Rates Of Radiation Pneumonitis Research Articles

Association of Artificial Intelligence-Screened Interstitial Lung Disease with Radiation Pneumonitis and Mortality in Locally Advanced Non-Small Cell Lung Cancer

Radiation pneumonitis (RP) is a common and dose-limiting toxicity following radiotherapy for non-small cell lung cancer (NSCLC). Patients with interstitial lung disease (ILD) are believed to be at increased risk of developing complications including RP, ILD progression, or death. An automated method to identify patients prior to radiotherapy at high risk of developing toxicities or death may allow clinicians to mitigate risk through informed treatment planning and careful patient monitoring. All locally advanced NSCLC patients treated with definitive radiation from 2006-2021 with a minimum 1 year of follow-up were assessed. RP and mortality data were prospectively collected and retrospectively reviewed. A convolutional neural network (CNN) was previously developed and validated to identify patients with radiographic ILD using planning computed tomography (CT) images, with an accuracy of 0.82. Planning CT scans for the retrospective cohort were used as input to the CNN, with artificial intelligence-screened ILD (AI-ILD) score as an output. AI-ILD scores above our established threshold were labeled as AI-ILD+. The association between AI-ILD score, AI-ILD+/-, mean lung dose (MLD), and the primary outcome of grade ≥2 (G2+) RP or mortality, as well as the secondary outcomes of G2+ RP and mortality were assessed using Wilcoxon rank sum test, univariate and multivariable logistic regression, and Kaplan-Meier survival analysis. Of 799 patients reviewed, 745 eligible patients were included in the analysis; grade 0-5 RP was reported in 51.3%, 27.1%, 16.9%, 4.0%, 0.1%, and 0.5% of patients respectively. Overall, 22.9% of patients were AI-ILD+, and therefore at high risk (>20% chance) of having true ILD. On UVA, AI-ILD score, AI-ILD+ and MLD were significantly associated with the primary outcome of G2+ RP or mortality, as well as the secondary outcome of mortality. However, only MLD was significantly associated with the secondary outcome of G2+ RP. On MVA, both AI-ILD+ (OR 1.42, 95% CI 1.02-1.97, p = 0.04) and MLD (OR 1.13, 95% 1.05-1.21, p = 0.008) were significantly associated with G2+ RP or mortality. On Kaplan-Meier analysis, the median toxicity-free survival (TFS) time for AI-ILD+ and AI-ILD- patients were 1.7 and 3.4 years respectively, with a 2-year TFS of 48.3% vs. 59.3% (log-rank test: p = 0.02). There was no significant difference in rates of G2+ RP. The AI-ILD algorithm can detect high risk patients with significantly decreased TFS following definitive treatment for NSCLC. AI-ILD classification was not associated with a significant difference in rates of RP when accounting for MLD. Future work will focus on improving the classification algorithm, expert radiologist validation of this dataset, and exploring reasons for the mortality difference in AI-ILD+ patients.

Planning Considerations for the Primary Lung Tumor Stereotactic Body Radiation Therapy Followed by Concurrent Mediastinal Radiotherapy for Locally-Advanced Non-Small Cell Lung Cancer

Phase III prospective randomized trial of primary lung tumor stereotactic body radiation therapy followed by concurrent mediastinal chemoradiation for locally-advanced non-small cell lung cancer (NRG LU-008), designed to lower the rates of radiation pneumonitis and improve the progression-free survival, is expected to become active nationally in July 2023. Due to the specific nature of the cases selected for this trial, a new approach to treatment planning had to be developed to satisfy the conditions of the trial. Levice Cancer Institute (Atrium Health, North Carolina) ran the initial Phase II trial and investigated several approaches, providing recommendations for the future dosimetry planning approach. A total of 60 patients were selected for the initial trial and treated with a combination of SBRT treatment to the primary tumor (50-54 Gy in 3-5 fractions) and conventional IMRT treatment to 60 Gy to the involved lymph nodes for patients with stage 3 or unresectable stage II NSCLC, combined with chemotherapy. Depending on the location of the primary tumor, all cases could be subdivided into no overlap between the SBRT and IMRT targets, adjacent targets, and overlapping targets. All SBRT plans were done with a 6X-FFF beam, advanced dose calculation algorithm, and 0.1 cm grid size. IMRT targets were primarily treated with VMAT plans, though a minority of cases were planned with the DMLC technique, with a 6X beam, advanced dose calculation algorithm, and 0.25 cm grid size. Various approaches to the planning included target cropping, avoidance via adjusting optimization objectives and utilizing the base dose of the SBRT plan to optimize the dose for the IMRT nodal plan. Various geometries utilized in the plan included a variation in the number of arcs, covered arc angles, and the number of beams. A significant reduction in the side effects was achieved throughout the trial, with only three patients experiencing grade 3 or higher pneumonitis, 3 patients experiencing grade 3 or higher cardiotoxicity, and 1 patient experiencing grade 3 esophagitis. For targets with no significant overlap between the primary tumor and nodal target, standard planning techniques proved to be sufficient. For the overlapping targets, the planning approach of utilizing 2 arcs, >180-degree coverage, for the SBRT plan, and using ¼ of the base SBRT dose to plan the IMRT nodal plan provided the best target coverage while achieving sufficient OAR sparing. Planning the joint SBRT-IMRT plan in the cases of a significant target overlap requires a careful approach, but is feasible with the proposed guideline and should be achievable for any center electing to participate in the NRG LU-008 trial.

Risk of Radiation Pneumonitis in Patients Receiving Osimertinib and Thoracic Radiotherapy

Risk of Radiation Pneumonitis in Patients Receiving Osimertinib and Thoracic Radiotherapy

Comprehensive Pneumonitis Profile of Thoracic Radiotherapy Followed by Immune Checkpoint Inhibitor and Risk Factors for Radiation Recall Pneumonitis in Lung Cancer.

PurposeWhilst survival benefits of thoracic radiotherapy (TRT) followed by immune checkpoint inhibitor (ICI) have been reported in patients with lung cancer, the potential high risk of treatment-related pneumonitis remains a concern. Asians may be more sensitive to lung toxicity than other races. This retrospective study intended to provide a comprehensive pneumonitis profile of TRT followed by ICI and investigate the risk factors from a Chinese cohort of lung cancer.Methods and MaterialsFrom January 2016 to July 2021, 196 patients with lung cancer who received TRT prior to ICI were retrospectively analyzed. Treatment-related pneumonitis, including checkpoint inhibitor pneumonitis (CIP), radiation pneumonitis (RP), and radiation recall pneumonitis (RRP), were recorded and graded through medical records and chest computed tomography. Characteristics predictive of pneumonitis were assessed using logistic regression models, and the receiver operating characteristic analyses were performed to identify optimal cut points for quantitative variables.ResultsWith a median follow-up of 18 months, a total of 108 patients (55.1%) developed treatment-related pneumonitis during ICI therapy, with an incidence of 25.5% for grade 2 or higher (G2+) and 4.1% for G3+. The overall rates of CIP, RP and RRP were 8.2% (n=16), 46.9% (n=92) and 7.1% (n=14), respectively. With a total mortality rate of 1.5%, vast majority of the patients recovered from pneumonitis or remained stable. No patients died of RRP. Half of the patients with G2+ RP who withheld ICI therapy restarted ICI safely after resolution of RP. The history of chronic pulmonary diseases (P=0.05), mean lung dose (MLD, P=0.038), percent volume of lung receiving ≥5 Gy (V5, P=0.012) and percent volume of lung receiving ≥20 Gy (V20, P=0.030) predicted the occurrence of RRP in univariate analyses. Interval between TRT and ICI less than 3 months was an independent predictor for G2+ treatment-related pneumonitis in a multivariate model (Odds ratio OR=2.787, P=0.004).ConclusionsTreatment-related pneumonitis, especially RRP, is acceptable and manageable in the setting of TRT followed by ICI in this Asian population. Dosimetric parameters MLD, V5 and V20 may improve the predictions of RRP in clinical practice.

Angiotensin-Converting Enzyme Inhibitors or Angiotensin Receptor Blocker use During Stereotactic Body Radiation Therapy Associated with Decreased Pneumonitis: A Multi-center Analysis

Radiation pneumonitis (RP) is a serious adverse effect associated with lung radiation therapy (RT). The use of angiotensin-converting enzyme inhibitors (ACEI) is associated with a lower risk of RP in the setting of conventional lung RT. However, whether ACEI use during stereotactic body radiation therapy (SBRT) has protective properties against RP is unknown. Similarly, the effect of angiotensin receptor blockers (ARB) use on the incidence of RP is not known. The purpose of this study is to examine the impact of ACEI and ARB use during lung SBRT treatment on the development of RP. Under an Institutional Review Board-approved protocol, the records of 252 consecutive patients from 2009 – 2015 at 4 related academic institutions with lung cancer treated with SBRT were reviewed. Presence of RP was determined using all available records, including follow-up data from radiation oncology, pulmonology, medical oncology, and hospitalizations, and graded using the Common Terminology Criteria for Adverse Events Version 4.0. Univariate and multivariate analysis was performed to identify factors associated with clinical outcomes. Kaplan-Meier methods were used to determine OS. A total of 208 patients were used for the analysis with a median follow-up time of 23 months. Median age was 71 years old. Median tumor size was 2.1cm, and 63% of the tumors were peripheral in location. 68% of the tumors were T1, 48% were T2, 7% were T3, and 2% were T4, 8% were node positive. 77 patients (37%) received either ACEI (26%) or ARB (11%) therapy during SBRT. 25 patients developed grade 1 pneumonitis (12%), 20 patients developed grade 2 pneumonitis (10%), 14 patients developed grade 3 pneumonitis (7%), 5 patients developed grade 4 pneumonitis (2%), and 2 patients developed grade 5 pneumonitis (1%). In total 32% of patients developed pneumonitis of any grade. Significantly fewer patients developed any grade of RP if ACEI or ARB were taken during SBRT compared to those who did not - 16.6% vs. 38.4% at 1 year, and 25.6% vs. 39.6% at 2 years (p<=0.005). ACEI or ARB use was associated with higher 5-year overall survival rates, 44.5% vs. 28.5% (HR 0.60, p=0.042). On subset univariate analysis in patients receiving either 3, 4 or 5 fraction SBRT, 5 fraction SBRT was associated with higher rates of any grade RP compared to those treated with 3 or 4 fraction SBRT (HR 2.15, p=0.029). On subset multivariable analysis ACEI/ARB use was significant for lower rates of any grade RP (HR 0.41, p=0.003), and; 5 fraction SBRT and age >65 years were associated with higher rates of any grade RP (HR 2.5, p=0.01, HR 1.92, p=0.049 respectively). ACEI or ARB use during SBRT was associated with significantly greater freedom from any grade RP, and higher likelihood of 5-year survival. ACEI or ARB use during SBRT should be prospectively evaluated.

Stereotactic Body Radiation Therapy to Multiple Sites of Intrathoracic Disease: A Multi-Institutional Analysis

There are limited data regarding the safety of stereotactic body radiotherapy (SBRT) to multiple sites of intrathoracic disease. We sought to assess rates of radiation pneumonitis (RP) and outcomes for patients treated with SBRT to multiple intrathoracic tumors. Thirty-eight patients with 84 synchronous (within 3 months) or metachronous lung nodules were treated with a total of 72 courses of SBRT between 2009 and 2017 at three tertiary hospitals. Clinical and dosimetric data were collected. Rates of RP (graded per CTCAE v4.0) and Kaplan-Meier estimates of oncological outcomes were calculated. Thirty-one patients were treated to 2 sites of disease, while six patients were treated to 3 sites, and one patient was treated to 4 sites. Nine patients received SBRT to two lesions simultaneously with one plan, while 13 and 9 patients received SBRT to synchronous or metachronous lesions, respectively. The median time interval between SBRT courses was 28.5 days (IQR: 18.5-43 days) for synchronous lesions and 14.7 months (IQR: 8.5-24.8) for metachronous lesions. Fifty-six (66.7%) of the treated lesions were primary lung cancers, while 28 (33.3%) were metastatic nodules (included for RP endpoint only). The most common fractionation scheme was 50 Gy in 5 fractions. Seventy-nine (94.0%) nodules received a biological effective dose of at least 100Gy. The median treated nodule size was 1.8 cm (IQR: 1.2-2.7). Median follow-up from the first SBRT course was 29.0 months. Grade 2 RP was diagnosed in 2 patients (5.2%) following the first SBRT course and 1 patient (2.6%) following the second SBRT course. Grade 3 RP was diagnosed in 2 patients following the second SBRT course (5.2%). Neither the number of treated sites nor the number of SBRT courses was associated with development of RP (P=0.48 and P=0.15, respectively) or grade of radiation pneumonitis (P=0.64 and P=0.16, respectively). Eighteen patients with a median age of 74 years (IQR: 67-80) received at least 2 courses of SBRT to a total of 40 primary Stage IA-IIB non-small cell lung cancers (NSCLC). At a median of 22.8 months (IQR: 14.0-40.9), the in-site recurrence rate was 5.6% (N=1), the ipsilateral lung recurrence rate was 27.8% (N=5), and the distant recurrence rate was 38.9% (N=7). The Kaplan-Meier estimate for 3-year freedom from in-site recurrence was 91.7% (95% CI: 77.3-100.0), 3-year freedom from locoregional recurrence was 63.1% (95% CI: 39.0-100.0), and 3-year overall survival was 62.5% (95% CI: 40.7-95.9). In this series of patients, more than one course of SBRT to synchronous or metachronous intrathoracic tumors was not associated with higher rates of RP. Excellent locoregional control was achieved among patients treated for early stage NSCLC. While larger studies are required, receipt of previous SBRT should not necessarily preclude consideration of further SBRT.

Clarithromycin mitigates radiation pneumonitis in patients with lung cancer treated with stereotactic body radiotherapy.

Radiation pneumonitis is a critical pulmonary toxicity after irradiation of the lung. Macrolides including clarithromycin (CAM) are antibiotics. They also have immunomodulatory properties and are used to treat respiratory inflammatory diseases. Radiation pneumonitis has similar pathology to them. Adverse reactions to macrolides are few and self-limited. We thus administered CAM to patients with high-risk factors for radiation pneumonitis, and retrospectively investigated whether CAM mitigated radiation pneumonitis following stereotactic body radiotherapy (SBRT). Among consecutive patients treated with SBRT, we retrospectively examined lung cancer patients treated with a total dose of 40-60 Gy in 5-10 fractions and followed ≥6 months. Since January 2014, CAM has been administered in patients with pretreatment predictable radiation pneumonitis high-risk factors, including idiopathic interstitial pneumonias (IIPs), and elevated Krebs von den Lungen-6 (KL-6) and/or surfactant protein D (SP-D), and in patients developing early onset radiation pneumonitis. Five hundred and eighty eligible patients were identified and divided into 445 patients during the non-CAM-administration era (non-CAM-era) (before December 2013) and 136 patients during the CAM-administration era (CAM-era) (after January 2014). Median follow-up durations were 38.0 and 13.9 months, respectively. The rates of radiation pneumonitis ≥ grade 2 and ≥ grade 3 were significantly lower in CAM-era (grade ≥2, 16% vs. 9.6%, P=0.047; grade ≥3, 3.8% vs. 0.73%, P=0.037). For patients with the pretreatment predictable high-risk factors, the rate of radiation pneumonitis ≥ grade 3 was significantly lower, and that of grade ≥2 had a lower tendency (grade ≥3, 7.2% vs. 0%, P=0.011; grade ≥2, 21% vs. 9.6%, P=0.061). For patients developing early onset radiation pneumonitis, the rate of radiation pneumonitis ≥ grade 3 was also significantly lower (23% vs. 0%, P<0.05). Multivariate analysis revealed that dose-volumetric factor, the pretreatment predictable high-risk factors and non-CAM-administration era were significantly associated with or trended toward radiation pneumonitis ≥ grade 2 and ≥ grade 3. CAM mitigated radiation pneumonitis following SBRT. The efficacy of CAM should be confirmed in prospective studies.

Predictive factors of symptomatic radiation pneumonitis in primary and metastatic lung tumors treated with stereotactic ablative body radiotherapy.

PurposeAlthough stereotactic ablative body radiotherapy (SABR) is widely used therapeutic technique, predictive factors of radiation pneumonitis (RP) after SABR remain undefined. We aimed to investigate the predictive factors affecting RP in patients with primary or metastatic lung tumors who received SABR.Materials and MethodsFrom 2012 to 2015, we reviewed 59 patients with 72 primary or metastatic lung tumors treated with SABR, and performed analyses of clinical and dosimetric variables related to symptomatic RP. SABR was delivered as 45–60 Gy in 3–4 fractions, which were over 100 Gy in BED when the α/β value was assumed to be 10. Tumor volume and other various dose volume factors were analyzed using median value as a cutoff value. RP was graded per the Common Terminology Criteria for Adverse Events v4.03.ResultsAt the median follow-up period of 11 months, symptomatic RP was observed in 13 lesions (12 patients, 18.1%), including grade 2 RP in 11 lesions and grade 3 in 2 lesions. Patients with planning target volume (PTV) of ≤14.35 mL had significantly lower rates of symptomatic RP when compared to others (8.6% vs. 27%; p = 0.048). Rates of symptomatic RP in patients with internal gross tumor volume (iGTV) >4.21 mL were higher than with ≤4.21 mL (29.7% vs. 6.1%; p = 0.017).conclusionsThe incidence of symptomatic RP following treatment with SABR was acceptable with grade 2 RP being observed in most patients. iGTV over 4.21 mL and PTV of over 14.35 mL were significant predictive factors related to symptomatic RP.

SU‐F‐BRB‐13: Correlation of Improved Target and Organ‐At‐Risk Dosimetric Quantities and Clinical Outcomes for Helical Tomotherapy Treated Mesothelioma

Purpose:We have observed improved local control probability (LCP) for adjuvant mesothelioma radiotherapy following pleurectomy/decortication using Tomotherapy compared to the conventional 3D technique (p&lt;0.05). This work assesses the correlation between the improved clinical outcomes against dosimetry quantities.Methods:Thirty‐eight mesothelioma cases consecutively treated at our clinic were retrospectively analyzed. Sixteen patients were treated using 3D technique planned on the Eclipse for c‐arm accelerators prior to 7/2012; the other 22 cases were treated on Tomotherapy using helical IMRT after 7/2012. Typical 3D plans consisting of 15 MV AP/PA photon fields prescribed to 10 cm depth followed by matching electron fields with energy ranging from 8–16 MeV. Tomotherapy plans were designed using 2.5cm jaw, 0.287 pitch with directional blocking of the contralateral lung. The same prescription of 45 Gy (1.8GyX25) was used for both techniques. The dosimetry metrics for the critical structures: ipsilateral‐/contralateral‐lung, heart, cord, esophagus, etc were compared between two techniques.Results:Superior LCP is closely associated with improved target coverage. Tomotherapy plans yielded dramatically better target coverage and less dose heterogeneity despite of more advanced/larger disease. The averaged PTV volumes were 2287.3±569.9 (Tomotherapy) vs. 1904.8±312.3cc (3D); V100s were: 91.1±4.0 (%) vs. 47.8±12.7 (%) with heterogeneity indices of 1.20±0.1 vs.1.37±0.38 and for the Tomotherapy and 3D plans, respectively. Compared to the 3D technique, we observed significant lower maximum cord doses (p&lt;0.001), lower mean esophagus doses (p&lt;0.002), and lower heart mean doses when tumor was left‐sided (p=0.002). For ipsilateral‐/contralateral‐lungs, however, the mean doses and V20, V5 of Tomotherapy plans were significantly higher than the 3D plans (p&lt;0.01) regardless which sides of lung were treated. However, rates of radiation pneumonitis were no different.Conclusion:Tomotherapy achieved great improvement of plan quality including target coverage, resulting in significantly better local control over the traditional 3D technique for adjuvant radiotherapy for mesothelioma.

Risk of Pneumonitis After Stereotactic Body Radiation Therapy in Patients With Previous Anatomic Lung Resection

BackgroundStereotactic body radiation therapy (SBRT) has emerged as a standard treatment of early-stage, medically inoperable lung cancer. Limited data have evaluated the radiation pneumonitis (RP) risk with SBRT after previous anatomic lung resection (ALR). We assessed the incidence of RP and all pulmonary toxicity (PT) in patients who underwent lung SBRT after ALR and compared them with those of patients without previous ALR. Materials and MethodsWe reviewed the medical records of 84 consecutively treated patients with stage T1-T2b non–small-cell lung cancer (NSCLC) treated with 88 courses of SBRT for 94 lung tumors from January 2007 to December 2014, including 17 patients with previous ALR. The rates of RP and all PT were compared between the patients with and without previous ALR. ResultsAt a median follow-up duration of 18.3 months (range, 1.8-85.6 months), the crude grade 2+ RP rate was 5.9% and 2.8% for patients with and without previous ALR, respectively (P = .51). The corresponding 2-year estimates of freedom from RP were 89% and 97% (P = .51). The crude rate of all grade 2+ PT was 11.8% and 2.8% for those with and without previous ALR (P = .11), with 2-year estimates of freedom from PT of 97% and 84% (P = .11), respectively. The 2 cohorts were well matched by the mean lung dose, percentage of lung volume receiving 20 Gy (P = .86), and prescribed dose (P = .75). The 2-year estimates of local control, cause-specific survival, and overall survival were similar between the 2 cohorts. ConclusionThe observed rates of PT were low among all patients, with a trend toward increased grade 2 and 3 lung toxicity among patients with previous ALR. Previous ALR did not increase the risk of grade 4 and 5 RP, and SBRT appears safe and effective in this population.

Abstract 864: Increased rates of radiation pneumonitis in patients receiving stereotactic ablative radiotherapy for central versus peripheral lung tumors

Abstract Purpose: Treatment of central lung tumors with stereotactic ablative radiotherapy (SABR) has been associated with higher rates of toxicities than patients with peripheral tumors. Here we report our institution's experience in treating central lung tumor patients with SABR, compared to patients treated for peripheral lung tumors. Methods: We retrospectively reviewed outcomes in 82 patients with a total of 96 primary or metastatic lung tumors treated by SABR. The cohort included 47 central and 49 peripheral tumors and all were treated with 50 Gy in 4-5 fractions. Outcomes and radiation-associated toxicities were compared between the two groups, not including patients in whom central and peripheral tumors were concurrently treated (8 such patients). Dosimetric analysis was performed on patients with central tumors to determine max point dose (MPD) and volumetric max dose (Vmax) to central structures. Results: Median follow-up time was 15 months (range 1 to 59 months). Median overall survival was 34 and 40 months (p=0.75) for patients with central and peripheral tumors, respectively. We observed no hemoptysis and no grade 5 toxicities. Rates of symptomatic toxicity were higher in patients with central tumors (grade 2+, 38% vs. 11%, p=0.0056) but were equivalent for severe toxicity (grade 3+, 5.4% vs. 5.4%, p=0.93). The vast majority of toxicities were due to radiation pneumonitis, incidence of which was significantly greater in patients with central tumors (grade 2+, 30% vs. 2.7%, p=0.0021; grade 3+, 5.4% vs. 0%, p=0.15). Dosimetric analysis of 36 central tumor treatment plans revealed that 23 (64%) exceeded at least one of the dose constraints used in RTOG 0813, most commonly for central airway. Rates of grade 2+ pneumonitis were not significantly different between patients exceeding RTOG 0813 central airway dosing constraints vs. those meeting them (24% vs. 20%, p=0.69), but trended towards significance for grade 3+ radiation pneumonitis, with patients exceeding RTOG 0813 central airway dosing constraints experiencing higher rates (0% vs. 13%, p=0.095). Conclusions: Central lung tumor patients treated with SABR appear to have greater risk for symptomatic radiation pneumonitis than patients with peripheral tumors. Exceeding RTOG 0813 dosimetric constraints for central airway may predispose to higher risk for severe radiation pneumonitis. Citation Format: Aadel A. Chaudhuri, Chad Tang, Nicholas Trakul, Jacob Wynne, Billy Loo, Maximilian Diehn. Increased rates of radiation pneumonitis in patients receiving stereotactic ablative radiotherapy for central versus peripheral lung tumors. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 864. doi:10.1158/1538-7445.AM2014-864

Risk of Pneumonitis After Stereotactic Body Radiation Therapy for Non-Small Cell Lung Cancer in Patients With Prior Anatomic Resection

Purpose/Objective(s): Stereotactic body radiation therapy (SBRT) has emerged as a standard treatment option for early stage, medically inoperable non-small cell lung cancer (NSCLC). Dosimetric factors including lung volume receiving 20 Gy (V20) >10%and mean lung dose (MLD) >4 Gy are established risk factors for radiation pneumonitis (RP) following SBRT, but limited data evaluate the relative risk of RP in patients undergoing SBRT following prior anatomic lung resection (ALR). This study assessed the incidence of RP and all grade 2+ pulmonary toxicity in patients treated with SBRT for NSCLC following ALR and compare toxicity rates to patients without prior ALR. Materials/Methods: The medical records of 83 consecutive patients with T1-T3 NSCLC treated with 87 courses of SBRT for 93 lung tumors (16 central, 77 peripheral) between January 2007 and September 2013 were reviewed. Sixteen patients with a history of prior ALR were identified, including lobectomy (n Z 12), bilobectomy (nZ 1), and pneumonectomy (n Z 3), with 67 patients without history of prior ALD. The most commonly used fractionation regimen was 50Gy in 5 fractions. Toxicities were graded according to the Common Terminology Criteria for Adverse Events (CTCAE) v.4.0. Rates of grade 2+ RP and any grade 2+ pulmonary toxicity were compared between patients with and without prior ALR. Crude rates of RP and all grade 2+ pulmonary toxicity were compared using Fisher’s exact test. Actuarial estimates of freedom from RP (FFRP), in-lobe control (ILC), and overall survival (OS) were calculated with the Kaplan-Meier method and compared between cohorts via the log rank method. Results: At a median follow up of 11.9 months (range 1.2 to 81 months), 3 patients developed grade 2+ RP at a median of 4.0 months (range: 1.0-14.8 months). The crude rates of RP were 6.3% and 2.9% for patients with and without prior ALD, respectively (p>0.05). The 2 year Kaplan-Meier estimates of freedom from RP were 86% and 97% (p>0.05). Crude rates of all grade 2+ pulmonary toxicity were 11.8% and 2.9%, respectively, with associated 2 year estimates of 97% and 81%, respectively (p>0.05). The 2 cohorts were well matched by mean lung dose (4.67 Gy vs 4.15 Gy), lung V20 (5.16% vs 4.35%), mean PTV (30.63 cc vs 36.16 cc), and median prescribed dose (50 Gy vs 54) (p>0.05 for all). Conclusions: Observed rates of pulmonary toxicity were low among patients treated by SBRT after ALR. These data provide reassurances that SBRT can be performed safely for patients with prior ALR when conventional lung DVH constraints are utilized. Author Disclosure: J.T. Hayes: None. A.M. Chen: None. M.E. Daly: None.

Radiation pneumonitis after stereotactic radiation therapy for lung cancer.

Stereotactic body radiation therapy (SBRT) has a local control rate of 95% at 2 years for non-small cell lung cancer (NSCLC) and should improve the prognosis of inoperable patients, elderly patients, and patients with significant comorbidities who have early-stage NSCLC. The safety of SBRT is being confirmed in international, multi-institutional Phase II trials for peripheral lung cancer in both inoperable and operable patients, but reports so far have found that SBRT is a safe and effective treatment for early-stage NSCLC and early metastatic lung cancer. Radiation pneumonitis (RP) is one of the most common toxicities of SBRT. Although most post-treatment RP is Grade 1 or 2 and either asymptomatic or manageable, a few cases are severe, symptomatic, and there is a risk for mortality. The reported rates of symptomatic RP after SBRT range from 9% to 28%. Being able to predict the risk of RP after SBRT is extremely useful in treatment planning. A dose-effect relationship has been demonstrated, but suggested dose-volume factors like mean lung dose, lung V20, and/or lung V2.5 differed among the reports. We found that patients who present with an interstitial pneumonitis shadow on computed tomography scan and high levels of serum Krebs von den Lungen-6 and surfactant protein D have a high rate of severe radiation pneumonitis after SBRT. At our institution, lung cancer patients with these risk factors have not received SBRT since 2006, and our rate of severe RP after SBRT has decreased significantly since then.

Tumor Volume-Adapted Dosing in Stereotactic Ablative Radiotherapy of Lung Tumors

Current stereotactic ablative radiotherapy (SABR) protocols for lung tumors prescribe a uniform dose regimen irrespective of tumor size. We report the outcomes of a lung tumor volume-adapted SABR dosing strategy. We retrospectively reviewed the outcomes in 111 patients with a total of 138 primary or metastatic lung tumors treated by SABR, including local control, regional control, distant metastasis, overall survival, and treatment toxicity. We also performed subset analysis on 83 patients with 97 tumors treated with a volume-adapted dosing strategy in which small tumors (gross tumor volume <12 mL) received single-fraction regimens with biologically effective doses (BED) <100 Gy (total dose, 18-25 Gy) (Group 1), and larger tumors (gross tumor volume ≥12 mL) received multifraction regimens with BED ≥100 Gy (total dose, 50-60 Gy in three to four fractions) (Group 2). The median follow-up time was 13.5 months. Local control for Groups 1 and 2 was 91.4% and 92.5%, respectively (p = 0.24) at 12 months. For primary lung tumors only (excluding metastases), local control was 92.6% and 91.7%, respectively (p = 0.58). Regional control, freedom from distant metastasis, and overall survival did not differ significantly between Groups 1 and 2. Rates of radiation pneumonitis, chest wall toxicity, and esophagitis were low in both groups, but all Grade 3 toxicities developed in Group 2 (p = 0.02). A volume-adapted dosing approach for SABR of lung tumors seems to provide excellent local control for both small- and large-volume tumors and may reduce toxicity.

Incidence of Radiation Pneumonitis after Thoracic Intensity Modulated Radiation Therapy

Combined radiotherapy and chemotherapy are the basis for treatment for many thoracic malignancies. Therapy is limited by acute, sub-acute, and long term side effects. Radiation pneumonitis is an acute to sub-acute side effect that can be life threatening. This study examines the Mayo Clinic experience with thoracic IMRT and uses dosimetric data to predict risk of pulmonary radiation toxicity. A retrospective review was conducted of the medical records of 96 consecutive patients who completed Intensity Modulated Radiation Therapy (IMRT) for thoracic malignancies at the Mayo Clinic from 2003-2008. NCI Common Toxicity Criteria Version 4 (CTC) pulmonary toxicity grades were used to identify patients with grade 2 or greater radiation pneumonitis during and up to 9 months after receiving radiation therapy. Extensive baseline demographic data was obtained on all patients. Lung dosage (V5, 8, 10, 13, 15, 20, 25, 30 Gy), mean lung dose, and total lung dose was obtained using dose volume histograms. Statistical analysis evaluated the predictive ability of each indicator in predicting development of radiation pneumonitis. Of the 96 patients 9 cases (9%) of CTC grade 2 or greater toxicity were identified. There was a single grade 3 event (1.5%). Median values for V5-V30 were 58.25% (V5), 45% (V8), 37.5% (V10), 30% (V13), 25.25% (V15), 17.25% (V20), 14% (V25), and 10.5% (V30). The median prescribed treatment dose was 60 Gy, and higher mean lung dose correlated with all grades of pneumonitis (p < 0.05) by univariate logistic regression analysis. All dosimetric parameters were predictive of subsequent development of pneumonitis, with V15 and V30 being most prognostic by receiver operating characteristic (ROC) analysis. Parameters V15 and V30 ROC area under the curves (AUC) were 0.762 and 0.767, indicating strong ability to predict the primary outcome: grade 2 or higher toxicity. ROC area under the curves for other parameters varied from 0.70 to 0.746. Lower baseline diffusion limiting capacity of carbon monoxide (DLCO) was also predictive of developing grade 2 or greater pneumonitis. Radiation pneumonitis is a clinically important side effect of thoracic radiation therapy. Rates of radiation pneumonitis in patients treated with IMRT appear to be equal or less than previously reported rates of pneumonitis in patients receiving 3DCRT. CTC toxicity levels of 2 or greater indicate clinically significant pneumonitis. Mean lung dose, the dosimetric variables V15 and V30, and baseline DLCO are all highly correlated with subsequent grade 2 or higher lung toxicity and should be carefully considered in treatment planning in order to minimize the incidence of severe pulmonary side effects.

Analysis of Dose-Volume Metrics Associated with Radiation Pneumonitis after Stereotactic Body Radiotherapy for Lung Cancer

The objective was to find dose-volume factors associated with radiation pneumonitis (RP) after stereotactic body radiotherapy (SBRT) for lung cancer. Seventy-four patients who underwent SBRT for primary lung cancer were analyzed in the present study. Fifty-five were male, and nineteen were female. A median of age was 77 years old (range, 63-88). Chemotherapy was not administered unless disease progression was confirmed. Prescription dose for SBRT was uniformly 48 Gy in 4 fractions at the isocenter. Irradiation was performed with 6-MV X-ray beams, which were shaped into the planning target volume (PTV) plus 5-mm margins, from a linear accelerator (Clinac 2300 C/D; Varian). Dose distribution was re-calculated with the analytical anisotropic algorithm in Eclipse (Varian). RP was graded according to the CTCAE version 3, and high-grade RP was herein defined as Grade 2 or worse. Optimal cut points dividing the patient population into two subgroups based on incidence of high-grade RP were searched using the recursive partitioning method in the following dose-volume metrics: PTV volume (cc), mean lung dose (Gy), V5, V10, V15, V20, V25, V30, V35, and V40, where Vd was defined as a relative volume (%) of the lung other than PTV which received more than a threshold dose d Gy. RP Grade 2 or worse was observed in 15 patients (20.2%), including 1 patient of Grade 3, with a median follow-up duration of 31 months. Optimal cut points for pulmonary doses were found in V25 and V20. These factors were highly correlated with each other (R = 0.99), and V25 was more significant than V20. High-grade RP rate was 14.8% in the patients with V25 less than 4.2%, while the rate was 46.2% in the remainder (p = 0.02). PTV volume was found as the other significant factor. High-grade RP rate was significantly lower in the group with PTV volume less than 37.7 cc compared with the larger PTV group (11.1% vs. 34.5%, p = 0.02). Correlation between lung V25 and PTV volume was not strong (R = 0.58). When dividing the patient population into three subgroups: (1) PTV < 37.7 cc; (2) PTV ≥ 37.7 cc and V25 < 4.2%; and (3) PTV ≥ 37.7 cc and V25 ≥ 4.2%, incidence rates of high-grade RP were 11.1%, 23.5%, and 50.0%, respectively (p = 0.01). Lung V25 and PTV volume were suggested as significant factors associated with RP after SBRT.

Dose-volumetric Parameters for Predicting Severe Radiation Pneumonitis and Skin Toxicity in Breast Cancer Patients Treated with Three Dimensional Conformal Radiation Therapy and Paclitaxel

Delaying the initiation of adjuvant radiation therapy (RT) adversely affects local-regional control and RT given concomitantly with chemotherapy may increase rates of radiation pneumonitis (RP) and skin toxicity (ST). For this reason, it is important to identify dosimetric parameters that would permit the safe administration of this treatment. Our aim was to identify potential clinical factors and dosimetric factors for RP and ST following concomitant paclitaxel and RT. Records of 57 patients treated with weekly paclitaxel at 80 mg/m2 for 12 cycles and 50 Gy RT plus a boost to the surgical bed of 16-20 Gy between January 2005 and December 2007 were reviewed. All patients had either node positive or high risk node negative breast cancer. RP and ST were graded according to the RTOG criteria. Factors including performance status, comorbidities, smoking status, tamoxifen use, body mass index (BMI), plastic cup (PC) use, breast volume (BV), dose-volume parameters (V5, V20, V25, V30), MLD (mean lung dose), and radiation fields were analyzed and correlated with clinical toxicity. Median follow-up was 30 months (range, 7.87-56 months). Twenty-six and 31 patients, respectively, received two-field radiotherapy (2FRT) and three-field radiotherapy (3FRT). In no case was the internal mammary chain irradiated. Grade ≥2 RP was observed in 14% of cases. All cases of RP resolved without any clinical sequelae. The mean time to develop RP after RT was 50 days. The mean ipsilateral V5, V20, V25, V30, MLD were 22.55%, 8.9%, 8.07%, 7.3%, and 6.35 Gy, respectively, for patients with 2FRT group and 41.7%, 21.6%, 19.64%, 17.8%, 11.97 Gy, respectively, for patients with 3FRT group. These values were significantly correlated. There was no significant association between specific RT fields and RP. By univariate analyses, MLD (p = 0.03), V5 (p = 0.003), V20 (p = 0.03), V25 (p = 0.04), V30 (p = 0.04), V25 cc (p = 0.03), and V30 cc (p = 0.04) were found to be significantly associated with RP. By multivariate analysis, only V20 (p = 0.01) and V30 (p = 0.001) were significant factors. There was a significant trend for increasing RP with V20 values ≥17% (p = 0.05) and V30 ≥14% (p = 0.043). Using ST scoring criteria, 21 patients (37%) experienced grade 3-4 toxicity. By univariate analysis, mean BMI (p = 0.01), BV (p = 0.009) and use of PC (p = 0.011) were predictors of grade 3-4 ST. Multivariate analysis revealed the BMI (p = 0.004) and BV (p = 0.002) to be significant predictors of ST. Given the high rate of RP observed with concomitant paclitaxel and RT, the V20 and V30 ipsilateral constraints should be adhered to closely in order to decrease the risk of RP. BMI and BV are the main predictors of ST in these patients.

Efficacy of Liangxue Jiedu Huoxue Decoction in prevention of radiation pneumonitis: a randomized controlled trial

Radiation pneumonitis is one of the most common complications during radiotherapy of thoracic tumors. It impacts the quality of life of the patients and has life-threatening danger. However, there is a lack of drugs for prevention and treatment of this disease. To evaluate the efficacy of Liangxue Jiedu Huoxue Decoction, a compound traditional Chinese herbal medicine, in prevention of radiation pneumonitis. A prospective randomized clinical study was conducted. A total of 100 patients diagnosed with lung cancer from Department of Radiotherapy, Chinese PLA General Hospital, who were planning to receive radiotherapy, were randomly assigned into treatment group and control group, with 50 patients in each group. In the treatment group 3 cases were lost to follow-up and one case was excluded, while in the control group 6 cases were lost to follow-up and 2 cases were excluded. Patients in the treatment group were treated with Liangxue Jiedu Huoxue Decoction in addition to radiotherapy, while patients in the control group were treated with radiotherapy alone. The incidence rates of radiation pneumonitis in the two groups were calculated. Acute radiation injury scoring criteria by Radiation Therapy Oncology Group (RTOG), clinical-radiographic-physiologic (CRP) score system, and Karnofsky Performance Status Scale (KPS) were used to evaluate the status of the patients. The incidence rate of radiation pneumonitis was lower in the treatment group than in the control group (13.04% versus 33.33%, P<0.05). According to the RTOG scale, the extent of lung injury was improved in the treatment group as compared with that in the control group (P<0.05). The CRP score in the treatment group was significantly lower than that in the control group (P<0.05). The KPS score in the treatment group was significantly higher than that in the control group (P<0.05). Liangxue Jiedu Huoxue Decoction can decrease the incidence rate of radiation pneumonitis, reduce the extent of the lung injury, alleviate the symptoms of radiation pneumonitis, and improve life quality of the patients.

Radiation pneumonitis in patients treated for malignant pulmonary lesions with hypofractionated radiation therapy

Purpose We evaluated the relationship between the mean lung dose (MLD) and the incidence of radiation pneumonitis (RP) after stereotactic body radiation therapy (SBRT), and compared this with conventional fractionated radiation therapy (CFRT). Materials and methods For both SBRT ( n = 128) and CFRT ( n = 142) patients, RP grade ⩾2 was scored. Toxicity models predicting the probability of RP as a function of the MLD were fitted using maximum log likelihood analysis. The MLD was NTD (Normalized Total Dose) corrected using an α/ β ratio of 3 Gy. Results SBRT patients were treated with 6–12 Gy per fraction with a median MLD of 6.4 Gy (range: 1.5–26.5 Gy). CFRT patients were treated with 2 Gy or 2.25 Gy per fraction, the median MLD was 13.2 Gy (range: 3.0–23.0 Gy). The crude incidence rates of RP were 10.9% and 17.6% for the SBRT and CFRT patients, respectively. A significant dose–response relationship for RP was found after SBRT, which was not significantly different from the dose–response relationship for CFRT ( p = 0.18). Conclusion We derived a significant dose–response relationship between the risk of RP and the MLD for SBRT from the clinical data. This relation was not significantly different from the dose–response relation for CFRT, although statistical analysis was hampered by the low number of patients in the high dose range.

Acute radiation esophagitis in a phase I dose-escalation trial evaluating helical tomotherapy for inoperable non-small cell lung cancer (NSCLC)

7694 Background: In an attempt to improve the poor local control in patients with locally advanced and medically inoperable lung cancer we investigated helical tomotherapy as a means to decrease radiation dose to critical normal structures while escalating tumor dose. Methods: Thirty-six patients with Stage I-IV NSCLC requiring definitive radiotherapy and judged not to be surgical candidates due to medical comorbidities or advanced tumor stage were enrolled in this phase I trial. Chemotherapy was given sequentially but not allowed concurrently. Pts were placed in 1 of 4 dose-per-fraction bins, all treated for 25 fractions, with dose per fraction ranging from 2.28 to 3.22 Gy. Bins were calculated to yield normalized total dose (NTD) equivalents in 2 Gy fractions of 60–100 Gy. Dose escalation limiting constraints included esophageal maximum NTD, lung NTD mean, and esophageal effective volume (Veff). Radiotherapy was limited to the primary site and clinically proven or suspicious nodal regions. Elective nodal irradiation (ENI) was not performed. A graded-response logistic regression analysis was performed to identify dosimetric and clinical factors associated with esophagitis. Results: No grade 3 (CTCAE v3.0 and RTOG) acute esophageal toxicities were observed. Only 6 patients (16.7%) required narcotic analgesia (RTOG gr. 2 toxicity). Average mean NTD dose to the esophagus (Dmean)=15.3 Gy. Average volume of the esophagus receiving NTD 55 Gy (V55)=3.65%. Both Dmean and V55 were significantly associated with the grade of esophagitis, with P- values of 0.018 and 0.010, respectively. In this limited series, there was no significant effect of sequential chemotherapy, in agreement with previous studies. Conclusions: 1) Acute esophageal toxicity was minimal despite dose escalation via helical tomotherapy for inoperable NSCLC cancer. 2) The observed significant associations between V55, Dmean, and grade of esophagitis validate improved dose distribution as a strategy to permit radiation dose escalation. Pending acceptable rates of radiation pneumonitis the addition of concurrent chemotherapy is anticipated. Supported by NIH Grant CA-88960. No significant financial relationships to disclose.