Standard-dose versus high-dose conformal radiotherapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non-small-cell lung cancer (RTOG 0617): a randomised, two-by-two factorial phase 3 study.

BACKGROUND: We aimed to compare overall survival after standard-dose versus high-dose conformal radiotherapy with concurrent chemotherapy and the addition of cetuximab to concurrent chemoradiation for patients with inoperable stage III non-small-cell lung cancer. METHODS: In this open-label randomised, two-by-two factorial phase 3 study in 185 institutions in the USA and Canada, we enrolled patients (aged ≥ 18 years) with unresectable stage III non-small-cell lung cancer, a Zubrod performance status of 0-1, adequate pulmonary function, and no evidence of supraclavicular or contralateral hilar adenopathy. We randomly assigned (1:1:1:1) patients to receive either 60 Gy (standard dose), 74 Gy (high dose), 60 Gy plus cetuximab, or 74 Gy plus cetuximab. All patients also received concurrent chemotherapy with 45 mg/m(2) paclitaxel and carboplatin once a week (AUC 2); 2 weeks after chemoradiation, two cycles of consolidation chemotherapy separated by 3 weeks were given consisting of paclitaxel (200 mg/m(2)) and carboplatin (AUC 6). Randomisation was done with permuted block randomisation methods, stratified by radiotherapy technique, Zubrod performance status, use of PET during staging, and histology; treatment group assignments were not masked. Radiation dose was prescribed to the planning target volume and was given in 2 Gy daily fractions with either intensity-modulated radiation therapy or three-dimensional conformal radiation therapy. The use of four-dimensional CT and image-guided radiation therapy were encouraged but not necessary. For patients assigned to receive cetuximab, 400 mg/m(2) cetuximab was given on day 1 followed by weekly doses of 250 mg/m(2), and was continued through consolidation therapy. The primary endpoint was overall survival. All analyses were done by modified intention-to-treat. The study is registered with ClinicalTrials.gov, number NCT00533949. FINDINGS: Between Nov 27, 2007, and Nov 22, 2011, 166 patients were randomly assigned to receive standard-dose chemoradiotherapy, 121 to high-dose chemoradiotherapy, 147 to standard-dose chemoradiotherapy and cetuximab, and 110 to high-dose chemoradiotherapy and cetuximab. Median follow-up for the radiotherapy comparison was 22.9 months (IQR 27.5-33.3). Median overall survival was 28.7 months (95% CI 24.1-36.9) for patients who received standard-dose radiotherapy and 20.3 months (17.7-25.0) for those who received high-dose radiotherapy (hazard ratio [HR] 1.38, 95% CI 1.09-1.76; p=0.004). Median follow-up for the cetuximab comparison was 21.3 months (IQR 23.5-29.8). Median overall survival in patients who received cetuximab was 25.0 months (95% CI 20.2-30.5) compared with 24.0 months (19.8-28.6) in those who did not (HR 1.07, 95% CI 0.84-1.35; p=0.29). Both the radiation-dose and cetuximab results crossed protocol-specified futility boundaries. We recorded no statistical differences in grade 3 or worse toxic effects between radiotherapy groups. By contrast, the use of cetuximab was associated with a higher rate of grade 3 or worse toxic effects (205 [86%] of 237 vs 160 [70%] of 228 patients; p<0.0001). There were more treatment-related deaths in the high-dose chemoradiotherapy and cetuximab groups (radiotherapy comparison: eight vs three patients; cetuximab comparison: ten vs five patients). There were no differences in severe pulmonary events between treatment groups. Severe oesophagitis was more common in patients who received high-dose chemoradiotherapy than in those who received standard-dose treatment (43 [21%] of 207 patients vs 16 [7%] of 217 patients; p<0.0001). INTERPRETATION: 74 Gy radiation given in 2 Gy fractions with concurrent chemotherapy was not better than 60 Gy plus concurrent chemotherapy for patients with stage III non-small-cell lung cancer, and might be potentially harmful. Addition of cetuximab to concurrent chemoradiation and consolidation treatment provided no benefit in overall survival for these patients. FUNDING: National Cancer Institute and Bristol-Myers Squibb.

Lung Stereotactic Body Radiation Therapy.

Lung stereotactic body radiation therapy (SBRT) is a novel and effective modality for treatment of early stage non-sail cell lung cancer (NSCLC), with expanding indications in locally advanced and metastatic disease. Herein, we will review current treatment recommendations for early stage NSCLC, detail treatment planning of SBRT, and discuss future directions.

Method and Atlas to Enable Targeting for Cardiac Radioablation Employing the American Heart Association Segmented Model.

PURPOSE: Cardiac radioablation using stereotactic body radiation therapy is gaining popularity as a noninvasive treatment for otherwise refractory ventricular arrhythmias. As radiation oncologists might be unaccustomed to the lexicon used by cardiologists to describe the location of arrhythmogenic foci, a preliminary guide to cardiac-specific anatomy and orientation is needed to foster effective communication between the radiation oncologist and cardiology team. METHODS AND MATERIALS: Electrocardiogram-gated and respiratory-gated computed tomography imaging was acquired per institutional protocol. Additional relevant imaging modalities are described. The American Heart Association 17-segment model is described in detail because this framework is used frequently by cardiologists to describe the location left ventricular abnormalities. RESULTS: A step-by-step guide is provided for properly rotating the heart from standard orthogonal views obtained during radiation simulation to the cardiac-specific orientation needed to appreciate the 17-segment model. Once the proper configuration is achieved, the location of each segment is defined in detail. CONCLUSIONS: This atlas serves as an introduction to the relevant anatomy and principles, and it provides a suggested approach to help delineate cardiac radioablation targets using the established American Heart Association 17-segment model.

A single-institution phase I feasibility study of dose-escalated IMRT for non-operative locally advanced esophageal carcinoma.

BACKGROUND AND PURPOSE: Radiation dose escalation to improve poor outcomes with chemoradiation in locally advanced esophageal carcinoma is limited in part by increased toxicity. This Phase I study investigates the use of IMRT to improve tolerability of dose escalation. MATERIALS AND METHODS: A single-institution, prospective study was conducted between 2007 and 2013 for individuals with inoperable esophageal carcinoma. Gross disease received 60 Gy in 30 fractions and at-risk sites received 54 Gy with simultaneous integrated boost. Concurrent chemotherapy primarily consisted of cisplatin/5-FU. The primary objective was to assess feasibility (<15% rate of grade 4-5 toxicity). Secondary objectives included assessment of overall survival (OS), progression free survival (PFS), and locoregional (LRR) and distant recurrence. RESULTS: Twenty-six patients were enrolled with median follow up of 17.6 months (range 0.1 to 152.0). The majority were AJCC 7th edition Stage III (54%), distal esophagus primary (81%), and adenocarcinoma histology (85%). Twenty-one patients (81%) completed their course of radiation therapy, while only 55% received 2 cycles of concurrent cisplatin/5-FU. One grade 5 and one grade 4 cardiac event occurred, both during chemoradiation and before receiving 50 Gy. The 3-year OS was 48.6% (95% CI: 32.5 to 72.2%) and PFS was 28.5% (95% CI: 14.6 to 55.5%). Half developed distant failure with LRR occurring in 10 patients (38%), isolated in 5 patients. CONCLUSION: While feasibility was demonstrated, toxicity and compliance remained limiting factors with outcomes similar to historical controls. There remains an uncertain role for dose escalation in definitive management of locally advanced esophageal cancer.

Higher Radiation Dose to the Immune Cells Correlates with Worse Tumor Control and Overall Survival in Patients with Stage III NSCLC: A Secondary Analysis of RTOG0617.

Background: We hypothesized that the Effective radiation Dose to the Immune Cells (EDIC) in circulating blood is a significant factor for the treatment outcome in patients with locally advanced non-small-cell lung cancer (NSCLC). Methods: This is a secondary study of a phase III trial, NRG/RTOG 0617, in patients with stage III NSCLC treated with radiation-based treatment. The EDIC was computed as equivalent uniform dose to the entire blood based on radiation doses to all blood-containing organs, with consideration of blood flow and fractionation effect. The primary endpoint was overall survival (OS), and the secondary endpoints were progression-free survival (PFS) and local progression-free survival (LPFS). The EDIC-survival relationship was analyzed with consideration of clinical significant factors. Results: A total of 456 patients were eligible. The median EDIC values were 5.6 Gy (range, 2.1-12.2 Gy) and 6.3 Gy (2.1-11.6 Gy) for the low- and high-dose groups, respectively. The EDIC was significantly associated with OS (hazard ratio [HR] = 1.12, p = 0.005) and LPFS (HR = 1.09, p = 0.02) but PFS (HR = 1.05, p = 0.17) after adjustment for tumor dose, gross tumor volume and other factors. OS decreased with an increasing EDIC in a non-linear pattern: the two-year OS decreased first with a slope of 8%/Gy when the EDIC < 6 Gy, remained relatively unchanged when the EDIC was 6-8 Gy, and followed by a further reduction with a slope of 12%/Gy when the EDIC > 8 Gy. Conclusions: The EDIC is a significant independent risk factor for poor OS and LPFS in RTOG 0617 patients with stage III NSCLC, suggesting that radiation dose to circulating immune cells is critical for tumor control. Organ at risk for the immune system should be considered during RT plan.

Thin layer chromatography-based assay of O6-methylguanine-DNA methyltransferase activity in tissue.

Expression of the DNA repair enzyme O(6)-methylguanine-DNA methyltransferase (MGMT) in tumor correlates with resistance to alkylating agents, and depletion of MGMT activity can enhance chemotherapy-induced tumor cytotoxicity. The most common assays of MGMT activity are time-consuming and employ radioactivity. The assay described here uses a fluorescently labeled O(6)-benzylguanine derivative in conjunction with thin layer chromatography to eliminate the use of radioactivity and allows MGMT activity to be rapidly measured in minimally prepared cell or tissue extracts.

Treatment of oligometastatic lung cancer with brain metastases using stereotactic radiosurgery (SRS) and stereotactic body radiation therapy (SBRT).

BACKGROUND: There is increasing interest in treating oligometastatic non-small cell lung cancer (NSCLC) patients with stereotactic radiation. We aimed to address whether patients definitively treated with synchronous thoracic stereotactic body radiation therapy (SBRT) and brain stereotactic radiosurgery (SRS) had favorable outcomes with local therapy. MATERIALS AND METHODS: We reviewed a database of patients receiving lung SBRT as well as a database for brain metastasis patients treated with SRS between June 2004 and January 2016. We selected for cT1-2aN0M1 NSCLC patients with brain metastases and calculated their overall survival (OS), freedom from progression (FFP), and local control (LC) rates. RESULTS: Six patients had oligometastatic NSCLC with 1-3 synchronous brain metastases treated with lung SBRT and brain SRS. No patients received immunotherapy and two-thirds did not receive systemic therapy. Median follow-up was 9 months for the entire cohort (range, 2-95 months) and 95 months for the surviving patient. Median OS was 12.4 months (95% confidence interval [CI], 7-18 months). At 1 year, patients had 67% OS (95% CI, 29-100%), 17% FFP (95% CI, 0-46%), and 100% LC. Their brain disease had 80% 1-year LC (95% CI, 45-100%) and 53% 1-year FFP (95% CI, 5-100%). Two patients had no distant progression, two had brain progression, one had adrenal gland progression, and one had bone and liver progression. CONCLUSION: In patients presenting with oligometastatic lung cancer limited to the brain, treatment with both lung SBRT and brain SRS achieves good LC of all sites with encouraging OS.

VA-Radiation Oncology Quality Surveillance Program.

PURPOSE: We sought to develop a quality surveillance program for approximately 15,000 US veterans treated at the 40 radiation oncology facilities at the Veterans Affairs (VA) hospitals each year. METHODS AND MATERIALS: State-of-the-art technologies were used with the goal to improve clinical outcomes while providing the best possible care to veterans. To measure quality of care and service rendered to veterans, the Veterans Health Administration established the VA Radiation Oncology Quality Surveillance program. The program carries forward the American College of Radiology Quality Research in Radiation Oncology project methodology of assessing the wide variation in practice pattern and quality of care in radiation therapy by developing clinical quality measures (QM) used as quality indices. These QM data provide feedback to physicians by identifying areas for improvement in the process of care and identifying the adoption of evidence-based recommendations for radiation therapy. RESULTS: Disease-site expert panels organized by the American Society for Radiation Oncology (ASTRO) defined quality measures and established scoring criteria for prostate cancer (intermediate and high risk), non-small cell lung cancer (IIIA/B stage), and small cell lung cancer (limited stage) case presentations. Data elements for 1567 patients from the 40 VA radiation oncology practices were abstracted from the electronic medical records and treatment management and planning systems. Overall, the 1567 assessed cases passed 82.4% of all QM. Pass rates for QM for the 773 lung and 794 prostate cases were 78.0% and 87.2%, respectively. Marked variations, however, were noted in the pass rates for QM when tumor site, clinical pathway, or performing centers were separately examined. CONCLUSIONS: The peer-review protected VA-Radiation Oncology Surveillance program based on clinical quality measures allows providers to compare their clinical practice to peers and to make meaningful adjustments in their personal patterns of care unobtrusively.

Hippocampal Avoidance During Whole-Brain Radiotherapy Plus Memantine for Patients With Brain Metastases: Phase III Trial NRG Oncology CC001.

PURPOSE: Radiation dose to the neuroregenerative zone of the hippocampus has been found to be associated with cognitive toxicity. Hippocampal avoidance (HA) using intensity-modulated radiotherapy during whole-brain radiotherapy (WBRT) is hypothesized to preserve cognition. METHODS: This phase III trial enrolled adult patients with brain metastases to HA-WBRT plus memantine or WBRT plus memantine. The primary end point was time to cognitive function failure, defined as decline using the reliable change index on at least one of the cognitive tests. Secondary end points included overall survival (OS), intracranial progression-free survival (PFS), toxicity, and patient-reported symptom burden. RESULTS: Between July 2015 and March 2018, 518 patients were randomly assigned. Median follow-up for alive patients was 7.9 months. Risk of cognitive failure was significantly lower after HA-WBRT plus memantine versus WBRT plus memantine (adjusted hazard ratio, 0.74; 95% CI, 0.58 to 0.95; P = .02). This difference was attributable to less deterioration in executive function at 4 months (23.3% v 40.4%; P = .01) and learning and memory at 6 months (11.5% v 24.7% [P = .049] and 16.4% v 33.3% [P = .02], respectively). Treatment arms did not differ significantly in OS, intracranial PFS, or toxicity. At 6 months, using all data, patients who received HA-WBRT plus memantine reported less fatigue (P = .04), less difficulty with remembering things (P = .01), and less difficulty with speaking (P = .049) and using imputed data, less interference of neurologic symptoms in daily activities (P = .008) and fewer cognitive symptoms (P = .01). CONCLUSION: HA-WBRT plus memantine better preserves cognitive function and patient-reported symptoms, with no difference in intracranial PFS and OS, and should be considered a standard of care for patients with good performance status who plan to receive WBRT for brain metastases with no metastases in the HA region.

Anatomical Adaptation-Early Clinical Evidence of Benefit and Future Needs in Lung Cancer.

Definitive treatment of locally advanced non-small-cell lung cancer with radiation is challenging. During the course of treatment, anatomical changes such as tumor regression, tumor displacement/deformation, pleural effusion, and/or atelectasis can result in a deviation of the administered radiation dose from the intended prescribed treatment and thereby worsen local control and toxicity. Adaptive radiotherapy can help correct for these changes and can be generally categorized into 3 philosophical paradigms: (1) maintenance of prescribed dose to the initially defined target volume; (2) dose reduction to healthy organs while maintaining initial prescribed dose to a regressing tumor volume; or (3) dose escalation to a regressing tumor volume with isotoxicity to healthy organs. Numerous single institution studies have investigated these methods, and results from large prospective clinical trials will hopefully provide consensus on the method, utility, and efficacy of implementing adaptive radiation therapy (ART) in a clinical setting. Additional development into standardization and automation of the ART workflow, specifically in identifying when ART is warranted and in reducing the manual clinical effort needed to produce an adaptive plan, will be paramount to making ART feasible for the broader radiation therapy community.

Stereotactic Body Radiotherapy for Early-Stage Multiple Primary Lung Cancers.

BACKGROUND: Patients with multiple primary lung cancers increasingly receive multiple courses of stereotactic body radiotherapy (SBRT). We aimed to clarify the efficacy and safety of such treatments. PATIENTS AND METHODS: We reviewed a prospective lung SBRT database of patients treated for stage I non-small-cell lung cancer between June 2004 and December 2015. RESULTS: A total of 374 patients received a single course of SBRT, 14 received synchronous SBRT, 48 received metachronous SBRT alone, and 108 received surgery and metachronous SBRT. Median follow-up was 37.0 months for survivors. Patients who received a single course had a 3-year overall survival (OS) of 54.2% (95% confidence interval [CI], 48.8-59.3), 3-year freedom from progression (FFP) of 67.3% (95% CI, 60.9-72.9), and grade 3 or higher toxicity of 3.5%. Compared to single-course patients, patients receiving metachronous SBRT alone and patients receiving surgery and metachronous SBRT had improved OS (79.7% [95% CI, 64.4-88.9%], P < .0001 and 95.4% [95% CI, 89.2-98.0%], P < .0001, respectively) and FFP (85.8% [95% CI, 70.7-93.5], P = .03 and 95.4% [95% CI, 89.2-98.0%], P < .0001, respectively). Patients receiving synchronous SBRT had similar OS (46.4% [95% CI, 19.3-69.9%], P = .75) and similar FFP (57.5% [95% CI, 25.3-80.0%], P = .17) as single-course patients. There were no significant differences in rates of grade 3 or higher toxicity or of grade 1 or higher toxicity between single-course patients and the other groups. CONCLUSION: Patients who received either synchronous or metachronous SBRT had no significant detriment in OS or toxicity compared to single-course patients. This supports the use of SBRT in patients with multiple primary lung cancers.

Defining Optimal Comorbidity Measures for Patients With Early-Stage Non-small cell lung cancer Treated With Stereotactic Body Radiation Therapy.

PURPOSE: Comparison of overall survival (OS) between stereotactic body radiation therapy (SBRT) and other treatments for early-stage non-small cell lung cancer is confounded by differences in age, performance status, and medical comorbidity. We sought to define the most robust measurement for this population among 5 indices: age, Eastern Cooperative Oncology Group performance status, Adult Comorbidity Evaluation 27, Charlson Comorbidity Index (CCI), and age-adjusted CCI (CCIa). METHODS AND MATERIALS: A total of 548 patients with stage I non-small cell lung cancer treated with SBRT were analyzed. Patients were divided into high- and low-risk groups for OS for each index using the log-rank test. Continuous and dichotomized models were compared via Akaike information criterion and the Vuong test. Multivariate Cox regression modeling was used with demographic information to determine the independent prognostic value of the continuous and dichotomized versions of the indices. The best was used to stratify the patients into as many significantly different cohorts as possible. RESULTS: Optimal cut-points between high-risk and low-risk OS groups for age, Eastern Cooperative Oncology Group status, Adult Comorbidity Evaluation 27, CCI, and CCIa were ≥75 years, ≥1, ≥3, ≥3, and ≥6 with hazard ratios for death of 1.23 (95% confidence interval, 1.00-1.50), 1.66 (1.28-2.15), 1.37 (1.12-1.67), 1.43 (1.17-1.76), and 1.47 (1.20-1.80), respectively. Dichotomizing did not result in a significant loss of prognostic power. Although there was no significant difference in prognostic power among the indices, CCIa best predicted OS. CCIa divided the patients into 3 cohorts with median OS of 42 months, 33 months, and 23 months for scores of ≤5, 6 to 7, and ≥8, respectively. CONCLUSIONS: CCIa was the best indicator of OS in every model employed with no loss of prognostic power with dichotomization. Dichotomization of CCIa (≥6) could be implemented in future comparisons of SBRT with OS. No cohort could be identified with a median survival of less than a year, for which treatment could be deemed futile.

Empiric Radiotherapy for Lung Cancer Collaborative Group multi-institutional evidence-based guidelines for the use of empiric stereotactic body radiation therapy for non-small cell lung cancer without pathologic confirmation.

The standard of care for managing early stage non-small cell lung cancer (NSCLC) is definitive surgical resection. Stereotactic body radiation therapy (SBRT) has become the standard treatment for patient who are medically inoperable, and it is increasingly being considered as an option in operable patients. With the growing use of screening thoracic CT scans for patients with a history of heavy smoking, as well as improved imaging capabilities, the discovery of small lung nodes has become a common dilemma. As a result, clinicians are increasingly faced with managing lung nodules in patients in whom diagnostic biopsy is not safe or feasible. Herein, we describe the scope of the problem, tools available for predicting the probability that a lung nodule is a malignancy, staging procedures, benefits of pathology-proven and empiric SBRT, considerations of safety based on location of the lesion of concern, and overall efficacy of SBRT.

Optimizing radiation dose and fractionation for the definitive treatment of locally advanced non-small cell lung cancer.

Radiation therapy is the foundation for treatment of locally advanced non-small cell lung cancer (NSCLC), a disease that is often inoperable and has limited long term survival. Local control of disease is strongly linked to patient survival and continues to be problematic despite continued attempts at changing the dose and fractionation of radiation delivered. Technological advancements such as 4-dimensional computed tomography (CT) based planning, positron emission tomography (PET) based target delineation, and daily image guidance have allowed for ever more accurate and conformal treatments. A limit to dose escalation with conventional fractions of 2 Gy once per day appears to have been reached at 60 Gy in the randomized trial Radiation Therapy Oncology Group (RTOG) 0617. Higher doses were surprisingly associated with worse overall survival. Approaches other than conventional dose escalation have been explored to better control disease including accelerating treatment to limit tumor repopulation both with hyperfractionation and its multiple small (<2 Gy) fractions each day and with hypofractionation and its single larger (>2 Gy) fraction each day. These accelerated regimens are increasingly being used with concurrent chemotherapy, and multiple institutions have reported it as tolerable. Tailoring treatment to individual patient disease and normal anatomic characteristics has been explored with isotoxic dose escalation up to the tolerance of organs at risk, with both hyperfractionation and hypofractionation. Metabolic imaging during and after treatment is increasingly being used to boost doses to residual disease. Boost doses have included moderate hypofractionation of 2-4 Gy, and more recently extreme hypofractionation with stereotactic body radiation therapy (SBRT). In spite of all these changes in dose and fractionation, lung and cardiovascular toxicity remain obstacles that limit disease control and patient survival.

Low blue carbon storage in eelgrass (Zostera marina) meadows on the Pacific Coast of Canada.

Seagrass habitats provide important ecosystem services, including their ability to take up and store substantial amounts of organic carbon, known as 'blue carbon.' However, the paucity of geospatial and carbon storage information along the Pacific Coast of Canada hinders the inclusion of blue carbon storage data in conservation planning and policy development in coastal habitats. We assessed the carbon storage and accumulation rates in three eelgrass (Zostera marina) meadows in southern Clayoquot Sound on the Pacific Coast of British Columbia. The intertidal and subtidal portions of each meadow were mapped and sampled to estimate eelgrass density, biomass, and carbon, and sediment cores were analyzed to estimate sediment carbon storage and accumulation rates. Aboveground biomass measurements were consistent with estimates for Z. marina in other regions, with average aboveground carbon biomass estimates of 16.78 g C m-2 and 16.25 g C m-2 in the intertidal and subtidal areas, respectively. However, the estimated aboveground to belowground biomass ratio was an order of magnitude higher than for seagrass species in temperate/tropical areas, largely because belowground biomass was up to 10 times lower than for other Z. marina meadows, averaging 6.17 g C m-2 and 5.03 g C m-2 in the intertidal and subtidal zones, respectively. Sediment carbon concentrations did not exceed 1.30%Corg, and carbon accumulation rates ranged from 2.90-39.61 g Corg m-2 yr-1, decreasing with depth and averaging 10.8 ± 5.2 g Corg m-2 yr-1. While sediment carbon stocks were generally higher in the eelgrass meadows relative to non-vegetated reference sites, carbons stocks averaged 1343 ± 482 g Corg m-2, substantially less than global averages. These carbon results confirm that eelgrass does contribute to carbon storage in Clayoquot Sound but at lower rates than identified for more tropical seagrasses. By improving the quantification of site-specific carbon dynamics, eelgrass' role in climate change mitigation and conservation planning can be assessed.

Brain Metastases at Presentation in Patients With Non-Small Cell Lung Cancer.

OBJECTIVE: We used brain radiotherapy as a surrogate for the presence of brain metastases in patients with non-small cell lung cancer (NSCLC) to determine the prevalence of brain metastases using the Surveillance Epidemiology and End Results database. METHODS: Patients with NSCLC diagnosed between 1988 and 1997 were subdivided according to brain radiotherapy status at presentation into: "none" or "radiation therapy indicated." We calculated the frequency of brain radiotherapy use in all patients. Odds ratios (ORs) for the indication of brain radiotherapy were calculated for individual prespecified covariates of interest. All statistical tests were 2-sided and P<0.05 were considered significant. RESULTS: At presentation, brain radiotherapy was indicated in 10,963 (8.3%) of the 131,456 patients diagnosed with NSCLC between 1988 and 1997. On multivariable analysis the following were significantly associated with brain radiotherapy use: age (OR, 0.653 per 10 y increase in age; 95% confidence interval [CI]: 0.642, 0.665); female sex (OR, 1.05; 95% CI: 1.01, 1.10]); adenocarcinoma histology (HR, 1.67; 95% CI: 1.58, 1.76) or large cell or other histology (OR, 1.67; 95% CI: 1.57, 1.77); tumor size>3 cm (3.1 to 5 cm OR, 1.22; 95% CI: 1.14, 1.30 and >5 cm OR, 1.25; 95% CI: 1.17, 1.33); tumor grade >II (grade III OR, 1.82; 95% CI: 1.69, 1.95 and grade IV OR, 1.91; 95% CI: 1.73, 2.11); and nodal involvement N1 (OR, 1.33; 95% CI: 1.20, 1.47), N2 (OR, 2.24; 95% CI: 2.10, 2.40), and N3 (OR, 2.39; 95% CI: 2.19, 2.60). CONCLUSIONS: Brain radiotherapy is indicated in over 8% of patients with NSCLC at presentation. We demonstrated that the risk of brain metastasis at presentation may be stratified with the use of 6 clinical factors.

Non-small-cell Lung Cancer With Brain Metastasis at Presentation.

BACKGROUND: Data on the prevalence of brain metastases at presentation in patients with non-small-cell lung cancer (NSCLC) are limited. We queried the National Cancer Data Base to determine prevalence, clinical risk factors, and outcomes of patients with NSCLC presenting with brain metastases. PATIENTS AND METHODS: Patients with NSCLC diagnosed between 2010 and 2012 were identified using the National Cancer Data Base. The risk of brain metastases for individual variables was summarized by odds ratios and calculated using logistic regression analysis. The Kaplan-Meier product limit method was used to calculate the median and 1-, 2-, and 3-year overall survival (OS). RESULTS: Brain metastases were observed in 47,546 (10.4%) of the 457,481 patients with NSCLC overall. The prevalence of brain metastases was much higher (26%) in patients with stage IV disease at presentation. On multivariate analysis, younger age, adenocarcinoma or large cell histology, tumor size > 3 cm, tumor grade ≥ II, and node-positive disease were associated with brain metastases. The prevalence of brain metastases ranged from as low as 0.57% in patients with only 1 risk factor to as high as 22% in patients with all 5 risk factors. The median and 1-, 2-, and 3-year OS for patients with brain metastases were 6 months and 29.9%, 14.3%, and 8.4%, respectively, with the 3-year OS increasing to 36.2% in those with T1/2 and N0/1 undergoing surgery for the primary site. CONCLUSIONS: In patients with NSCLC, the risk of brain metastases at presentation may be calculated based on 5 clinical variables. Selected patients with brain metastases at presentation may achieve prolonged benefit.

Stereotactic Body Radiation Therapy for Central Early-Stage NSCLC: Results of a Prospective Phase I/II Trial.

INTRODUCTION: We report results from a prospective phase I/II trial for patients with centrally located, early-stage NSCLC receiving stereotactic body radiation therapy. METHODS: Eligible patients were medically inoperable with biopsy-proven NSCLC within 2 cm of the proximal bronchial tree or 5 mm of the mediastinal pleura or parietal pericardium. Phase I had four dose levels using 5 fractions: 9, 10, 11, and 12 Gy per fraction. The primary phase II objective was to determine if the maximum tolerated dose in phase I achieved local control greater than 80% at 2 years. RESULTS: Seventy-four patients were enrolled; 23 to phase I and 51 to phase II. Two phase I patients treated with 10 Gy × 5 fractions developed unrelated acute grade 3 lung toxicities which resolved. The phase II dose level selected was 11 Gy × 5 fractions. The median follow-up for living phase II patients was 27 months (range, 9 to 58 months). Two-year local control using 11 Gy × 5 fractions was 85% (95% confidence interval [CI]: 62%-95%). Two-year overall survival was 43% (95% CI: 28%-57%). Three patients (6%, 95% CI: 1%-17%) experienced acute grade 3 and 4 cardiac or pulmonary toxicities. Of the 41 patients evaluable for late cardiac and pulmonary toxicity, 11 (27%, 95% CI: 14%-43%) developed grade 3, 5 (12%, 95% CI: 4%-26%) developed grade 4, and 1 (4%, 95% CI: 0%-13%) died of grade 5 toxicity. CONCLUSION: Stereotactic body radiation therapy for central NSCLC using 11 Gy × 5 fractions is tolerable and has excellent local control, but is associated severe late toxicity in some patients.

Can dose outside the PTV influence the risk of distant metastases in stage I lung cancer patients treated with stereotactic body radiotherapy (SBRT)?

BACKGROUND AND PURPOSE: In an era where little is known about the "abscopal" (out-of-the-field) effects of lung SBRT, we investigated correlations between the radiation dose proximally outside the PTV and the risk of cancer recurrence after SBRT in patients with primary stage I non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: This study included 217 stage I NSCLC patients across 2 institutions who received SBRT. Correlations between clinical and dosimetric factors were investigated. The clinical factors considered were distant metastasis (DM), loco-regional control (LRC) and radiation pneumonitis (RP). The dose (converted to EQD2) delivered to regions of varying size directly outside of the PTV was computed. For each feature, area under the curve (AUC) and odds ratios with respect to the outcome parameters DM, LRC and RP were estimated; Kaplan-Meier (KM) analysis was also performed. RESULTS: Thirty-seven (17%) patients developed DM after a median follow-up of 24 months. It was found that the mean dose delivered to a shell-shaped region of thickness 30 mm outside the PTV had an AUC of 0.82. Two years after treatment completion, the rate of DM in patients where the mean dose delivered to this region was higher than 20.8 Gy2 was 5% compared to 60% in those who received a dose lower than 20.8 Gy2. KM analysis resulted in a hazard ratio of 24.2 (95% CI: 10.7, 54.4); p < 10-5. No correlations were found between any factor and either LRC or RP. CONCLUSIONS: The results of this study suggest that the dose received by the region close to the PTV has a significant impact on the risk of distant metastases in stage I NSCLC patients treated with SBRT. If these results are independently confirmed, caution should be taken, particularly when a treatment plan results in a steep dose gradient extending outwards from the PTV.

Internal dose escalation is associated with increased local control for non-small cell lung cancer (NSCLC) brain metastases treated with stereotactic radiosurgery (SRS).

OBJECTIVE: To identify potentially actionable dosimetric predictors of local control (LC) for non-small cell lung cancer (NSCLC) brain metastases treated with single-fraction stereotactic radiosurgery (SRS). METHODS AND MATERIALS: Patients with NSCLC brain metastases treated with single-fraction SRS were identified. Eligible patients had at least 1 follow-up magnetic resonance imaging scan and were without prior metastasectomy or SRS to the same lesion. LC and overall survival (OS) were estimated using the Kaplan-Meier method. The Cox proportional hazards model was used for univariate (UVA) and multivariate analysis (MVA). Receiver operating characteristic (ROC) analysis was used to identify optimal cut points for dose-volume histogram metrics relative to LC. RESULTS: A total of 612 NSCLC brain metastasis were identified in 299 patients with single-fraction SRS between 1999 and 2014. Median follow-up was 10 months. Median OS from time of SRS was 11 months. Overall LC was 75% and 66% at 1 and 2 years, respectively. On UVA, increasing dose by any measure was associated with improved LC. On MVA, volume receiving at least 32 Gy (V32; hazard ratio [HR], 0.069; P < .000), along with higher prescription isodose (HR, 0.953; P = .031) and lower volume (HR, 1.359; P < .000), were independent predictors of improved LC. ROC analysis demonstrated a V32 of 24% to be most predictive for LC. For the entire cohort, 1-year LC for V32 ≥24% was 89% versus 67% for V32 <24% (P = .000). Stratifying by volume, lesions ≤2 cm (n = 323) had a 1-year LC of 95% versus 82% (P = .005) for V32 above and below 24%, respectively. For lesions 2.1 to 3 cm (n = 211), 1-year LC was 79% versus 59% (P = .003) for V32 above and below 24%, respectively. Total tumor volume alone was predictive for OS. CONCLUSIONS: Volume, prescription isodose line, and V32 are independent predictors of LC. V32 represents an actionable SRS treatment planning parameter for NSCLC brain metastases.