Ultracentral Tumors Research Articles

Toxicity in patients receiving radiotherapy for ultracentral stage I non-small cell lung cancer: A secondary analysis of the LUSTRE randomized trial

Background and PurposeStereotactic body radiotherapy (SBRT) carries potentially higher risks for ultracentral (UC) NSCLC with limited prospective data to guide decision making. We conducted a secondary analysis from a randomized trial of SBRT and conventionally hypofractionated radiation (CRT) to assess these risks. Materials and MethodsPatients (n = 233) with medically inoperable stage I NSCLC were recruited from 2014 to 2020. Patients with UC targets directly overlapping the proximal bronchial tree (PBT) were identified. The primary objective was the occurrence of related grade 3–5 toxicity > 3 months following radiation. Secondary endpoints included local control, survival, and evaluation of PBT dose and its association with late toxicity. ResultsThirty UC tumors were identified (23 − SBRT 60 Gy/8 fractions, 7 − CRT 60 Gy/15 fractions). Median age was 72 years, and median tumor size was 2.8 cm. Most patients (67 %) had histologically confirmed NSCLC. At a median follow-up of 2.9 years, 3 and 1 patients developed grade 3 and 5 toxicity respectively (all SBRT). 3-year local control was 85 %. Mean PBT dose (converted to 2 Gy dose equivalents) was higher in patients with grade ≥ 3 toxicity, particularly for 4 cc (105.5 vs 51.8 Gy, p = 0.0004), 5 cc (84 vs 46.1 Gy, p = 0.003), and volumetric doses (V65 – V100Gy). The patient with grade 5 toxicity had the highest 5 cc dose (117 Gy), V90Gy (8.2 cc), and V100Gy (7 cc). ConclusionsSBRT for UC NSCLC provides good local control but carries a high rate of late grade 3–5 toxicity. An apparent association between toxicity and PBT volumetric dose was observed, which should be considered if SBRT is offered.

Stereotactic body radiotherapy in ultracentrally located lung tumors

Stereotactic body radiotherapy (SBRT) is a highly conformal radiotherapy technique that delivers high doses of radiation per fraction, typically in 1 – 5 fractions. It is a standard treatment option for patients with early-stage non-small cell lung cancer that is peripherally located, for those who are medically inoperable, or for patients who do not opt for surgery. Similarly, SBRT is considered an effective treatment option for oligometastatic lung tumors. However, in the case of ultracentrally located lung tumors—tumors situated close to the central airway and mediastinal region—there is an increased risk of severe toxicities (grade 4 – 5) due to the dose tolerances of the surrounding organs at risk. The definition of ultracentrally located lung tumors remains unclear. Some studies define an ultracentral lung tumor as one in which the gross tumor volume directly involves the proximal bronchial tree or trachea, while others define it as the planning target volume (PTV) that includes the trachea or main bronchial system. In addition, some studies consider tumors whose PTV touches or overlaps with the central bronchial tree, esophagus, pulmonary vein, or pulmonary artery as ultracentral. In addition, the optimal SBRT regime and organ-at-risk dose limitations for ultracentral tumors have yet to be clearly established. The aim of this review is to explore and discuss the role of SBRT in the treatment of ultracentrally located lung tumors.

Stereotactic Radiation for Ultra-Central Non-Small Cell Lung Cancer: A Safety and Efficacy Trial (SUNSET)

The use of stereotactic body radiotherapy (SBRT) for tumors in close proximity to the central mediastinal structures has been associated with a high risk of toxicity. This study (BLINDED FOR REVIEW) aimed to determine the maximally tolerated dose (MTD) of SBRT for ultra-central (UC) non-small cell lung carcinoma (NSCLC), using a time-to-event continual reassessment methodology (TITE-CRM). Patients with T1-3N0M0 (≤ 6 cm) NSCLC were eligible. The MTD was defined as the dose of radiotherapy associated with a ≤ 30% rate of grade (G) 3-5 pre-specified treatment-related toxicity occurring within 2 years of treatment. The starting dose level was 60 Gy in 8 daily fractions. The dose-maximum hotspot was limited to 120% and within the planning tumor volume (PTV); tumors with endobronchial invasion were excluded. This primary analysis occurred two years after completion of accrual. Between March 2018 and April 2021, 30 patients were enrolled at 5 institutions. The median age was 73 years (range: 65-87) and 17 (57%) were female. PTV was abutting proximal bronchial tree in 19 (63%), esophagus 5 (17%), pulmonary vein 1 (3.3%) and pulmonary artery 14 (47%). All patients received 60 Gy in 8 fractions. The median follow-up was 37 months (range: 8.9-51). Two patients (6.7%) experienced G3-5 adverse events related to treatment: 1 patient with G3 dyspnea and 1 G5 pneumonia; the latter had CT findings consistent with a background of interstitial lung disease. Three-year overall survival was 72.5% (95% confidence interval [CI]: 52.3-85.3%), progression-free survival 66.1% (95% CI: 46.1-80.2%), local control 89.6% (95% CI: 71.2-96.5%), regional control 96.4% (95% CI: 77.2-99.5%) and distant control 85.9% (95% CI: 66.7-94.5%). Quality of life scores declined numerically over time, but the decreases were not clinically or statistically significant. 60 Gy in 8 fractions, planned and delivered with only a moderate hotspot, has a favorable adverse event rate within the pre-specified acceptability criteria, and results in excellent control for UC tumors.

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.

Ultra-Central Tumors Treated with Stereotactic Body Radiotherapy: Clinical Outcome and Prognostic Factors

Stereotactic body radiotherapy (SBRT) reported excellent outcomes and a good tolerability profile in case of central lung tumors. High grade toxicity was more frequently observed in ultra-central (UC) tumors. We aim to identify prognostic factors associated with survival for UC tumors treated with SBRT. We retrospectively evaluated patients treated between 2006 and 2020 with risk-adaptive SBRT for primary or oligometastatic (≤5) UC lung tumors. Ultra-central tumors were defined as tumors whose planning target volume (PTV) touches or overlaps the trachea, mainstem-, intermediate-, upper-, middle- or lower- lobe bronchus or the esophagus. SBRT schedules ranged from 45 to 60 Gy in 5 to 7 fractions. A total number of 126 UC lung tumors were reviewed. Table 1 summarizes the patient, treatment and tumor characteristics. Median follow-up time was 23 months. Median OS was 29.3 months (95% CI 22.4-36.21). The 1-, 2- and 5- year OS rates were 75%, 58% and 23%, respectively. PFS and LC rates at 1 ,2 and 5 years rates were 63%, 41% and 15% (median 16 months, 95% CI 8.9-23.1) and 86%, 78% and 61%, respectively. Female gender (HR, 0.61 95% CI, 0.4-0.9, p 0.027) were significantly associated with better OS (Figure 1) and age ≥ 70 years (HR 1.91, 95% CI 1.2-3.0, p 0.005) and tumor ≥ 5 cm (HR 1.64, 95% CI 1.1-2.5, p 0.028) correlated with worse OS (Figure 1) at univariate analysis. A borderline detrimental association (p 0.07) between OS and tumor-trachea distance > 5 mm was also found. In the multivariate analysis female gender (HR 0.6 95% 0.4-1.0, p 0.05), age ≥ 70 years (HR 1.9 95% CI 1.2-3.0, p 0.006) and tumor-trachea distance > 5 mm (HR 2.2 95% CI 1.2-4.2, p 0.015) resulted as independent factors significantly associated with OS. The patients treated for primary tumors showed a significantly better PFS at Kaplan-Meier analysis (p < 0.001). The median PFS was 26.2 months (95% CI 0.5-52.0) and 12.4 months (95% CI 7.3-17.5) for group of primary tumors and oligometastases, respectively. Kaplan-Meier curves showed a positive trend for tumor < 5 cm and PFS (p 0.068). Moreover, in the subset of patients with primary lung cancer, tumor < 5 cm was correlated with a significantly better PFS (p 0.004). 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 the patients, consisting of pain and dyspnea in 4 and 1 patients, respectively. Risk-adaptive SBRT for UC tumors is safe and effective even if it remains a high-risk clinical scenario. Patients with larger tumor, elderly and male patients treated for UC lung tumors report a worse OS and should carefully evaluated for treatment eligibility.

Dose-Escalated vs. Conventional Hypofractionated Radiotherapy for Lung Cancer Patients in Predominantly Central Locations

Hypofractionated radiation therapy (HFRT) is an increasingly utilized treatment option for patients with lung cancers unamenable to stereotactic body radiotherapy (SBRT). Conventional HFRT (C-HFRT) is often prescribed to 60 Gy in 15 fractions, which has a lower biologically effective dose (BED10 of 84.0) than SBRT. We compared outcomes of patients treated with a dose-escalated HFRT regimen (DE-HFRT, 72 Gy in 18 fractions, BED10 of 100.8) to those treated with C-HFRT. We aimed to evaluate local control (LC), overall survival (OS), and grade 3+ toxicity between patients who received C-HFRT vs. DE-HFRT as we hypothesized DE-HFRT may be superior/equivalent to C-HFRT. A database was created of all patients at our institution who received either thoracic C-HFRT or DE-HFRT between 2013 and 2020. Baseline variables were compared by chi-square analysis and logistic regression. We analyzed the association between treatment regimens with LC and OS (log-rank test and Cox proportional hazards regression), as well as grade 3+ toxicity. A total of 107 patients were included, among whom 55 (51.4%) received C-HFRT and 52 (48.6%) received DE-HFRT. Median age was 73, 88.8% of patients had non-small cell lung cancer, 81.3% received lung-only treatment, and 52.3% had an ultra-central tumor location (within 1 cm of proximal tracheobronchial tree, esophagus, or heart). Patients with DE-HFRT were more likely to have lung-only treatment (92.3% vs. 70.9%, p = 0.005) and stage I disease (47.1% vs 24.1%, p = 0.01) than those with C-HFRT, but had a similar proportion of ultra-central tumors (57.1% vs. 54.9%, p = 0.82). Patients with DE-HFRT had a non-statistically significant trend towards higher LC (2-year 81.0% vs. 72.3%, 3-year 77.3% vs 52.3%, HR 0.53 [95% CI 0.26-1.09], p = 0.09) and OS (2-year 61.3% vs. 44.8%, 3-year 44.9% vs 33.9%, HR 0.68 [95% CI 0.41-1.11], p = 0.13) compared to those with C-HFRT. Similar findings were noted among those with lung-only treatment. Among those with ultra-central tumors, patients with DE-HFRT had statistically significantly higher LC (2-year 86.6% vs 71.2%, 3-year 86.6% vs 42.2%, HR 0.26 [95% CI 0.08-0.84] p = 0.02) and a non-statistically significant trend towards higher OS (2-year 63.8% vs 40.0%, 3-year 46.2% vs 31.1% HR 0.55 [95% CI 0.28-1.09] p = 0.09) compared to those with C-HFRT. There was no statistically significant difference in grade 3+ toxicities between DE-HFRT and C-HFRT (15.4% vs. 10.9%, OR 1.48 [95% CI 0.47-4.61], p = 0.49). We noted promising local control and overall survival for patients treated with 72 Gy in 18 fractions compared to 60 Gy in 15 fractions, especially among those with ultra-central tumors. Grade 3+ toxicities were not significantly higher for patients undergoing dose escalation. Hence, our findings suggest that DE-HFRT to the lung is a safe and effective treatment regimen for highly selected patients who cannot undergo SBRT.

Sinoatrial Node Irradiation in Patients Undergoing Definitive Stereotactic Body Radiation Therapy (SBRT) for Central Lung Cancers

The clinical consequences of sinoatrial node (SAN) and atrioventricular node (AVN) irradiation in patients undergoing thoracic stereotactic body radiation therapy (SBRT) remains unclear. We examined the relationship between SAN and AVN dose with survival outcomes in patients with central non-small cell lung cancer (NSCLC) tumors. A single-institutional retrospective review of patients with primary NSCLC undergoing definitive SBRT for centrally located tumors from February 2007 to December 2021 was performed. Central tumors were defined as within 2 cm of the proximal airway, mediastinum, great vessels, or spinal cord whereas ultracentral tumors were directly abutting any of the above structures. All patients underwent five-fraction SBRT to a total dose of 50 to 60 Gy. The SAN and AVN were contoured in accordance with a published contouring atlas and the maximum dose (Dmax) and mean dose (Dmean) for each structure were calculated. Sequential log rank testing between the 50th and 90th percentiles was used to identify potential cutoff values for the corresponding dosimetric parameters and non-cancer associated survival. Among 93 eligible patients, the median age was 72.5 years (Inter-Quartile Range [IQR], 66.6-78.3), median follow up was 32.4 months (IQR, 13.0-49.6), and 48 patients were female (52%). There were 49 ultracentral tumors (53%) and the median planning target volume (PTV) was 31.0 cc (IQR, 18.0-53.3). The median SAN Dmax and Dmean were 95 cGy (IQR, 37-1,072) and 58 cGy (IQR, 26-641), respectively. The median AVN Dmax and Dmean were 45 cGy (IQR, 19-506) and 34 cGy (IQR, 15-160), respectively. Candidate cutoff values for SAN Dmax and Dmean were 1,309 cGy and 814 cGy, respectively. No significant cutoff values were identified for either AVN parameter. Kaplan-Meier analysis for the proposed SAN Dmean constraint was significantly associated with overall (p = 0.016) and non-cancer associated survival (p = 0.028). The SAN Dmax constraint was significantly associated with only overall survival (p = 0.029). In a multivariate model, the SAN Dmean cutoff significantly correlated with both overall (Hazard Ratio [HR] 2.1 [1.13-3.78], p = 0.019) and non-cancer associated survival (HR 2.39 [1.12-5.10], p = 0.025) whereas the SAN Dmax cutoff was only significantly associated with overall survival (HR 1.95 [1.03-3.68], p = 0.041). SAN Dmax and Dmean were associated with significantly worse overall survival using cut-off values of 1,309 cGy and 814 cGy, respectively. SAN dose should be considered in radiation planning and further study on the consequence of SAN irradiation during SBRT is warranted.

Hyperfractionated Reirradiation for Locally Recurrent Thoracic Tumors

For patients with locally recurrent thoracic tumors or second primaries within previously irradiated volumes, hyperfractionated reirradiation (re-RT) may mitigate late toxicity compared to conventional fractionation, but clinical outcomes have not been extensively studied. We herein report our institutional experience with thoracic hyperfractionated reirradiation. We identified 26 cases among 23 patients treated with re-RT to either primary or metastatic thoracic tumors, 60 Gy in 50 fractions, twice daily over 5 weeks using highly conformal image guided RT with motion management. Nineteen patients had dosimetry data available. The primary outcome was Grade (G2) or higher toxicity rates per CTCAEv5.0. Secondary endpoints were 12-month local control (LC), progression free survival (PFS)-determined by treating physician and/or multidisciplinary tumor board-and overall survival (OS). Median follow-up was 13 months. Half had non-small cell lung cancer, 95.8% had ultracentral tumors, 57.7% had single prior thoracic RT course; 38.5%, 11.5% and 11.5% received concurrent chemotherapy, immunotherapy, and targeted agents, respectively. Minimum and median intervals between RT courses were 10 and 39.5 months, respectively; 94.7% of re-irradiation plans had overlapping 80% isodose volumes. Median OS and PFS were 13 and 10 months, respectively. Crude 12-month LC was 73.1%. Of those with a recurrence, the first recurrence occurred locally in 6 (54.6%), regionally in 3 (27.3%), and distantly in 8 (72.7%) patients. ≥G2 and ≥G3 toxicity rates were 30.8% and 7.69%, respectively (one G3 atrial fibrillation; one G5 pneumonitis). Using the American Radium Society guidelines for thoracic reirradiation, only 10.5% met all dose volume constraint recommendations. Definitive hyperfractionated thoracic re-RT was well tolerated with promising local control. ≥G3 toxicities were rare. Patients should be counseled on the low but potential risk of life-threatening toxicity. Consensus guidelines for dose constraints may be difficult to meet in reirradiation setting; in this cohort, rates of severe toxicity were low despite exceeding putative constraints in most patients.

Long-Term Toxicity in Patients Receiving Radiotherapy for Ultracentral Stage I Non-Small Cell Lung Cancer – A Secondary Analysis of the LUSTRE Randomized Trial

Hypofractionated and stereotactic body radiotherapy (SBRT) are increasingly used in the treatment of centrally located, early-stage non-small cell lung cancer (NSCLC), though there are concerns of increased morbidity and mortality in patients with ultracentral tumors (UC). We report on the long-term toxicity of patients with UC lung cancer treated on a prospective randomized clinical trial of SBRT versus conventionally hypofractionated radiotherapy (CRT) for stage I NSCLC (NCT01968941). Patients with UC tumors, defined as those where the planning target volume directly overlaps with the proximal bronchial tree (PBT), were identified from the larger cohort of patients treated on the trial. These patients received either SBRT with 60 Gy in 8 fractions or CRT with 60 Gy in 15 fractions. The primary endpoint of this secondary analysis was development of any grade 3 or higher toxicity defined using CTCAE version 3.0. Secondary endpoints included local control, as well as dosimetric analysis of the PBT, using EQD2 with α/β ratio of 3 to assess the relationship between dose to the PBT and toxicity. Twenty-nine patients were identified with UC tumors; 21 received SBRT and 8 received CRT. Median age was 72 years (range 55-88 years) and 59% were female. Median FEV1 was 1.46L (range 0.64-2.37L). Patients had either T1 (59%) or T2 (41%) lesions, with median tumor size 2.5cm (range 1.1-4.9cm). Most patients had histologically confirmed disease (squamous cell, n = 10; adenocarcinoma, n = 8; radiographically suspicious, n = 11). The median follow-up was 2.9 years (range 0.7-5.2 years). The 3-year local control rate of all patients was 88.3% (95% confidence interval: 75.7-100%). There were 3 patients with late (>3 months) grade 3 toxicity (bronchial stricture, chest pain, and atelectasis) and 1 patient with late grade 5 toxicity (bleeding/hemorrhage), all treated in the SBRT arm. Median EQD2 dose to PBT in patients with grade ≥3 late toxicity compared to the rest of the cohort was: Dmax, 132 vs 129 Gy; D0.1cc, 129 vs 119 Gy; D1cc, 124 vs 80 Gy; and D5cc, 83 vs 41 Gy. Median EQD2 volumetric doses in grade ≥3 patients (compared to the rest) to PBT were: V65 Gy, 9.7 vs 2.2cc; V80 Gy, 7.9 vs 1.1cc; V90 Gy, 6.2 vs 0.4cc; and V100 Gy, 4.8 vs 0.3cc. The single patient with grade 5 toxicity had the highest D5cc (116 Gy) and V100 Gy (7cc) among all patients. Stereotactic radiation with 60 Gy in 8 fractions for UC lung cancer provides good local control but carries an approximately 15-20% rate of late grade ≥3 toxicity. There appears to be a dosimetric association between toxicity and dose to the PBT. It may be more important to minimize volumetric PBT dose rather than maximum point dose to reduce risk of severe late toxicity.

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

BackgroundStereotactic 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). MethodsWe 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. Results602 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. ConclusionSBRT 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.

PO-1329 Survival and prognostic factors of ultra-central tumors treated with stereotactic body radiotherapy

PO-1329 Survival and prognostic factors of ultra-central tumors treated with stereotactic body radiotherapy

Pulmonary Hemorrhage in Patients Treated With Thoracic Stereotactic Ablative Radiotherapy and Antiangiogenic Agents

IntroductionSevere pulmonary hemorrhage can occur in patients treated with thoracic stereotactic ablative radiotherapy (SABR) and vascular endothelial growth factor inhibitors (VEGFis). There is limited understanding of which patients are at risk for toxicity with the combination of thoracic SABR and VEGFis or how the risk differs over either therapy alone. MethodsWe evaluated a prospectively maintained cohort of 690 patients with 818 pulmonary tumors treated with highly conformal SABR. Rates of any-grade and grade 3 plus (G3+) pulmonary hemorrhage were compared between patients treated with or without VEGFi therapy across tumor locations. Outcomes were compared between patients treated with SABR plus VEGFi and a propensity-matched cohort of those treated with VEGFi therapy alone. ResultsTreatment with VEGFi plus SABR was associated with higher rates of G3+ pulmonary hemorrhage compared with those treated with SABR alone for the overall cohort (3-y incidence: 7.9% versus 0.6%, p < 0.01) and those with central tumors (19.1% versus 3.3%, p = 0.04). When further subdivided, there were significantly higher toxicity rates with VEGFi for the ultracentral (9.0% versus 45.0%, p = 0.044), but not central nonabutting tumors (0.0% versus 1.3%, p = 0.69). There was an increased incidence of G3+ hemorrhage in patients treated with VEGFi plus SABR compared with VEGFi alone (9.6% versus 1.3%, p = 0.04). ConclusionsThe combination of VEGFi and SABR was associated with an increased risk of high-grade pulmonary hemorrhage over either therapy alone. Low rates of toxicity were observed when excluding patients with SABR to ultracentral tumors and applying highly conformal SABR techniques.

Magnetic Resonance-Guided Stereotactic Body Radiation Therapy/Hypofractionated Radiation therapy for Metastatic and Primary Central and Ultracentral Lung Lesions

IntroductionThe recent results from the Nordic-HILUS study indicate stereotactic body radiation therapy (SBRT) is associated with high-grade toxicity for ultracentral (UC) tumors. We hypothesized that magnetic resonance-guided SBRT (MRgSBRT) or hypofractionated radiation therapy (MRgHRT) enables the safe delivery of high-dose radiation to central and UC lung lesions. MethodsPatients with UC or central lesions were treated with MRgSBRT/MRgHRT with real-time gating or adaptation. Central lesions were defined as per the Radiation Therapy Oncology Group and UC as per the HILUS study definitions: (1) group A or tumors less than 1 cm from the trachea and/or mainstem bronchi; or (2) group B or tumors less than 1 cm from the lobar bronchi. The Kaplan-Meier estimate and log-rank test were used to estimate survival. Associations between toxicities and other patient factors were tested using the Mann-Whitney U test and Fisher’s exact test. ResultsA total of 47 patients were included with a median follow-up of 22.9 months (95% confidence interval: 16.4–29.4). Most (53%) had metastatic disease. All patients had central lesions and 55.3% (n = 26) had UC group A. The median distance from the proximal bronchial tree was 6.0 mm (range: 0.0–19.0 mm). The median biologically equivalent dose (α/β = 10) was 105 Gy (range: 75–151.2). The most common radiation schedule was 60 Gy in eight fractions (40.4%). Most (55%) had previous systemic therapy, 32% had immunotherapy and 23.4% had previous thoracic radiation therapy. There were 16 patients who underwent daily adaptation. The 1-year overall survival was 82% (median = not reached), local control 87% (median = not reached), and progression-free survival 54% (median = 15.1 mo, 95% confidence interval: 5.1–25.1). Acute toxicity included grade 1 (26%) and grade 2 (21%) with only two patients experiencing grade 3 (4.3%) in the long term. No grade 4 or 5 toxicities were seen. ConclusionsPrevious studies noted high rates of toxicity after SBRT to central and UC lung lesions, with reports of grade 5 toxicities. In our cohort, the use of MRgSBRT/MRgHRT with high biologically effective doses was well tolerated, with two grade 3 toxicities and no grade 4/5.

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.

External validation of pulmonary radiotherapy toxicity models for ultracentral lung tumors

IntroductionPulmonary toxicity is dose-limiting in stereotactic body radiation therapy (SBRT) for tumors that abut the proximal bronchial tree (PBT), esophagus, or other mediastinal structures. In this work we explored published models of pulmonary toxicity following SBRT for such ultracentral tumors in an independent cohort of patients. MethodsThe PubMed database was searched for pulmonary toxicity models. Identified models were tested in a cohort of patients with ultracentral lung tumors treated between 2008 and 2017 at one large center (N = 88). This cohort included 60 % primary and 40 % metastatic tumors treated to 45 Gy in 5 fractions (fx), 50 Gy in 5 fx, 60 Gy in 8 fx, or 60 Gy in 15 fx prescribed as 100 % dose to PTV. ResultsSeven published NTCP models from two studies were identified. The NTCP models utilized PBT max point dose (Dmax), D0.2 cm3, V65, V100, and V130. Within the independent cohort, the ≥ grade 3 toxicity and grade 5 toxicity rates were 18 % and 7–10 %, respectively, and the Dmax models best described pulmonary toxicity. The Dmax to 0.1 cm3 model was better calibrated and had increased steepness compared to the Dmax model. A re-planning study minimizing PBT 0.1 cm3 to below 122 Gy in EQD23 (for a 10 % ≥grade 3 pulmonary toxicity) was demonstrated to be completely feasible in 4/6 patients, and dose to PBT 0.1 cm3 was considerably lowered in all six patients. ConclusionsPulmonary toxicity models were identified from two studies and explored within an independent ultracentral lung tumor cohort. A modified Dmax to 0.1 cm3 PBT model displayed the best performance. This model could be utilized as a starting point for rationally constructed airways constraints in ultracentral patients treated with SBRT or hypofractionation.

Advances in stereotactic body radiation therapy for early stage non-small cell lung cancer

: Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related mortality in the United States, but as lung cancer screening expands to include younger patients with shorter smoking histories, an increasing number of cases are detected at early, more treatable stages. Stereotactic body radiation therapy (SBRT) has emerged as an effective, non-invasive treatment option for patients with medically inoperable NSCLC. Over the past decade, several retrospective and prospective studies have shown SBRT to achieve superior local control and overall survival compared to conventionally fractionated radiation therapy (CFRT). Advances in tumor targeting and radiation delivery have reduced treatment times while delivering higher doses of radiation to the tumor. SBRT is generally well-tolerated and the risk of grade 3 or greater toxicity is low with dose constraints in place to monitor and limit radiation delivered to surrounding normal tissues. Approaches to dose and fractionation vary depending on the tumor location relative to critical mediastinal structures, as toxicity profiles differ greatly among peripheral, central, and ultra-central tumors. While surgery remains the standard of care for operable patients and tumors, clinical trials are ongoing to compare SBRT with lobar and sub-lobar resection. Further studies combining SBRT with anti-PD-L1 and anti-PD-1 immunotherapy agents and radiosensitizing agents are in progress.

Patterns of Care and Outcomes in Non-Operative, Early-Stage Non-Small Cell Lung Cancer when Stereotactic Body Radiation Therapy is not Feasible

<h3>Purpose/Objective(s)</h3> Stereotactic body radiation therapy (SBRT) is the standard of care treatment for non-operative patients with early-stage non-small cell lung cancer (NSCLC). However, there are cases where safe delivery of SBRT is precluded (e.g., ultracentral tumors or those abutting brachial plexus/stomach) or where SBRT is not available (e.g., centers without SBRT capability). The optimal management with regards to radiation dose/fractionation and whether sensitizing chemotherapy should be considered is unclear. <h3>Materials/Methods</h3> We identified node-negative NSCLC patients with tumors <3 cm (cT1 N0) who received definitive RT in the National Cancer Data Base from 2004-2016. Patients receiving SBRT (defined as 48-60 Gy in £5 fractions or BED₁₀≥100 Gy) were excluded. The use of chemotherapy (none vs. sequential vs. concurrent) and RT type was examined (conventionally fractionated, [CFRT], defined as 59.4-70.2 Gy in 30-39 fractions; and hypofractionated RT [HFRT] defined as 50-72 Gy in >5 fractions using >2 Gy/fraction). Factors associated with receipt of chemotherapy were analyzed via univariable (UV) and multivariable (MV) logistic regression. Overall survival (OS) was evaluated with Kaplan-Meier analyses and log-rank test as well as UV and MV Cox proportional hazards. Propensity score matching was also performed for comparison of OS between groups. P-values less than 0.05 were considered significant. <h3>Results</h3> A total of 2,851 patients were included with 69% receiving CFRT and 31% receiving HFRT. Nearly 26% of patients received chemotherapy, delivered either concurrently (21%) or sequentially (5%). On MV analysis, receipt of chemotherapy was associated with younger age (<70 years, p<0.001), larger tumor size (2+ cm, p<0.001), BED₁₀<80 Gy (p<0.001) and receipt of CFRT (p<0.001). OS was significantly improved for patients receiving concurrent chemotherapy with CFRT compared to patients receiving CFRT alone (p<0.001) and HFRT alone (p=0.003), which remained significant after propensity score matching. On MV analysis, improved OS remained associated with concurrent chemotherapy (p<0.001), as was younger age (<70 years, p=0.024), female gender (p<0.001), fewer comorbidities (Charlson-Deyo score <2, p<0.001), private insurance (p<0.001), treatment at an academic center (p=0.026), smaller tumor size (<2 cm, p<0.001), and non-squamous histology (p=0.004). <h3>Conclusion</h3> Patterns of care for non-operative early-stage NSCLC patients when SBRT is not feasible vary greatly. A surprising proportion of patients (21%) receive concurrent chemotherapy. Interestingly, concurrent chemotherapy with CFRT was associated with improved OS compared to HFRT or CFRT alone, however this finding requires additional validation given the inherent biases of our study.

Dosimetric Impact of Deformable Image Registration-Based Target Volume Propagation in Stereotactic Body Radiotherapy of Ultracentral Lung Tumors

In stereotactic body radiotherapy (SBRT) of non-small cell lung cancer (NSCLC), the use of steep dose gradients and reduced margins has improved local control while limiting toxicity. Clinical benefit of these techniques is dependent on accurate target definition. NSCLC patients are vulnerable to errors in target definition because lung tumors deform with respiratory motion. For ultracentral lung tumors, phantom studies suggest that auto-propagation of internal gross tumor volumes (IGTVs) can be inaccurate. In SBRT of ultracentral tumors, deformable image registration (DIR) is widely used for target volume propagation. We hypothesized that errors in DIR-based IGTV propagation could jeopardize SBRT target coverage for ultracentral tumors despite use of population-based safety margins.Nine patients with ultracentral NSCLC tumors appropriate for SBRT were studied. For each patient, (1) 4D CT was acquired into 10 discrete phase-based bins; (2) the GTV was manually segmented on all phases; and (3) DIR-based IGTV propagation was carried out for each manual GTV on every phase, resulting in 10 propagated IGTVs (P-IGTVs) per patient and 90 for the entire cohort. Ground truth IGTV (GT-IGTV) was defined as the union of all manual GTVs from all 10 phases. Dice coefficient was used to measure the similarity of P-IGTV relative to GT-IGTV. For each patient, SBRT plans were generated for P-IGTVs with greatest (Plan A) and least (Plan B) Dice coefficients using a PTV margin of 5 mm. Prescriptions were 60 Gy in 8 fractions with V60 Gy > 95% PTV. Dose constraints for organs-at-risk (OARs) were defined according to published prospective trials. For each patient, dosimetric differences between Plans A and B for the ground truth PTV (GT-IGTV + 5 mm margin) and OARs were examined.All tumors (6 in the right lung, 3 in the left) were within 2 cm of the proximal bronchial tree and at hilar level. Table 1 compares IGTVs and target coverage with median and range values. Plans A and B differed significantly in ground truth PTV (GT-PTV) coverage at both 99% and 95% of Rx dose (Kruskal-Wallis tests; P = 0.003). There were no significant differences between plans for dose to OARs. For Plan A, 7 out 9 plans were generated from GTVs at near-end of inhalation (respiratory phases 8 or 9); for Plan B, 7/9 plans were generated from GTVs at end of inhalation through mid-exhalation (phases 0 through 3).In SBRT of ultracentral tumors, patterns of error exist in DIR-based IGTV propagation that can compromise target coverage despite the use of population-based safety margins. These findings are important to enhance efforts for more robust and accurate targeting in lung SBRT.

External Validation of Pulmonary Toxicity Risk Model for Ultracentral Lung Tumors

Pulmonary toxicity attributed to the proximal bronchial tree (PBT) is dose-limiting in stereotactic body radiation therapy (SBRT) for central lung tumors. The toxicity is of particular concern in ultracentral lesions, which are defined as the gross tumor volume abutting the PBT, esophagus, or other mediastinal structures. In this work we tested published pulmonary toxicity models associated with dose to the airway structures after SBRT for ultracentral tumors in an independent institutional cohort of patients.The PubMed database was scrutinized for toxicity models evaluating pulmonary and airway toxicity for SBRT or hypofractionated radiation treatment for central tumors in the lung. The following search term criteria were used: (central) AND (lung tumor) AND (normal tissue complication probability) AND (radiation). Identified models were explored in all patients with ultracentral lung tumors treated between 2008 and 2017 at one large center (N = 88). This cohort included 60% primary lung and 40% metastatic patients that had been treated to 45 Gy in 5 fractions (fx), 50 Gy in 5 fx, 60 Gy in 8 fx, or 60 Gy in 15 fx. 16% of the patients received anti-VEGF therapy, which as previously shown, was associated with higher incidence of grade 5 hemorrhage.A total of six NTCP models were identified from work by Tekatli et al 2018. Of these, three models were for ≥grade 3 and three for grade 5 toxicity and included bronchial max dose, V60, V100, and V130. Clinical pulmonary toxicity consisted of radiation pneumonitis, atelectasis due to main stem bronchus occlusion, and/or hemoptysis. The pulmonary toxicity rate was 15% and 8% for ≥grade 3 toxicity and grade 5 toxicity, respectively, in the original study. Within the independent cohort, the corresponding values were 18% and 10%. Two maximum dose models were shown to be valid in our institutional dataset; other models failed this validation test. The model was made more robust by expanding the max dose region of the bronchial volume by focusing on the max dose to 0.1 cm3, 1 cm3 and 3 cm3. The max dose (0.1 cm3) model had improved performance with increased steepness. Generally, models from literature underestimated our institutional complication rates.Pulmonary toxicity models for central tumors were identified from one study and explored within an independent cohort. The models derived from primarily central lung tumors systematically underestimated the pulmonary toxicity rate in the solely ultracentral tumor cohort, possibly also due to anti-VEGF therapy used in the independent cohort. A modified model from the best-performing max dose model was designed, and this model could be utilized for rationally constructed airways constraints in ultracentral patients treated with SBRT or hypofractionation.I. Chen: None. M. Thor: None. A.J. Wu: Research Grant; CivaTech Oncology, Inc. Honoraria; 1199SEIU. Consultant; AstraZeneca, MORE Health. Advisory Board; Simphotek, Inc. Travel Expenses; AlphaTau Medical. Stock; Simphotek, Inc. A. Iyer: None. A. Apte: None. A. Rimner: Research Grant; Varian Medical Systems, Boehringer Ingelheim, Astra Zeneca, Pfizer, Merck. Consultant; MoreHealth. Advisory Board; Boehringer Ingelheim, Astra Zeneca, Merck; International Thymic Malignancies Interest Group, International Mesothelioma Interest Group. D.R. Gomez: Research Grant; Merck, AstraZeneca. Honoraria; BMS, Varian, Research to Practice. Speaker's Bureau; Merck. Advisory Board; AstraZeneca, Olympus. J.O. Deasy: Research Grant; Varian Corp., NIH, Breast Cancer Research Foundation. Stock; Paige.AI; AAPM.A. Jackson: None.

Analysis of Toxicity and Local Control for Ultra-Central Lung Tumors Undergoing Stereotactic Body Radiation Therapy

High toxicity rates have been reported for ultra-central lung tumors undergoing stereotactic body radiation therapy (SBRT). We retrospectively analyze a cohort of patients undergoing five fraction SBRT at our institution for ultra-central tumors defined as GTV abutting the proximal bronchial tree (PBT), aorta or esophagus.All patients treated with SBRT during 2012 to 2018 at a single institution were reviewed to identify ultra-central lesions undergoing 5 fraction SBRT. Cases were identified as GTV abutting PBT, esophagus or aorta. Patients who received at least 800 cGy per fraction were included. The primary endpoint was grade 3+ adverse events attributable to SBRT, based on CTCAE 4.0. Secondary endpoints were local control (LC) and overall survival (OS). Kaplan-Meier analysis was used to estimate LC and OS.A total of 30 patients were identified (Age 39-92), 26 with GTV abutting the PBT, 2 with GTV abutting aorta and 2 with GTV abutting esophagus. Median follow up time was 12.5 months (1 - 58 months). Five fraction doses were 50 Gy (53%), 45 Gy (26.7), 42.5 Gy (10%) and 40 Gy (10%). Tumor size ranged from 0.6 to 4.9cm. Only 1 grade 5 (3.3%) Hemoptysis toxicity was reported 1 year after SBRT and 4 Grade 3+ toxicities (13.3%), including 2 radiation pneumonitis, 1 pleural effusion and 1 large cavitary lesion with 2/4 receiving 50 Gy. LC was 75.5% at 1 year, and 56.8% at 2 years. With BED > 100, 1 year LC was 92.3% and 2 year LC was 82.1%. OS was 89.1% at 1 year, 85.4% at 2 years and 65.7% at 3 years.SBRT achieves high rates of local control at 2 years in our cohort undergoing 5 fraction SBRT with BED > 100 for ultra-central lesions with acceptable grade 3 toxicities, and potential small risk of grade 5 toxicity. Five fraction SBRT remains an acceptable option for ultra-central lesions.