Extracting the speed of sound in quark-gluon plasma with ultrarelativistic lead-lead collisions at the LHC.

Ultrarelativistic nuclear collisions create a strongly interacting state of hot and dense quark-gluon matter that exhibits a remarkable collective flow behavior with minimal viscous dissipation. To gain deeper insights into its intrinsic nature and fundamental degrees of freedom, we determine the speed of sound in an extended volume of quark-gluon plasma using lead-lead (PbPb) collisions at a center-of-mass energy per nucleon pair of 5.02 TeV. The data were recorded by the CMS experiment at the CERN LHC and correspond to an integrated luminosity of 0.607 nb-1. The measurement is performed by studying the multiplicity dependence of the average transverse momentum of charged particles emitted in head-on PbPb collisions. Our findings reveal that the speed of sound in this matter is nearly half the speed of light, with a squared value of0.241±0.002(stat)±0.016(syst)in natural units. The effective medium temperature, estimated using the mean transverse momentum, is219±8(syst)MeV. The measured squared speed of sound at this temperature aligns precisely with predictions from lattice quantum chromodynamic (QCD) calculations. This result provides a stringent constraint on the equation of state of the created medium and direct evidence for a deconfined QCD phase being attained in relativistic nuclear collisions.

Safety and Efficacy of Moderate-Intensity Stereotactic Body Radiation Therapy for Ultra-Central Lung Tumor.

Background and Objectives: Ultra-central (UC) lung tumors are defined as those abutting the proximal bronchial tree. Stereotactic body radiation therapy (SBRT) for UC tumors is difficult because of concerns about severe toxicities. Therefore, we report the safety and efficacy of moderate-intensity SBRT for UC tumors at our institution. Materials and Methods: From January 2017 to May 2021, we treated 20 patients with UC tumors with SBRT at a dose of 45-60 Gy in 10 fractions. The primary endpoints were local control (LC) and overall survival (OS). Results: The median follow-up time was 15.8 months (range: 2.7-53.8 months). Ten of the 20 patients (50.0%) showed a complete response, five (25.0%) had a partial response, two (10.0%) had stable disease, and three (15.0%) showed progressive disease (PD). The response and disease control rates were 75.0% and 85.0%, respectively. Patients with PD showed local progression at median 8.3 months (range: 6.8-19.1 months) after SBRT. One-year and 2-year OS rates were 79.4% and 62.4%, respectively. One-year and 2-year LC rates are 87.1% and 76.2%, respectively. Eight patients died due to a non-radiation therapy related cause. One patient experienced grade 5 massive hemoptysis 6 months after SBRT, resulting in death. One patient experienced grade 2 esophageal pain and two experienced grade 2 radiation pneumonitis. Otherwise, no grade 3 or higher toxicities were reported. Conclusions: Moderate-intensity SBRT offers effective control of UC tumors and is a well-tolerated treatment for such tumors.

Stereotactic body radiotherapy of central lung tumours using a 1.5 T MR-linac: First clinical experiences.

Background: MRI-guidance may aid better discrimination between Organs at Risk (OARs) and target volumes in proximity of the mediastinum. We report the first clinical experiences with Stereotactic Body Radiotherapy (SBRT) of (ultra)central lung tumours on a 1.5 T MR-linac. Materials and Methods: Patients with an (ultra)central lung tumour were selected for MR-linac based SBRT treatment. A T2-weighted 3D sequence MRI acquired during free breathing was used for daily plan adaption. Prior to each fraction, contours of Internal Target Volume (ITV) and OARs were deformably propagated and amended by a radiation oncologist. Inter-fractional changes in volumes and coverage of target volumes as well as doses in OARs were evaluated in offline and online treatment plans. Results: Ten patients were treated and completed 60 Gy in 8 or 12 fractions. In total 104 fractions were delivered. The median time in the treatment room was 41 min with a median beam-on time of 8.9 min. No grade ≥3 acute toxicity was observed. In two patients, the ITV significantly decreased during treatment (58 % and 37 %, respectively) due to tumour shrinkage. In the other patients, 81 % of online ITVs were within ±15 % of the volume of fraction 1. Comparison with the pre-treatment plan showed that ITV coverage of the online plan was similar in 52 % and improved in 34 % of cases. Adaptation to meet OAR constraints, led to decreased ITV coverage in 14 %. Conclusions: We describe the workflow for MR-guided Radiotherapy and the feasibility of using 1.5 T MR-linac for SBRT of (ultra) central lung tumours.

Dosimetric analysis of 17 cardiac Sub-structures, Toxicity, and survival in ultra central lung tumor patients treated with SBRT.

•Data on cardiac toxicity after SBRT for ultra-central lung tumors remains limited.•We analyzed the dose to 18 cardiac sub-structures and cardiovascular toxicity.•A SBRT regimen of 45 Gy in 8-10 fractions yields good local control and low toxicity.•The highest cardiac doses were observed in the pulmonary artery and left atrium.•Higher doses to the base of the heart seem to be associated with non-cancer deaths.

Stereotactic body radiotherapy for Ultra-Central lung Tumors: A systematic review and Meta-Analysis and International Stereotactic Radiosurgery Society practice guidelines.

BACKGROUND: Stereotactic body radiotherapy (SBRT) is an effective and safe modality for early-stage lung cancer and lung metastases. However, tumors in an ultra-central location pose unique safety considerations. We performed a systematic review and meta-analysis to summarize the current safety and efficacy data and provide practice recommendations on behalf of the International Stereotactic Radiosurgery Society (ISRS). METHODS: We performed a systematic review using PubMed and EMBASE databases of patients with ultra-central lung tumors treated with SBRT. Studies reporting local control (LC) and/or toxicity were included. Studies with <5 treated lesions, non-English language, re-irradiation, nodal tumors, or mixed outcomes in which ultra-central tumors could not be discerned were excluded. Random-effects meta-analysis was performed for studies reporting relevant endpoints. Meta-regression was conducted to determine the effect of various covariates on the primary outcomes. RESULTS: 602 unique studies were identified of which 27 (one prospective observational, the remainder retrospective) were included, representing 1183 treated targets. All studies defined ultra-central as the planning target volume (PTV) overlapping the proximal bronchial tree (PBT). The most common dose fractionations were 50 Gy/5, 60 Gy/8, and 60 Gy/12 fractions. The pooled 1- and 2-year LC estimates were 92 % and 89 %, respectively. Meta-regression identified biological effective dose (BED10) as a significant predictor of 1-year LC. A total of 109 grade 3-4 toxicity events, with a pooled incidence of 6 %, were reported, most commonly pneumonitis. There were 73 treatment related deaths, with a pooled incidence of 4 %, with the most common being hemoptysis. Anticoagulation, interstitial lung disease, endobronchial tumor, and concomitant targeted therapies were observed risk factors for fatal toxicity events. CONCLUSION: SBRT for ultra-central lung tumors results in acceptable rates of local control, albeit with risks of severe toxicity. Caution should be taken for appropriate patient selection, consideration of concomitant therapies, and radiotherapy plan design.

Accelerated hypofractionated radiotherapy with 3 Gy per fraction for central/ultra-central lung tumors: toxicity to mediastinal organs.

BACKGROUND: Accelerated hypofractionated radiotherapy with 3 Gy per fraction is routinely performed for central lung tumors in Japan. However, the tolerable doses to mediastinal organs at risk during this procedure are unclear. This study aimed to clarify the rate of toxicities and tolerable doses to mediastinal organs. METHODS: Patients treated with accelerated hypofractionated radiotherapy using a total dose of 60-75 Gy, with 3 Gy per fraction, for central lung tumors (July 2009-April 2021) were retrospectively reviewed. We extracted patients who received ≥30 Gy irradiation to each mediastinal organ and analyzed dosimetric factors, including doses to 0.03, 0.5, 1, 4 and 10 mL of each organ, in relation to grade 3-5 toxicities, except for radiation pneumonitis. RESULTS: In total, 251 organs in 91 (ultra-central, 24) lesions were analyzed, with a median follow-up duration of 26 months (range, 4-94). The prescribed doses were 75/72/69/66/63/60 Gy for 52/14/16/3/2/4 lesions, respectively. Grade 3 bronchopulmonary hemorrhage was confirmed in two (2.2%) patients, whose tumors were located ultra-centrally. The two patients with toxicity received up to 74.5 and 71.6 Gy to the bronchus. Among patients who received 70 Gy or more to the bronchus, the incidence rate was 7% (2/28 patients). CONCLUSION: The rate of severe toxicities was low (2.2%). Although we did not identify the dose tolerance of the organs, because of the low incidence rate, we did note that doses of >70 Gy to the bronchus were likely to cause bronchopulmonary hemorrhage.

Survival and Prognostic Factors of Ultra-Central Tumors Treated with Stereotactic Body Radiotherapy.

Introduction: Stereotactic body radiotherapy (SBRT) reported excellent outcomes and a good tolerability profile in case of central lung tumors, as long as risk-adapted schedules were adopted. High grade toxicity was more frequently observed for tumors directly touching or overlapping the trachea, proximal bronchial tree (PBT), and esophagus. We aim to identify prognostic factors associated with survival for Ultra-Central (UC) tumors. Methods: We retrospectively evaluated patients treated with SBRT for primary or metastatic UC lung tumors. SBRT schedules ranged from 45 to 60 Gy. Results: A total number of 126 ultra-central lung tumors were reviewed. The Median follow-up time was 23 months. Median Overall Survival (OS) and Progression Free Survival (PFS) was 29.3 months and 16 months, respectively. Local Control (LC) rates at 1 and 2 were 86% and 78%, respectively. Female gender, age < 70 years, and tumor size < 5 cm were significantly associated with better OS. The group of patients with tumors close to the trachea but further away from the PBT also correlated with better OS. The acute G2 dysphagia, cough, and dyspnea were 11%, 5%, and 3%, respectively. Acute G3 dyspnea was experienced by one patient. Late G3 toxicity was reported in 4% of patients. Conclusion: risk-adaptive SBRT for ultra-central tumors is safe and effective, even if it remains a high-risk clinical scenario.

Safety and Efficacy of Stereotactic Ablative Radiotherapy for Ultra-Central Lung Cancer.

Background: Ultra-central lung cancer (UCLC) is difficult to achieve surgical treatment. Over the past few years, stereotactic ablative radiotherapy (SABR) or stereotactic body radiotherapy (SBRT) obviously improved the clinical efficacy and survival of UCLC patients. However, the adapted scheme of radiation therapy is still controversial. For this, a single arm retrospective analysis was performed on UCLC patients treated with SBRT. Material and Methods: We retrospectively studied primary UCLC patients who were treated with SBRT of 56 Gy/6-8f between 2010 and 2018. UCLC was defined as planning target volume (PTV) touching or overlapping the proximal bronchial tree, trachea, esophagus, heart, pulmonary vein, or pulmonary artery within 2 cm around the bronchial tree in all directions. Results: A total of 58 patients whose median age was 68 years (range, 46-85) were included in our study, 79.3% of whom did not undergo any previous therapy. The median dose of the PTV was 77.8 Gy (range, 43.3-91.8), and the median PTV of tumors was 6.2 cm3 (range, 12.9-265.0). With a median follow-up of 57 months (range, 6-90 months), the median cumulative overall survival (OS) rate was 58 months (range, 2-105). In addition, the 1-year, 2-year and 5-year OS rates were 94.7%, 75.0% and 45.0%, respectively. In our univariable analysis (p=0.020) and multivariate analysis (p=0.004), the OS rate was associated with the PTV. The 5-year OS rates for PTV <53.0 cm3 and PTV ≥53.0 cm3 were 61.6% and 37.4%, respectively. Regarding toxicity after SBRT, there were two cases (3.5%) with grade ≥3 adverse events, of which 1 case died of sudden severe unexplained hemoptysis. Conclusions: Patients with UCLC can benefit from SBRT at a dose of 56 Gy/6-8f. On the other hand, smaller PTV was associated with superior outcomes, and the cure difference needs to be validated by prospective comparative trials.

Improving geometric sparing and therapeutic effectiveness of lung SBRT for central and ultra-central tumors.

The use of stereotactic body radiotherapy (SBRT) for central- and ultra-central lung tumors is a major therapeutic challenge since there are trade-offs between delivering adequate dose to the tumor and minimizing toxicity to critical mediastinal organs. This work investigates improving the therapeutic effectiveness of such SBRT treatments by enhancing the geometric sparing of normal tissue and systematically applying a planning target volume (PTV) margin smaller than the conventional values. Using plans from 10 previously SBRT-treated patients, we retrospectively created highly conformal plans with a reduced PTV margin of 2 mm and compared them to the clinical plans with a standard 5 mm PTV margin. We compared various dosimetric and biological parameters. We calculated the geometrical sparing factor (GSF) (ratio of biological dose between normal tissue and targets) for the mediastinal organs and the uncomplicated tumor control probability (UTCP) for the esophagus. We tracked tumor fraction doses using cone-beam computed tomography (CBCT) images. With geometric sparing, the median dose for critical mediastinal organs (proximal bronchial tree, great vessels, esophagus, and heart) dropped by 10 Gy (p ≤ 0.006). Dose sparing for the spinal cord and chest wall was 5 Gy and 8 Gy, respectively (p = 0.002). The geometrical sparing factor (GSF) dropped by 50% for the esophagus and the proximal bronchial tree (PBT) and 40% for the great vessels (p < 0.05). The CBCT fractional tumor dose varied by 2.7% (0.2 Gy) for the initially intended treatment volume and 4% (0.3 Gy) when accounting for daily volume changes. The expected delivered dose was above the prescribed value. Systematically reducing the PTV margin to 2 mm in lung SBRT of central and ultra-central tumors is feasible and ensures consistency in contouring and dose prescribing. It allows safe delivery of highly conformal treatments with significantly higher therapeutic effectiveness, potentially reducing treatment-related complications. Consequently, it may enable safer dose escalation, more effective fractionations, and safer management of retreatments and treatments of multiple synchronous lung tumors.

Ultra-central lung tumors: safety and efficacy of protracted stereotactic body radiotherapy.

BACKGROUND: For patients with early stage or medically inoperable lung cancer, stereotactic body radiotherapy (SBRT) is a general accepted and effective treatment option. The role of SBRT in ultra-central tumors remains controversial. The aim of this single-center retrospective analysis was to evaluate the safety and efficacy of protracted SBRT with 60 Gy in 12 fractions (with a biological effective dose (BED10) of 90-150 Gy) for patients with ultra-central lung tumors. MATERIALS AND METHODS: Patients with ultra-central lung tumors treated in our institution with 60 Gy in 12 fractions from January 2012 until April 2020 were included. Ultra-central tumors were defined as planning target volume (PTV) abutting or overlapping the main bronchi and/or trachea and/or esophagus. Data regarding patient-, tumor-, and treatment-related characteristics were evaluated. RESULTS: A total of 72 patients met the criteria for ultra-central tumor location. The PTV abutted the main bronchus, trachea or esophagus in 79%, 22% and 28% of cases, respectively. At a median follow-up of 19 months, 1- and 2-year local control rates were 98% and 85%, respectively. Overall survival rates at 1 and 2 years were 77% and 52%, respectively. Grade 3 or higher toxicity was observed in 21%, of which 10 patients (14% of total) died of bronchopulmonary hemorrhage. A significant difference between patients with or without grade ≥3 toxicity was found for the mean dose (Dmean) to the main bronchus (p = 0.003), where a Dmean BED3 of ≥91 Gy increased the risk of grade ≥3 toxicity significantly. DISCUSSION: A protracted SBRT regimen of 60 Gy in 12 fractions for ultra-central lung tumors leads to high local control rates with toxicity rates similar to previous series, but with substantial risk of fatal bronchopulmonary hemorrhage. Therefore, possible risk factors of bronchopulmonary hemorrhage such as dose to the main bronchus should be taken into account.

Ultra-central Thoracic Re-irradiation Using 10-fraction Stereotactic Body Radiotherapy for Recurrent Non-small-cell Lung Cancer Tumors: Preliminary Toxicity and Efficacy Outcomes.

BACKGROUND: We report our clinical outcomes of patients with recurrent non-small-cell lung cancer (NSCLC) tumors with ultra-central (UC) location treated with hypofractionated 10-fraction stereotactic body radiotherapy (hSBRT) in the context of thoracic re-irradiation. PATIENTS AND METHODS: This study was conducted from 2009 to 2017 on 20 patients with recurrent NSCLC from previous thoracic radiation treatment who underwent hSBRT to 21 total UC located recurrent tumors. The planning target volumes (PTVs) that overlapped with previous treatment fields (within the 50% isodose line) were included in this analysis with endpoints of overall survival, tumor control, and toxicity. RESULTS: The median follow-up time was 17.8 months. The median total dose of hSBRT and total biologically effective dose (BED10) were 65 Gy and 107.25 Gy, respectively. The median time from previous treatment was 14.6 months. The 1-year overall survival, progression-free survival, and local control rates were 68%, 35%, and 83%, respectively. The median time to local progression was 13.3 months. The most common toxicity was grade 2 or above pneumonitis (35%). One patient, whose tumor was abutting the esophagus, experienced grade 3 esophagitis. Two (10%) patients died from "unlikely" treatment-related hemorrhage from local tumor progression at 10 and 24 months after hSBRT. Bronchoscopic evaluation of 1 patient suggested endobronchial tumor progression, and clear radiographic evidence of treated hilar tumor progression was documented in the second patient's case. CONCLUSION: Despite having a high-risk population with recurrent ultra-central NSCLC tumors in the setting of re-irradiation, our results demonstrate that ablative doses of hSBRT may serve as a feasible option for these challenging cases and concur with current reported literature.

Dose coverage impacts local control in ultra-central lung oligometastases treated with stereotactic radiotherapy.

INTRODUCTION: The use of Stereotactic Body Radiotherapy (SBRT) is controversial in Ultra-Central lung tumors, a subset of central lung tumors characterized by proximity to critical mediastinal structures. This is of interest in oligometastatic (≤3 metastases) patients, who can yield survival benefit from local treatments. The aim of our study is to assess the determinants of efficacy and toxicity in this setting. MATERIALS AND METHODS: Clinical and dosimetric parameters were reviewed in a cohort of oligometastatic patients treated with SBRT for ultra-central tumors. Local control rate (LC) and toxicity were assessed. Statistical Analysis was carried out to assess the impact of those predictors on local recurrence and adverse events. RESULTS: One-hundred-nine consecutive patients were included. A median Biologic Effective Dose (BED) of 105 (75-132) Gy10 was prescribed. At a median follow-up of 17 (range 3-78) months, 2-year LC was 87%. Improved LC was correlated to Planning Treatment Volume (PTV) covered by 95% of the prescription dose (V95% PTV) > 85% (HR 0.15, 95%CI 0.05-0.49, p = 0.0017) and to Gross Tumor Volume (GTV) < 90 cm3 (HR 0.2, 95%CI 0.07-0.56, p = 0.0021). Overall and grade ≥ 3 toxicity incidence was 20% and 5%, respectively. Patients experiencing acute and late toxicities received significantly higher dose to 1 cm3 (D1cm3) of esophagus and lung volume receiving ≥5 Gy (V5Gy) (p = 0.016 and p = 0.013), and higher dose to 0.1 cm3 (D0.1cm3) of heart (p = 0.036), respectively. CONCLUSION: V95% PTV > 85% and GTV < 90 cm3 are independent predictors of LC. Dose to esophagus, lung and heart should be carefully assessed to minimize treatment-related toxicities.

Stereotactic Radiotherapy for Ultra-Central Lung Oligometastases in Non-Small-Cell Lung Cancer.

BACKGROUND: Stereotactic body radiotherapy (SBRT) in ultra-central (UC) lung tumors, defined in the presence of planning target volume (PTV) overlap or direct tumor abutment to the central bronchial tree or esophagus, may be correlated to a higher incidence of severe adverse events. Outcome and toxicity in oligometastatic (≤3 metastases) non-small-cell lung cancer (NSCLC) patients receiving SBRT for UC tumors were evaluated. METHODS: Oligometastatic NSCLC patients treated with SBRT for UC were retrospectively reviewed. Local control (LC), distant metastasis-free survival (DMFS), progression-free survival (PFS) and overall survival (OS) were calculated. Incidence and grade of toxicity were evaluated. Statistical analysis was performed to assess the impact of clinical and treatment-related variables on outcome and toxicity occurrence. RESULTS: Seventy-two patients were treated to a median biologically effective dose (BED) of 105 (75-132) Gy10. Two-year LC, DMFS, PFS, and OS were 83%, 46%, 43%, and 49%. BED>75 Gy10 was correlated to superior LC (p = 0.02), PFS (p = 0.036), and OS (p < 0.001). Grade ≥3 toxicity rate was 7%, including one fatal esophagitis. No variables were correlated to DMFS or to occurrence of overall and grade ≥3 toxicity. CONCLUSIONS: SBRT using dose-intensive schedules improves outcome in NSCLC patients. Overall toxicity is acceptable, although rare but potentially fatal toxicities may occur.

Stereotactic body radiotherapy for moderately central and ultra-central oligometastatic disease: Initial outcomes.

BACKGROUND: Delivery of SBRT to central thoracic tumours within 2 cm of the proximal bronchial tree (PBT), and especially ultra-central tumours which directly abut the PBT, has been controversial due to concerns about high risk of toxicity and treatment-related death when delivering high doses close to critical mediastinal structures. We present dosimetric and clinical outcomes from a group of oligometastatic patients treated with a risk-adapted SBRT approach. METHODS: Between September 2015 and October 2018, 27 patients with 28 central thoracic oligometastases (6 moderately central, 22 ultra-central) were treated with 60 Gy in 8 fractions under online CBCT guidance. PTV dose was compromised where necessary to meet mandatory OAR constraints. Patients were followed up for toxicity and disease status. RESULTS: Mandatory OAR constraints were met in all cases; this required PTV coverage compromise in 23 cases, with V100% reduced to <70% in 11 cases. No acute or late toxicities of Grade ≥ 3 were reported. One and 2 year in-field control rates were 95.2% and 85.7% respectively, progression-free survival rates were 42.8% and 23.4% respectively, and overall survival rates were 82.7% and 69.5% respectively. No significant differences were seen in control or survival rates by extent of PTV underdosage or between moderately and ultra-central cases. CONCLUSION: It appears that compromising PTV coverage to meet OAR constraints allows safe and effective delivery of SBRT to moderately and ultra-central tumours, with low toxicity rates and high in-field control rates. This treatment can be delivered on standard linear accelerators with widely available imaging technology.

Safety of stereotactic ablative body radiation for ultracentral stage I non-small cell lung cancer.

Recent data suggests that "ultra-central" tumors, generally defined as those abutting the proximal airways, are at particularly high risk for severe complications when treated with stereotactic ablative body radiation (SABR). However, this association has not been consistently demonstrated across reports, possibly due to small numbers, varying definitions of "ultra-central", and the lack of prospective data. New evidence suggests that exposure to VEGF-inhibiting agents may potentiate SABR toxicity and may partially explain the disproportionately high incidence of fatal complications in some reports. Efforts are underway to identify dose-volume limits that can predict complications involving central structures such as the proximal airways, heart, esophagus, and great vessels. The optimal dose for ultra-central SABR has not been determined, though there is a trend towards using more highly fractionated regimens. Further research into the safety of SABR for ultra-central tumors is needed, given the lack of other effective local therapy options for this clinical scenario.

Risk-adapted stereotactic body radiation therapy for central and ultra-central early-stage inoperable non-small cell lung cancer.

To determine the therapeutic efficacy and safety of risk-adapted stereotactic body radiation therapy (SBRT) schedules for patients with early-stage central and ultra-central inoperable non-small cell lung cancer. From 2006 to 2015, 80 inoperable T1-2N0M0 NSCLC patients were treated with two median dose levels: 60 Gy in six fractions (range, 48-60 Gy in 4-8 fractions) prescribed to the 74% isodose line (range, 58%-79%) for central lesions (ie within 2 cm of, but not abutting, the proximal bronchial tree; n = 43), and 56 Gy in seven fractions (range, 48-60 Gy in 5-10 fractions) prescribed to the 74% isodose line (range, 60%-80%) for ultra-central lesions (ie abutting the proximal bronchial tree; n = 37) on consecutive days. Primary endpoint was overall survival (OS); secondary endpoints included progression-free survival (PFS), tumor local control rate (LC), and toxicity. Median OS and PFS were 64.47 and 32.10 months (respectively) for ultra-central patients, and not reached for central patients. Median time to local failure, regional failure, and any distant failures for central versus ultra-central lesions were: 27.37 versus 26.07 months, 20.90 versus 12.53 months, and 20.85 versus 15.53 months, respectively, all P < .05. Multivariate analyses showed that tumor categorization (ultra-central) and planning target volume ≥52.76 mL were poor prognostic factors of OS, PFS, and LC, respectively (all P < .05). There was one grade 5 toxicity; all other toxicities were grade 1-2. Our results showed that ultra-central tumors have a poor OS, PFS, and LC compared with central patients because of the use of risk-adapted SBRT schedules that allow for equal and favorable toxicity profiles.

Outcomes and toxicity of stereotactic body radiation therapy for advanced stage ultra-central non-small cell lung cancer.

BACKGROUND: Previous studies have documented a high incidence of toxicity in patients with ultra-central non-small cell lung cancer (UC-NSCLC) treated with stereotactic body radiation therapy (SBRT). However, these studies mainly focused on early stage patients and included small sample populations. We reviewed the outcomes and toxicity of SBRT in patients with advanced stage UC-NSCLC treated at our institution. METHODS: Fifty-one consecutive patients with advanced UC-NSCLC treated with SBRT using a regular regimen of 35 Gy administered in five fractions between December 2014 and August 2017 were reviewed. UC was defined as tumors abutting or overlapping the trachea or the proximal bronchial tree. We included locally advanced patients who were unfit or unwilling to receive conventional chemoradiotherapy and patients with metastatic or postoperative recurrent disease. Clinical outcomes, dosimetric parameters, and SBRT toxicity were analyzed. RESULTS: The median age was 63 years (range: 35-82), and the median tumor diameter was 6.8 cm (range: 2.1-12.4). The overall median follow-up duration was 17 months (25.5 months for surviving patients). The median local control was 17 months for stage III patients and 11 months for stage IV or recurrent patients. Grade 3 or higher toxicity was observed in 9.8% of patients: G3 radiation pneumonitis (5.9%) and possible treatment-related death (3.9%). CONCLUSION: SBRT with a moderate dose in 4-6 fractions is effective and tolerable for patients with advanced stage UC-NSCLC. However, caution should be taken considering possible treatment-related death. Further studies are warranted.

A preliminary experience of moderate-intensity stereotactic body radiation therapy for ultra-central lung tumor.

Purpose: Administration of stereotactic body radiation therapy (SBRT) to ultra-central (UC) lung tumors, generally defined as those abutting the proximal bronchial trees, is difficult due to concerns about serious toxicities. Therefore, our institution has performed moderate-intensity SBRT. Patients and methods: Patients with UC tumors underwent SBRT at a dose of 50-60 Gy in 10 fractions, with Dmax in the target volume not exceeding 110% of the prescribed dose. The primary outcomes were tumor response and overall survival (OS). Results: From January 2017 to September 2018, we treated eight patients who had been diagnosed with UC tumors. The median follow-up time was 8.6 months (range: 2.7-14.9). Five of the eight patients (62.5%) showed a complete response (CR), two (25%) had a partial response (PR), and one (12.5%) had stable disease (SD); the response and disease control rates were 87.5% and 100%, respectively. Seven patients were alive with no evidence of disease or with controlled disease until the last follow-ups, except for one patient who died due to a non-RT cause at 3 months after SBRT. One patient experienced grade 2 esophageal pain and another had grade 1 cough. No grade 3 or higher toxicities were reported. Conclusion: Moderate-intensity SBRT might aid in achieving good control of UC tumors without excessive toxicities. Future studies involving larger numbers of patients and longer follow-up times are warranted to confirm the efficacy and feasibility.

Safety and Effectiveness of Stereotactic Ablative Radiotherapy for Ultra-Central Lung Lesions: A Systematic Review.

INTRODUCTION: The safety and effectiveness of stereotactic ablative radiotherapy (SABR) in patients with ultra-central lung tumors is currently unclear. We performed a systematic review to summarize existing data and identify trends in treatment-related toxicity and local control following SABR in patients with ultra-central lung lesions. METHODS: We performed a systematic review based on the Preferred Reporting Items for Systemic Reviews and Meta-Analyses guidelines using the PubMed and Embase databases. The databases were queried from dates of inception until September 27, 2018. Studies in the English language that reported treatment-related toxicity and local control outcomes post-SABR for patients with ultra-central lung lesions were included. Guidelines, reviews, non-peer reviewed correspondences, studies focused on re-irradiation, and studies with fewer than five patients were excluded. RESULTS: A total of 446 studies were identified, with 10 meeting all criteria for inclusion. The total sample size from the identified studies was 250 ultra-central lung patients and all studies were retrospective in design. Radiotherapy dose and fractionation ranged from 30 to 60 Gy in 3 to 12 fractions, with biologically effective doses (BED10) ranging from 48 to 138 Gy10 (median, 78-103 Gy10). Median treatment-related grade 3 or greater toxicity was 10% (range, 0-50%). Median treatment-related mortality was 5% (range, 0-22%), most commonly from pulmonary hemorrhage (55%). High-risk indicators for SABR-related mortality included gross endobronchial disease, maximum dose to the proximal bronchial tree greater than or equal to 180 Gy3 (BED3, corresponding to 45 Gy in 5 fractions or 55 Gy in 8 fractions), peri-SABR bevacizumab use, and antiplatelet/anticoagulant use. Median 1-year local control rate was 96% (range, 63%-100%) and 2-year local control rate was 92% (range, 57%-100%). CONCLUSIONS: SABR for ultra-central lung lesions appears feasible but there is a potential for severe toxicity in patients receiving high doses to the proximal bronchial tree, those with endobronchial disease, and those receiving bevacizumab or anticoagulants around the time of SABR. Prospective studies are required to establish the optimal doses, volumes, and normal tissue tolerances for SABR in this patient population.