orally twice daily (BID) in escalating doses (60-240 mg, Day -3 to 1 day after last dose of radiation) combined with weekly carboplatin (area under the curve [AUC] 2 mg/mL/min), paclitaxel (45 mg/m2), and daily radiation therapy (60 Gy in 30 fractions), followed by two cycles of veliparib (120-240 mg BID, Days -2 through 5 of each 21-day cycle), carboplatin (AUC 6 mg/mL/min, Day 1 of each cycle), and paclitaxel (200 mg/m2, Day 1 of each cycle) consolidation. Endpoints included veliparib maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), pharmacokinetics, safety, and efficacy. RESULTS: Forty-eight patients were enrolled. The MTD/RP2D of veliparib was 240 mg BID with chemoradiotherapy followed by 120 mg BID with consolidation. The most common any-grade adverse events (AEs) in this cohort for the whole treatment period were nausea (83%), esophagitis (75%), neutropenia (75%), and thrombocytopenia (75%). Dose-proportional pharmacokinetics of veliparib were observed. Median progression-free survival (mPFS) was 19.6 months (95% CI: 9.7-32.6). Median overall survival was estimated to be 32.6 months (95% CI: 15.0-not reached). In patients treated with the RP2D, mPFS was 19.6 months (95% CI: 3.0-not reached). CONCLUSIONS: When combined with standard concurrent chemoradiotherapy and consolidation chemotherapy in patients with stage III NSCLC, veliparib demonstrated an acceptable safety profile and antitumor activity with an mPFS of 19.6 months.

Rates of invasive disease and outcomes in NSCLC patients with biopsy suggestive of carcinoma in situ.

INTRODUCTION: Carcinoma in situ is a rare non-invasive histology of non-small cell lung cancer (NSCLC) with excellent survival outcomes with resection. However, management of lung biopsy suggestive of in situ disease remains unclear. To inform decision-making in this scenario, we determined the rate of invasive disease presence upon resection of lesions with an initial biopsy suggestive of purely in situ disease. METHODS: The study included 960 patients diagnosed with NSCLC from 2003 to 2017 in the National Cancer Database whose workup included a lung biopsy suggestive of in situ disease. Among the cohort who proceeded to resection, we identified the rate of invasive disease discovered on surgical pathology along with significant demographic and clinical contributors to invasion risk. Survival outcomes were measured for the observed cohort that did not receive local therapy after biopsy. RESULTS: Invasive disease was identified at resection in 49.3 % of patients. Lesion size was associated with risk of invasive disease: 35.7 % for ≤1 cm, 45.2 % for 1-2 cm, 55.7 % for 2-3 cm, and 87.5 % for 3-5 cm (p < 0.001). Of patients with squamous histology, 61.5 % had invasive disease versus 46.5 % with adenocarcinoma histology (p = 0.026). On multivariable logistic regression, invasive disease remained associated with tumor size (OR 1.9 per cm, 95 % CI 1.5-2.4, p < 0.001), and squamous histology (OR 1.8, 95 % CI 1.1-3.2, p = 0.028). Overall survival at 3 years was 51.5 % in the observed cohort. CONCLUSION: Nearly half of patients with biopsy suggestive of in situ disease had invasive disease at resection. Tumor size and histology are strong predictors of invasive disease and may be used for risk stratification. However, the findings support the practice of definitive therapy whenever feasible.

Mean Heart Dose Is an Inadequate Surrogate for Left Anterior Descending Coronary Artery Dose and the Risk of Major Adverse Cardiac Events in Lung Cancer Radiation Therapy.

PURPOSE: Mean heart dose (MHD) over 10 Gy and left anterior descending (LAD) coronary artery volume (V) receiving 15 Gy (V15Gy) greater than 10% can significantly increase the risk of major adverse cardiac events (MACE) in patients with non-small cell lung cancer (NSCLC). We sought to characterize the discordance between MHD and LAD dose and the association of this classification on the risk of MACE after radiation therapy. METHODS AND MATERIALS: The coefficient of determination for MHD and LAD V15Gy was calculated in this retrospective analysis of 701 patients with locally advanced NSCLC treated with radiation therapy. Four groups were defined on the basis of high or low MHD (≥10 Gy vs <10 Gy) and LAD V15Gy (≥10% vs <10%). MACE (unstable angina, heart failure, myocardial infarction, coronary revascularization, and cardiac death) cumulative incidence was estimated, and Fine and Gray regressions were performed. RESULTS: The proportion of variance in LAD V15Gy predictable from MHD was only 54.5% (R2 = 0.545). There was discordance (where MHD was high [≥10 Gy] and LAD low [V15Gy < 10%], or vice versa) in 23.1% of patients (n = 162). Two-year MACE estimates were 4.2% (MHDhigh/LADlow), 7.6% (MHDhigh/LADhigh), 1.8% (MHDlow/LADlow), and 13.0% (MHDlow/LADhigh). Adjusting for pre-existing coronary heart disease and other prognostic factors, MHDhigh/LADlow (subdistribution hazard ratio [SHR], 0.34; 95% CI, 0.13-0.93; P = .036) and MHDlow/LADlow (SHR, 0.24; 95% CI, 0.10-0.53; P < .001) were associated with a significantly reduced risk of MACE. CONCLUSIONS: MHD is insufficient to predict LAD V15Gy with confidence. When MHD and LAD V15Gy dose exposure is discordant, isolated low LAD V15Gy significantly reduces the risk of MACE in patients with locally advanced NSCLC after radiation therapy, suggesting that the validity of whole heart metrics for optimally predicting cardiac events should be reassessed.

Statin Use, Heart Radiation Dose, and Survival in Locally Advanced Lung Cancer.

PURPOSE: Patients with locally advanced non-small cell lung cancer (LA-NSCLC) have a high prevalence of pre-existing coronary heart disease and face excess cardiac risk after thoracic radiation therapy. We sought to assess whether statin therapy is a predictor of overall survival (OS) after thoracic radiation therapy. METHODS AND MATERIALS: We performed a retrospective analysis of 748 patients with LA-NSCLC treated with thoracic radiation therapy, using Kaplan-Meier OS estimates and Cox regression. RESULTS: Statin use among high cardiac risk patients (Framingham risk ≥20% or pre-existing coronary heart disease; n = 496) was 51.2%. After adjustment for baseline cardiac risk and other prognostic factors, statin therapy was associated with a significantly increased risk of all-cause mortality (adjusted hazard ratio, 1.39; 95% confidence interval [CI], 1.00-1.91; P = .048) but not major adverse cardiac events (adjusted hazard ratio, 1.18; 95% CI, 0.52-2.68; P = .69). Among statin-naïve patients, mean heart dose ≥10 Gy versus <10 Gy was associated with a significantly increased risk of all-cause mortality (hazard ratio, 1.32; 95% CI, 1.04-1.68; P = .022), with 2-year OS estimates of 46.9% versus 60.0%, respectively. However, OS did not differ by heart dose among patients on statin therapy (hazard ratio, 1.00; 95% CI, 0.76-1.32; P = 1.00; P-interaction = .031), with 2-year OS estimates of 46.9% versus 50.3%, respectively. CONCLUSIONS: Among patients with LA-NSCLC, only half of statin-eligible high cardiac risk patients were on statin therapy, reflecting the highest cardiac risk level of our cohort. Statin use was an independent predictor of all-cause mortality but not major adverse cardiac events. Elevated mean heart dose (≥10 Gy) was associated with increased risk of all-cause mortality in statin-naïve patients but not among those on statin therapy, identifying a group of patients in which early intervention with statins may mitigate the deleterious effects of high heart radiation therapy dose. This warrants evaluation in prospective trials.

Association of Left Anterior Descending Coronary Artery Radiation Dose With Major Adverse Cardiac Events and Mortality in Patients With Non-Small Cell Lung Cancer.

IMPORTANCE: Radiotherapy accelerates coronary heart disease (CHD), but the dose to critical cardiac substructures has not been systematically studied in lung cancer. OBJECTIVE: To examine independent cardiac substructure radiotherapy factors for major adverse cardiac events (MACE) and all-cause mortality in patients with locally advanced non-small cell lung cancer (NSCLC). DESIGN, SETTING, AND PARTICIPANTS: A retrospective cohort analysis of 701 patients with locally advanced NSCLC treated with thoracic radiotherapy at Harvard University-affiliated hospitals between December 1, 2003, and January 27, 2014, was performed. Data analysis was conducted between January 12, 2019, and July 22, 2020. Cardiac substructures were manually delineated. Radiotherapy dose parameters (mean, maximum, and the volume [V, percentage] receiving a specific Gray [Gy] dose in 5-Gy increments) were calculated. Receiver operating curve and cut-point analyses estimating MACE (unstable angina, heart failure hospitalization or urgent visit, myocardial infarction, coronary revascularization, and cardiac death) were performed. Fine and Gray and Cox regressions were adjusted for preexisting CHD and other prognostic factors. MAIN OUTCOMES AND MEASURES: MACE and all-cause mortality. RESULTS: Of the 701 patients included in the analysis, 356 were men (50.8%). The median age was 65 years (interquartile range, 57-73 years). The optimal cut points for substructure and radiotherapy doses (highest C-index value) were left anterior descending (LAD) coronary artery V15 Gy greater than or equal to 10% (0.64), left circumflex coronary artery V15 Gy greater than or equal to 14% (0.64), left ventricle V15 Gy greater than or equal to 1% (0.64), and mean total coronary artery dose greater than or equal to 7 Gy (0.62). Adjusting for baseline CHD status and other prognostic factors, an LAD coronary artery V15 Gy greater than or equal to 10% was associated with increased risk of MACE (adjusted hazard ratio, 13.90; 95% CI, 1.23-157.21; P = .03) and all-cause mortality (adjusted hazard ratio, 1.58; 95% CI, 1.09-2.29; P = .02). Among patients without CHD, associations with increased 1-year MACE were noted for LAD coronary artery V15 Gy greater than or equal to 10% (4.9% vs 0%), left circumflex coronary artery V15 Gy greater than or equal to 14% (5.2% vs 0.7%), left ventricle V15 Gy greater than or equal to 1% (5.0% vs 0.4%), and mean total coronary artery dose greater than or equal to 7 Gy (4.8% vs 0%) (all P ≤ .001), but only a left ventricle V15 Gy greater than or equal to 1% increased the risk among patients with CHD (8.4% vs 4.1%; P = .046). Among patients without CHD, 2-year all-cause mortality was increased with an LAD coronary artery V15 Gy greater than or equal to 10% (51.2% vs 42.2%; P = .009) and mean total coronary artery dose greater than or equal to 7 Gy (53.2% vs 40.0%; P = .01). CONCLUSIONS AND RELEVANCE: The findings of this cohort study suggest that optimal cardiac dose constraints may differ based on preexisting CHD. Although the LAD coronary artery V15 Gy greater than or equal to 10% appeared to be an independent estimator of the probability of MACE and all-cause mortality, particularly in patients without CHD, left ventricle V15 Gy greater than or equal to 1% appeared to confer an increased risk of MACE among patients with CHD. These constraints are worthy of further study because there is a need for improved cardiac risk stratification and aggressive risk mitigation strategies.

Cardiac Radiation Dose, Cardiac Disease, and Mortality in Patients With Lung Cancer.

BACKGROUND: Radiotherapy-associated cardiac toxicity studies in patients with locally advanced non-small cell lung cancer (NSCLC) have been limited by small sample size and nonvalidated cardiac endpoints. OBJECTIVES: The purpose of this analysis was to ascertain whether cardiac radiation dose is a predictor of major adverse cardiac events (MACE) and all-cause mortality (ACM). METHODS: This retrospective analysis included 748 consecutive locally advanced NSCLC patients treated with thoracic radiotherapy. Fine and Gray and Cox regressions were used to identify predictors for MACE and ACM, adjusting for lung cancer and cardiovascular prognostic factors, including pre-existing coronary heart disease (CHD). RESULTS: After a median follow-up of 20.4 months, 77 patients developed ≥1 MACE (2-year cumulative incidence, 5.8%; 95% confidence interval [CI]: 4.3% to 7.7%), and 533 died. Mean radiation dose delivered to the heart (mean heart dose) was associated with a significantly increased risk of MACE (adjusted hazard ratio [HR]: 1.05/Gy; 95% CI: 1.02 to 1.08/Gy; p < 0.001) and ACM (adjusted HR: 1.02/Gy; 95% CI: 1.00 to 1.03/Gy; p = 0.007). Mean heart dose (≥10 Gy vs. <10 Gy) was associated with a significantly increased risk of ACM in CHD-negative patients (178 vs. 118 deaths; HR: 1.34; 95% CI: 1.06 to 1.69; p = 0.014) with 2-year estimates of 52.2% (95% CI: 46.1% to 58.5%) versus 40.0% (95% CI: 33.5% to 47.4%); but not among CHD-positive patients (112 vs. 82 deaths; HR: 0.94; 95% CI: 0.70 to 1.25; p = 0.66) with 2-year estimates of 54.6% (95% CI: 46.8% to 62.7%) versus 50.8% (95% CI: 41.5% to 60.9%), respectively (p for interaction = 0.028). CONCLUSIONS: Despite the competing risk of cancer-specific death in locally advanced NSCLC patients, cardiac radiation dose exposure is a modifiable cardiac risk factor for MACE and ACM, supporting the need for early recognition and treatment of cardiovascular events and more stringent avoidance of high cardiac radiotherapy dose.

Clinical Outcomes After Lung Stereotactic Body Radiation Therapy in Patients With or Without a Prior Lung Resection.

OBJECTIVES: Tumor control (TC), toxicity and survival, following stereotactic body radiation therapy (SBRT) were compared between patients with and without a prior lung resection (PLR). MATERIALS AND METHODS: The study is comprised of 130 patients with 141 peripheral tumors treated with SBRT at our institution from 2009 to 2013. Primary TC and lobar control (LC) were defined per RTOG 0236. Toxicity was scored using Common Terminology Criteria for Adverse Events version 4.0. Survival/TC and toxicity were compared between patients with and without PLR using the Kaplan-Meier method and cumulative incidence, respectively. Fine and Gray regression was used for univariable/multivariable analysis for radiation pneumonitis (RP). RESULTS: Of the 130 patients with median age 70 years (range, 42 to 93 y), 50 had undergone PLR (median time between PLR and SBRT: 33 mo; range, 1 to 206), including pneumonectomy (12%), lobectomy (46%), wedge resection (42%). With a median follow-up of 21 months in survivors, the PLR group had better TC (1-y 100% vs. 93%; P<0.01) and increased grade ≥2 (RP; 1-y 12% vs. 1%; P<0.01). OS was not significantly different between the 2 groups (1-y 91% vs. 85%; P=0.24). On univariable/multivariable analyses, biologically effective dose was associated with TC (hazard ratios, 0.97; 95% confidence interval, 0.94-0.999; P=0.04). Chemotherapy use was associated with grade ≥2 RP for all patients (hazard ratios, 14.92; 95% confidence interval, 5.68-39.21; P<0.0001) in multivariable analysis. PLR was not associated with increased RP in multivariable analysis. CONCLUSIONS: Patients with PLR who receive lung SBRT for lung tumors have high local control and relatively low toxicity. SBRT is an excellent option to treat second lung tumors or pulmonary metastases in patients with PLR.

Radiation toxicity in patients with collagen vascular disease and intrathoracic malignancy treated with modern radiation techniques.

BACKGROUND AND PURPOSE: There is concern that patients with collagen vascular disease (CVD) are at higher risk of developing radiation toxicity. We analyzed radiation toxicities in patients with intrathoracic malignancy and CVD treated using modern radiotherapy. MATERIALS AND METHODS: This single-institution retrospective study included 31 patients with CVD and 825 patients without CVD treated from 1998 to 2014. Radiation esophagitis (RE) and radiation pneumonitis (RP) were scored by RTOG scales. RE was analyzed with logistic regression and RP with Cox regression. RESULTS: CVD patients experienced similar grade ≥3 RE compared to control patients (23% vs. 19%, p = 0.64) but more grade ≥3 RP (26% vs. 10%, p = 0.01). There was no significant association between CVD subtype and toxicities. In multivariate analysis, CVD and lung V20 >30% were associated with grade ≥3 RP. We identified V20 ≤30%, V5 ≤50%, and MLD ≤18 Gy as dose thresholds in patients with CVD. CVD patients with mild severity disease and only 1 organ system involved were at low risk for RP. CONCLUSIONS: Patients with CVD may be at higher risk of RP. However, CVD patients may be offered curative thoracic RT with particular attention to risk-reduction strategies and maintaining recommended dose constraints as described in this study.

Inter-scan and inter-observer tumour volume delineation variability on cone beam computed tomography in patients treated with stereotactic body radiation therapy for early-stage non-small cell lung cancer.

INTRODUCTION: Quantification of volume changes on cone beam computed tomography (CBCT) during lung stereotactic body radiation therapy (SBRT) for non-small cell lung cancer (NSCLC) may provide a useful radiological marker for radiation response and for adaptive treatment planning. This study quantifies inter-scan and inter-observer variability in tumour volume delineation on CBCT. METHODS: Three clinicians independently contoured the primary gross tumour volume (GTV) manually on CBCTs taken immediately before SBRT treatment (pre) and after the same SBRT treatment (post) for 19 NSCLC patients. Relative volume differences (RVD) were calculated between the pre- and post-CBCTs for a given treatment and between any two of three observers for a given CBCT. Coefficient of variation (CV) was used to quantitatively measure and compare the extent of variability. RESULTS: Inter-observer variability had a significantly higher CV of 0.15 ± 0.13 compared to inter-scan CV of 0.03 ± 0.04 with P < 0.0001. The greatest variability was observed with tumours (<2 cm in diameter) versus larger tumours with 95% limit of agreement (LOA) (Mean ± Standard Deviation) of 1.90% ± 19.55% vs. -0.97% ± 12.26% for inter-scan RVD and 29.99% ± 73.84% vs. 9.37% ± 29.95% for inter-observer RVD respectively. CONCLUSIONS: Inter-observer variability was greater than inter-scan variability for tumour volume delineation on CBCT with greatest variability for small tumours (<2 cm in diameter). LOA for inter-scan variability (~12%) helps defines a threshold for clinically meaningful tumour volume change during SBRT treatment for tumours with diameter greater than 2 cm, with larger thresholds needed for smaller tumours.

TGF-ß Inhibition Rescues Hematopoietic Stem Cell Defects and Bone Marrow Failure in Fanconi Anemia.

Fanconi anemia (FA) is an inherited DNA repair disorder characterized by progressive bone marrow failure (BMF) from hematopoietic stem and progenitor cell (HSPC) attrition. A greater understanding of the pathogenesis of BMF could improve the therapeutic options for FA patients. Using a genome-wide shRNA screen in human FA fibroblasts, we identify transforming growth factor-ß (TGF-ß) pathway-mediated growth suppression as a cause of BMF in FA. Blocking the TGF-ß pathway improves the survival of FA cells and rescues the proliferative and functional defects of HSPCs derived from FA mice and FA patients. Inhibition of TGF-ß signaling in FA HSPCs results in elevated homologous recombination (HR) repair with a concomitant decrease in non-homologous end-joining (NHEJ), accounting for the improvement in cellular growth. Together, our results suggest that elevated TGF-ß signaling contributes to BMF in FA by impairing HSPC function and may be a potential therapeutic target for the treatment of FA.

Updated patterns of failure after multimodality therapy for malignant pleural mesothelioma.

OBJECTIVE: We have previously described patterns of failure after extrapleural pneumonectomy and multimodality therapy for malignant pleural mesothelioma and sought to update our results with a larger cohort of recent patients. METHODS: A total of 169 patients underwent extrapleural pneumonectomy without preoperative chemotherapy between 2001 and 2010. Data for treatment, recurrence, and survival were determined from medical records. A thoracic radiologist reviewed postoperative computed tomography or positron emission tomography computed tomography scans to determine sites of recurrence. Time to recurrence was estimated by the Kaplan-Meier method. Rates were compared using the Fisher exact test. RESULTS: The median age of patients was 62 years. Histology on final pathology was epithelial for 104 patients (62%) and nonepithelial for 65 patients (38%). A total of 132 patients (78%) received heated intraoperative chemotherapy; 77 patients (45%) received adjuvant chemotherapy, and 71 patients (42%) received adjuvant radiation therapy. Most chemotherapy regimens included platinum or pemetrexed. Median radiation therapy dose was 54 Gy. Among 158 evaluable patients, a recurrence developed in 118 (75%). Median follow-up was 83 months, median time to recurrence was 13.1 months, and median survival was 15 months. Sites of first recurrence were in the ipsilateral hemithorax or mediastinum for 54% of patients, in the abdomen for 39% of patients, in the contralateral hemithorax for 28% of patients, and in other distant sites for 5% of patients. Some patients had simultaneous recurrences in multiple sites. CONCLUSIONS: The most common site of recurrence after extrapleural pneumonectomy and planned multimodality therapy remains the ipsilateral hemithorax (including mediastinum), and true distant failure (other than the abdomen or contralateral hemithorax) remains unusual. The distribution of recurrences is strikingly similar to our prior report.