Ultracentral Lung Tumors Research Articles

Exceeding Radiation Dose to Volume Parameters for the Proximal Airways with Stereotactic Body Radiation Therapy Is More Likely for Ultracentral Lung Tumors and Associated with Worse Outcome.

Simple SummaryThe optimal way to treat central (CLT) and ultracentral (UCLT) lung tumors with curative radiation is unclear. We evaluated 83 patients with CLT and UCLT who underwent a curative radiotherapy technique called stereotactic body radiation therapy (SBRT). On statistical analysis, patients with UCLT had worse overall survival. Using a cohort of patients matched for relevant variables such as gender and performance status, we evaluated radiation doses to critical central structures such as the airway and heart. In this group, patients with UCLT were more likely to exceed dose constraints as compared CLT, particularly constraints regarding the airway. Additionally, patients had worse non-cancer associated survival when radiation doses were higher than 18 Gy to 4cc’s of either the trachea or proximal bronchial tree. Based on these findings, patients with UCLT have worse outcomes which could be secondary to higher radiation doses to the trachea and proximal bronchial tree.The preferred radiotherapeutic approach for central (CLT) and ultracentral (UCLT) lung tumors is unclear. We assessed the toxicity and outcomes of patients with CLT and UCLT who underwent definitive five-fraction stereotactic body radiation therapy (SBRT). We reviewed the charts of patients with either CLT or UCLT managed with SBRT from June 2010–April 2019. CLT were defined as gross tumor volume (GTV) within 2 cm of either the proximal bronchial tree, trachea, mediastinum, aorta, or spinal cord. UCLT were defined as GTV abutting any of these structures. Propensity score matching was performed for gender, performance status, and history of prior lung cancer. Within this cohort of 83 patients, 43 (51.8%) patients had UCLT. The median patient age was 73.1 years with a median follow up of 29.9 months. The two most common dose fractionation schemes were 5000 cGy (44.6%) and 5500 cGy (42.2%) in five fractions. Multivariate analysis revealed UCLT to be associated with worse overall survival (OS) (HR = 1.9, p = 0.02) but not time to progression (TTP). Using propensity score match pairing, UCLT correlated with reduced non-cancer associated survival (p = 0.049) and OS (p = 0.03), but not TTP. Within the matched cohort, dosimetric study found exceeding a D4cc of 18 Gy to either the proximal bronchus (HR = 3.9, p = 0.007) or trachea (HR = 4.0, p = 0.02) was correlated with worse non-cancer associated survival. In patients undergoing five fraction SBRT, UCLT location was associated with worse non-cancer associated survival and OS, which could be secondary to excessive D4cc dose to the proximal airways.

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 (D mean) to the main bronchus (p = 0.003), where a D mean 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.

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.

Safety and Efficacy of Stereotactic Body Radiotherapy in Ultracentral Lung Tumors Using a Risk-optimized Fractionation Scheme

BackgroundDelivery of stereotactic body radiotherapy (SBRT) to ultracentral lung tumors remains a major challenge, with potentially excessive SBRT-related toxicity. This study investigates a risk-optimized approach to ultracentral SBRT in an elderly and comorbid patient cohort. Patients and MethodsAnalysis encompassed 129 patients (mean age: 70 ± 11 years, median Charlson comorbidity index: 4 [range, 3-5]) following risk-adapted SBRT to central or ultracentral primary and secondary lung tumors between 2012 and 2019 (78 central, 51 ultracentral). Ultracentral tumors were defined by planning target volume overlap with the proximal bronchial tree. Whereas ultracentral tumors were treated with a risk-optimized fractionation scheme of 50 Gy in 10 fractions, central tumors received higher-fractionated 60 Gy in 8 fractions. Outcome parameters and toxicity for ultracentral and central tumors were assessed using Kaplan-Meier and competing risk analyses. ResultsLocal failure rate was not significantly increased in ultracentral tumors compared with central tumors (2-year local failure rate ultracentral, 26.9%; 95% confidence interval [CI], 12.2%-44.2%; central, 14.6%; 95% CI, 6.6%-25.5%; P = .17). Overall survival was similar in both groups (2-year overall survival central, 55.4%; 95% CI, 44.5%-68.9%; ultracentral, 54.9%; 95% CI, 40.8%-73.9%; P = .6). Toxicity was moderate, with toxicity ≥ grade 3 rates of 15.3% (95% CI, 5.9%-28.9%) for ultracentral and 7.3% (95% CI, 2.7%-15.0%) for central tumors after 2 years (P = .27). No grade 4 toxicity and only 1 potential grade 5 toxicity were observed in the ultracentral cohort. ConclusionRisk-optimized SBRT to ultracentral lung tumors is a reasonably effective and safe treatment alternative in frail patients.

PO-1545: Dose-volume factors predicting esophageal after SBRT for ultra-central lung tumors

PO-1545: Dose-volume factors predicting esophageal after SBRT for ultra-central lung tumors

Progression of Pulmonary Function and Correlation with Survival Following Stereotactic Body Radiotherapy of Central and Ultracentral Lung Tumors.

Simple SummaryStereotactic body radiotherapy (SBRT) enables highly focused irradiation of lung tumors and has become a standard treatment. However, SBRT of lung tumors with close proximity to the central airways or mediastinum (central and ultracentral tumors) is associated with an increased risk for severe complications (bronchial bleeding, blockage of bronchi with loss of lung function). This retrospective study analyzed lung function and survival after risk-adapted approaches of SBRT in 107 central and ultracentral lung tumors. Lung function (vital capacity, forced expiratory volume in the first second) showed a statistically significant but in absolute numbers modest decrease that correlated moderately with the maximum radiation dose to the central airways. Stronger decrease in pulmonary function was found to be associated with limited survival. Consequently, lung function tests should be an integral element of follow-up after SBRT of lung tumors with proximity to the central airways or mediastinum.Stereotactic body radiotherapy (SBRT) to central and ultracentral lung tumors carries a risk of excessive toxicity. This study analyzed changes in pulmonary function tests (PFT) and their correlation with overall survival (OS) in 107 patients following central (n = 62) or ultracentral (n = 45) lung SBRT. Ultracentral location was defined as planning target volume overlap with the proximal bronchial tree (PBT). Vital capacity (VC) (−0.3 l, absolute −9.4% of predicted, both p < 0.001) and forced expiratory volume in the first second (FEV1s) (−0.2 l, absolute −7.7% of predicted, both p < 0.001) significantly decreased following SBRT. Higher maximum dose to the PBT significantly correlated with a steeper decline in VC (p = 0.005) and FEV1s (p = 0.03) over time. Pronounced decline in FEV1s between 6 and 12 months (HR = 0.90, p = 0.006) and pronounced decline in VC between baseline and 12 months (HR = 0.95, p = 0.004) independently correlated with worse OS. Consequently, PFT presented a statistically significant albeit clinically mild decrease in lung volumes following central and ultracentral SBRT that correlated moderately with maximum dose to the PBT. Stronger decline in pulmonary function was associated with constrained survival, advocating consequent performance of PFT during follow-up.

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

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. 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. 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. 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.

Analysis of pneumonitis and esophageal injury after stereotactic body radiation therapy for ultra-central lung tumors

ObjectivesSBRT has been associated with serious toxicity in ultra-central lung tumors, but little is known about the incidence and dosimetric correlates of pulmonary and esophageal complications in this setting. Materials and methodsWe retrospectively reviewed SBRT patients whose lung tumor abutted proximal airways, or whose planning target volume overlapped esophagus. All patients received 5–15 fractions of high-dose, image-guided radiation. The primary endpoint was SBRT-related toxicity, with local control and survival as secondary endpoints. ResultsWe included 88 patients. Nineteen patients (22 %) experienced grade ≥3 (G3+) toxicity, including 6 cases of G3+ radiation pneumonitis and 4 cases of G3+ esophageal injury. Two patients developed trachea-esophageal fistula. Overall incidence of radiation pneumonitis was 23 %. Ten patients (11.4 %) succumbed to SBRT-related complications. Multiple dosimetric parameters for lung (including mean lung dose and V20Gy) and esophagus (including maximum point dose) correlated with radiation pneumonitis and esophageal toxicity, respectively. No impact of fractionation on toxicity was seen. ConclusionThis analysis indicates that high rate and multiple manifestations of pulmonary and esophageal toxicity occur after SBRT for ultra-central tumors. In particular, severe radiation pneumonitis and tracheoesophageal fistula are possible. Dosimetric parameters such as mean lung dose and maximum esophageal dose are significantly correlated with toxicity. Further study is needed to optimize the safe delivery of SBRT in these patients.

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.

Outcomes of stereotactic body radiotherapy 60\u2009Gy in 8 fractions when prioritizing organs at risk for central and ultracentral lung tumors

BackgroundFor stereotactic body radiotherapy (SBRT) to central (C) and ultracentral (UC) lung tumors, our provincial practice has been to prioritize organs at risk (OARs) constraints by compromising target volume coverage if needed. The objectives are to report the treatment’s efficacy and safety.MethodsWe conducted a retrospective analysis of all provincial patients who underwent SBRT at 60Gy in 8 fractions to C and UC lung tumors, from 2013 to 2017.ResultsNinety-eight lesions were treated, 57 (58.2%) C and 41 (41.8%) UC. The median follow-up was 22.9 months (range 2.5–64.8 months). The 1- and 3-year local control (LC) was 97.8 and 84.5% respectively, with no differences between C and UC groups (p = 0.662). Fifty-three (54.1%) cases had optimal dose coverage (V60Gy ITV&PTV > 95%), 29 (29.6%) had compromised PTV coverage (V60Gy ITV > 95%/PTV < 95%), and 16 (16.3%) had both compromised ITV and PTV coverage (V60Gy ITV&PTV < 95%). No significant difference in LC was detected at 2 years between the 3 groups (95.6, 91.8 and 90.9%, p = 0.717). There were 3 episodes of grade 3 toxicity in the C group (2 dyspnea, 1 pneumonitis) and 2 in the UC group (1 dyspnea, 1 hemoptysis). There were no gr4/5 toxicities. On multivariable Cox regression analysis, ITV size was found to be a predictor for LC (p = 0.001).ConclusionsSBRT at 60Gy in 8 fractions achieves high rates of LC with low risks of significant toxicities, even if target volume coverage is reduced to meet OARs constraints.

P1.17-24 Treatment of Ultracentral Lung Tumors with Hypofractionated Radiation Therapy

The optimal dose schedule for ultracentral (UC) lung lesions remains poorly defined. The aim of this study is to report the efficacy and toxicity of hypofractionated radiation therapy (HFRT) in a single institution experience. An IRB approved retrospective review of patients with UC lung lesions treated with HFRT between 2008 and 2015 was performed. UC was defined as gross tumor volume (GTV) abutting the trachea, proximal bronchial tree (PBT), or esophagus. Both primary lung lesions and lung metastases were included. 4D simulation was typically employed, and respiratory management was utilized if appropriate (e.g. tumor motion exceeding 1 cm). Patient characteristics, treatment planning and delivery parameters, patient outcomes, and toxicity were collected. Toxicity was graded using CTCAE 4.03 and statistical analyses were performed using SPSS (Version 25). A total of 37 patients, 32 with primary lung tumors and 5 with metastases, were included. Primary lung tumors were stage T1, T2, T3, and T4, in 48%, 42%, 6% and 6% of patients, respectively. 39% had N1 disease and 16% were M1. Median age was 70 (range: 49-89) and 73% were male. The predominant histologies were adenocarcinoma (41%) and squamous cell carcinoma (43%). UC status was due to abutment of PBT in 78% of patients. 32% were treated with three dimensional conformal radiation therapy, and 68% with intensity modulated radiation therapy. 78% (29) of patients were treated in 20 fractions to 60 or 70 Gy, of which, 17 received concurrent weekly carboplatin and paclitaxel. A minority received regimens approximating stereotactic body radiotherapy (SBRT) dosing (60 Gy in 8 fractions in 10% and 50 Gy in 10 fractions in 6%). With a median follow up of 17 months, the crude local failure rate was 8%. Median overall survival was 33 months (range: 0-73 months). There were three grade 3 toxicities consisting of tracheal stenosis, hypoxia, and dysphagia, and no late grade 4/5 events. Notably, two patients receiving 60 and 70 Gy in 20 fractions died during the final week of treatment, after 51 and 60 Gy, respectively. One from sudden massive hemoptysis (hemoptysis to some extent dated back prior to HFRT), and one from complications of lung cancer, with additional details unclear. The GTV abutted/involved multiple critical structures in both cases, and attributability to treatment is uncertain. Local tumor control appears promising following treatment with HFRT for UC lung lesions. As with any regimen utilized in this anatomic location, caution is warranted. Additional prospective studies are required to further elucidate optimal dose and fractionation, and how it might compare with the therapeutic index of SBRT.

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

The safety and effectiveness of stereotactic ablative radiotherapy (SABR) for 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. We performed a systematic review using the PRISMA guidelines. The PubMed and Embase databases were queried from dates of inception until September 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. Ultra-central lung lesions were defined as lesion whose gross tumor volume (GTV) or planning target volume (PTV) abutted or invaded the proximal tracheo-bronchial tree (PBT) or other mediastinal structures such as the great vessels or esophagus. Guidelines, reviews, non-peer reviewed correspondences, studies focused on re-irradiation and studies with fewer than 5 patients were excluded. A total of 446 studies were identified, with 10 meeting all criteria for inclusion. A total of 250 patients with ultra-central lung lesions were included. All studies were retrospective in design. Radiotherapy dose and fractionation ranged from 30-60 Gy in 3-12 fractions, with median biologically-effective doses (BED10) ranging from 78-103 Gy10 in individual studies. Median treatment-related grade ≥3 toxicity was 10% (range: 0-50%). Median treatment-related mortality was 5% (range: 0-22%). The most common form of treatment-related mortality was pulmonary hemorrhage (55%). High-risk indicators for SABR-related mortality included gross endobronchial disease, maximum dose to the PBT ≥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%). SABR for ultra-central lung lesions appears feasible with good local control outcomes. There is a potential for severe toxicity in patients receiving high doses to the PBT, 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.

Dose-volume Factors Predicting Radiation Pneumonitis after SBRT for Ultra-central Lung Tumors

The safety of SBRT is uncertain for ultra-central tumors (near the proximal airways or esophagus). Predictors of toxicity in this population are urgently needed. We therefore studied dose-volume correlates of radiation pneumonitis after ultra-central SBRT. 88 patients with tumors abutting proximal bronchial tree (PBT) or PTVs overlapping esophagus (n = 76 and 23; 11 met both criteria) were included. 53 (60%) had primary/locally recurrent lung cancer, and 35 had lung metastases. All had 5, 8 or 15 fractions of image-guided radiotherapy with BED ≥84Gy (α/β=10). Primary endpoints were grade ≥2/3 radiation pneumonitis (RP2+/RP3+) using CTCAE 4.0. Dose-volume histograms (DVHs) using linear-quadratic equivalent doses in 2 Gy fractions (ED) were calculated for lung and heart (α/β= 3 Gy). Volumes of these organs exposed to equivalent doses (VEDX) were tested for correlation with RP2+/RP3+ using Cox proportional hazards models with ED values of 2.5 Gy, then from 5-70 Gy in 5 Gy steps. Age, gender, KPS, COPD, radiographic ILD, smoking, anti-VEGF agents, and GTV size were also tested and included in multivariate analysis with the most significant lung and heart DVH variables. Median follow up was 14.3 months. There were 24 (27%) and 9 (10%) cases of RP2+ and RP3+. Four patients (4.5%) died of RP. Univariately, significant correlations with RP2+ were seen for lung ED from 2.5-70 Gy (p < 0.002), with strongest correlations for ED from 10-20Gy(p < 10-5). One-year rates of RP2+ with Lung VED15< or > 14.7% (the median) were 13% and 46% respectively. Correlations with RP2+ were seen for heart ED from 2.5-50 Gy, with the strongest correlation for VED5(p=0.0001). Significant correlations with RP3+ were seen for lung ED from 2.5-35 Gy, with strongest correlations for VED10(p = 0.005). Correlations with RP3+ were also seen for heart ED from 2.5-15 Gy, with the strongest correlation for VED2.5(p=0.03). One-year rates of RP3+ with Lung VED10< or > 18% (the median) were 5% and 18% respectively. No clinical variables save ILD were significantly correlated with RP2+/RP3+ (p = 0.002 and 0.0001 respectively). Though ILD was statistically significant, only 2 patients in the cohort had ILD (both had RP3+, and one died of RP). The most significant lung and heart DVH variables were correlated with each other (p < 10-4). Multivariate models of RP2+ and RP3+ using Lung VED15and ILD were significant (p <10-5and p=0.02 respectively, for RP2+; p=0.02 and 0.001 respectively, for RP3+). We observed a high rate (27%) of RP after ultra-central SBRT, with a 4.5% rate of fatal RP. Lung dose-volume factors are highly correlated with RP. Presence of ILD warrants extreme caution. Our analysis suggests that RP3+ can be limited to 5% by keeping Lung VED10< 18%, and that RP2+ can be limited to 13% by keeping Lung VED15<14.7%.

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.

Stereotactic Ablative Radiotherapy for Central and Ultra-Central Lung Tumors.

Stereotactic ablative radiotherapy (SABR) has emerged as a standard-of-care treatment for patients with early stage non-small cell lung cancer (NSCLC) who are poor surgical candidates. Current evidence supports the consensus that lung SABR with BED ≥100 Gy leads to high local tumor control, and that the treatment is generally well-tolerated when applied to peripheral lung tumors. However, several studies present conflicting evidence for the treatment of central and ultra-central lung tumors, with some showing superb outcomes and others showing concerning rates of morbidity and mortality. Therefore, treatment of central and especially ultra-central lung tumors with SABR remains controversial. In this review, we aim to present the existing evidence for SABR treatment of central and ultra-central lung tumors and delineate the factors that could lead to significant toxicity.

Analysis of Toxic Effects With Antiangiogenic Agents Plus Stereotactic Body Radiation in Ultracentral Lung Tumors

This case series analyzes the association between antiangiogenic agents plus stereotactic body radiation for ultracentral lung tumors and toxic effects.

Tumor Control and Toxicity after SBRT for Ultracentral, Central, and Paramediastinal Lung Tumors

PurposeIncreased rates of toxicity have been described after stereotactic body radiation therapy (SBRT) for central lung tumors within 2 cm of the proximal bronchial tree (PBT). Recent studies have defined a new class of ultracentral tumors. We report our experience treating ultracentral, central, and paramediastinal tumors with SBRT and compare toxicity, disease control, and survival rates. Methods and materialsWe reviewed the records of patients with central lung tumors treated with SBRT between September 2009 and July 2017. Tumors were classified as central if within 2 cm of the PBT, ultracentral if the planning target volume touched the PBT or esophagus, and paramediastinal if touching mediastinal pleura. Actuarial rates of grades 2+ and 3+ toxicity, local control (LC), and overall survival were assessed using the Kaplan-Meier method and compared using a log-rank test. Toxicity was scored with the Common Terminology Criteria for Adverse Events, version 4.03. ResultsWe identified 68 patients with 69 central lung tumors, including 14 ultracentral, 15 paramediastinal, and 39 central tumors. Fifty-three patients were treated for early stage lung cancer and 15 for lung metastases. The prescribed dose ranged from 40 Gy to 60 Gy over 3 to 8 fractions. Most patients were treated using 5 fractions (83%), followed by 8 fractions (10%). Median follow-up was 19.7 months (range, 3.3-78.3 months). The 2-year estimates of LC (89%, 85%, and 93%, respectively; P = .72) and overall survival (76%, 73%, and 72%, respectively; P = .75) for ultracentral, central, and paramediastinal tumors were similar. Ultracentral tumors had an increased risk of grade 2+ toxicity (57.6% vs 14.2% vs 7.1%; P = .007) at 2 years. One patient with an ultracentral tumor developed grade 5 respiratory failure. ConclusionsThe oncologic outcomes after SBRT for ultracentral, central, and paramediastinal lung tumors were similar, with LC exceeding 85% at 2 years using predominantly 5-fraction schedules. Ultracentral lung tumors were associated with an increased risk of toxicity in our patient cohort. Additional studies are needed to minimize toxicity for ultracentral tumors.

Tumor Control and Toxicity Following SBRT for Ultracentral, Central and Paramediastinal Lung Tumors

Increased rates of toxicity have been described following stereotactic body radiotherapy (SBRT) for centrally located lung tumors within 2 cm of the central airways. Recent studies have defined a new class of “ultracentral” lung tumors directly abutting the proximal airways. We hypothesize that rates of toxicity for ultracentral tumors will exceed that of other central tumors. We report our institutional experience treating ultracentral, central, and paramediastinal lung tumors with SBRT and compare toxicity, disease control, and survival for each cohort. Following institutional review board approval, we retrospectively reviewed the records for all patients with centrally located lung tumors treated with SBRT between September 2009 and July 2017 at our institution. Tumors were classified as central if located within 2 cm of the proximal bronchial tree (PBT), ultracentral if the planning target volume (PTV) touched or overlapped the PBT or esophagus, and paramediastinal if touching the mediastinal pleura but not meeting criteria as central. Actuarial rates of grade 2+ and 3+toxicity, in-field local tumor control (LC), and overall survival (OS) were assessed using the Kaplan-Meier method and compared using a log-rank test. Toxicity was scored using CTCAE V4.03. We identified 68 patients with 69 centrally located lung tumors, including 14 ultracentral, 15 paramediastinal, and 39 central tumors. 53 patients were treated for early stage NSCLC and 15 patients for limited metastases involving the lungs. The median prescription dose was 50 Gy (range: 40-60 Gy) over 5 fractions (range: 3-8) and was similar between cohorts. Median follow up for living patients was 19.7 months (range: 3.3-78.3). Two-year estimates of LC (89%, 85%, and 93%; p=0.72) and OS (76%, 73%, and 72%; p=0.75) for ultracentral, central, and paramediastinal tumors, respectively, were similar between cohorts. Ultracentral tumors were at higher risk of developing grade 2+ toxicity (57.6% vs. 14.2% vs. 7.1%, p= 0.007) at 2 years compared to central and paramediastinal patients. We recorded 2 cases of grade 3 post-obstructive pneumonia in one central and one ultracentral case, and one grade 5 respiratory failure in an ultracentral case. Mean maximum PBT doses were higher for ultracentral cases (55.9 Gy) as compared to central (28.9 Gy) and paramediastinal (12.5 Gy) cases (p <0.001). Oncologic outcomes following SBRT for ultracentral, central, and paramediastinal lung tumors were similar, with LC exceeding 85% at 2 years using a predominantly 5-fraction regimen. Ultracentral lung tumors were associated with increased risk of toxicity in our patient cohort. Additional studies are needed to minimize SBRT toxicity for ultracentral tumors.

Modeling Patient-specific Risk Factors for Central Lung Tumor SBRT Planning

Although lung SBRT has shown impressive outcomes in peripheral, inoperable, early-stage lung tumors, the use of similar dose schedules in central and ultra-central lung tumors has been associated with higher rates of severe and even fatal toxicities in multiple studies. In current clinical practice, physicians rely on aggregated, population-based dose constraints and fractionation schemas, modified on a case-by-case basis according to institutional or individual experience, and most commonly, the constraints from the recently reported RTOG 0813, based on expert opinion. However, there is a critical need for a data-driven framework that enables physicians to make objective choices in treatment planning and fractionation to optimize patient outcomes in terms of local control and treatment-related toxicities. In this study, we develop a mathematical model to balance these tradeoffs for predicting outcomes with morbidity. Retrospective data from 58 consecutive central lung SBRT patients (46.5% females and 53.5% males) with median age of 70 years (range 48-94), median number of fractions of 5 (range 3-8), median dose per fraction of 10 Gy (range 7.5-20), and median tumor size of 2.0 cm (range 0.8-5.0), treated from 2009 to 2013, were analyzed in a multi-institutional study. At a median follow up of 36 months, 5%, 22% and 19% of patients experienced local failure (LF), nodal failure (NF), distant metastases (DM), respectively, and 29% died within 2 years from SBRT. Also, 3%, 9%, and 9% experienced rib fracture (RF), chest wall syndrome (CWS) and pneumonitis, respectively. Using multivariate logistic regression, predictive patient-specific outcome risk models were created and analyzed where 57 patients were used for training and 1 for validating in 58 iterations. Predictor variables included age, sex, diabetes, Eastern cooperative oncology group performance status (ECOG PS), smoking status, COPD, prior lung cancer (treated by either surgery, chemo or radiation), radiation dose and fractionation (as equivalent 4-fx dose) and tumor size. In addition, we performed survival and time-to-event analysis. Our model’s correct prediction rate for LF, NF, DM, dying within 2 years, RF, CWS and pneumonitis was 100%, 76%, 79%, 79%, 97%, 93%, and 93%, respectively. In addition to tumor size, dose, and history of prior lung cancers, increasing age, lower ECOG PS and diabetes were significant predictors of LF (P < 0.05). NF and RF were highly correlated with pneumonitis (P = 0.04), and CWS was highly correlated with the advent of DM (P = 0.01). The 4-year Kaplan-Meier outcomes were DM: 33.1% ± 8.9%, NF: 26.4% ± 6.3%, and LF: 9.6% ± 4.6%. Overall survival was reduced by a factor of 2.3 for females (P<0.05), and, a factor of 6.1 for patients with COPD (P<0.05). We generated a mathematical model toward a standardized adjustment of radiotherapy planning for an improved therapeutic ratio using patient-specific risk factors for central lung SBRT.

Late Toxicity and Long-Term Local Control in Patients with Ultra-Central Lung Tumors Treated by IMRT Based -Stereotactic Ablative Body Radiation Therapy (SABR)

Late Toxicity and Long-Term Local Control in Patients with Ultra-Central Lung Tumors Treated by IMRT Based -Stereotactic Ablative Body Radiation Therapy (SABR)