Symptomatic Radiation Pneumonitis Research Articles

Predictors of Local Control and Symptomatic Pneumonitis after Lung SBRT

Stereotactic body radiation therapy (SBRT) is commonly used to treat primary or oligometastatic malignancies in the lung, though most of the available data describing the safety and efficacy of SBRT is for smaller tumors. The purpose of this study was to evaluate the impact of tumor size, among other factors, on local control (LC) and radiation pneumonitis (RP) in patients who received lung SBRT. This retrospective study included patients with primary and metastatic lung tumors treated with SBRT at a single institution from 2012 - 2017. Patients were excluded for prior radiation to the targeted site. All patients underwent 4D-CT simulation with respiratory motion management as needed, and received 3-5 fractions of varying doses prescribed to the PTV on a linear accelerator using a highly conformal IMRT or VMAT technique. Factors evaluated for association with LC included GTV diameter and volume, PTV diameter and volume, volumetric ratio of PTV:GTV, histology, prescription biologically effective dose (BED10), and PTV maximum dose (Dmax). Additional factors evaluated for association with grade 2 or higher (symptomatic) RP included BED3, conformity index (CI), max and mean dose to the heart and central airway, mean lung dose (MLD), and the volume of lung that received at least 2.5 Gy (V2.5), 5 Gy (V5), 13 Gy (V13), 20 Gy (V20), 30 Gy (V30), 40 Gy (V40), and 50 Gy (V50). Analysis included the Mann-Whitney U-test and binary logistic regression. Recursive partitioning analysis was used to determine the optimal dose constraint (OC) predictive of RP. A total of 125 patients with 150 irradiated sites, consisting of 104 (69.3%) primary lung tumors and 46 (30.7%) metastatic lung tumors were included in the study. The median follow-up for survival/toxicity analysis and LC analysis were 13.0 months (IQR 7.0 - 26.0) and 11.5 months (IQR 6.0 – 20.0), respectively. A large range of tumor sizes were represented with a median GTV volume of 6.02 cm3 (IQR 2.19 – 13.79). LC rates at 12 and 24 months post-treatment were 92.6% and 85.9%, respectively. LC was associated with higher BED10 (median 112.5 Gy vs. 92.8 Gy, p=0.02), PTV Dmax (62.5 Gy vs. 53.1 Gy, p<0.01), and PTV:GTV (5.8 vs. 3.5, p=0.01), and there was a trend towards improved LC with smaller tumor diameter (2.8 cm vs. 4.0 cm, p=0.08). RP was associated with higher ipsilateral lung MLD (7.3 Gy vs. 5.3 Gy, p=0.02, OC=8.6 Gy), V2.5 (38.8% vs. 32.0%, p=0.03, OC=30.8%), V5 (32.9% vs. 24.9%, p=0.02, OC=26.8%), V13 (18.8% vs. 13.4%, p=0.03, OC=21.8%), V20 (11.7% vs. 8.0%, p=0.05, OC=14.9%), and heart Dmax (14.4 Gy vs. 6.1 Gy, p=0.02, OC=31.7 Gy). A higher PTV prescription dose, greater dose heterogeneity within the target, and larger PTV margins were significantly associated with improved LC, whereas a weaker association was observed between tumor size and LC. Ipsilateral lung doses were most correlated with RP.

P1.17-09 V30 May Better Predict Radiation Pneumonitis After Intensity-Modulated Radiation Therapy for Lung Cancer

V20 and MLD are the most commonly used dose constraints for radiation pneumonitis (RP) prediction. However, intensity-modulated radiation therapy (IMRT) has unrestricted beam arrangements, an infinite number of very different dose distributions could be generated in the lung volume outside the planning target volume (PTV). Conventional dose constraints from traditional 3D conformal RT may not be valid for IMRT treatment. We hypothesize that lung dosimetric parameters may have different RP predictive values from that of traditional constraints (largely generated from 3D treatment) in IMRT treated lung cancer patients. We retrospectively enrolled184 IMRT treated lung cancer patients from January 2014 to October 2017. The primary endpoint was acute grade 2 or higher symptomatic radiation pneumonitis (RP2), based on the National Cancer Institute’s Common Terminology Criteria for Adverse Events (version 4.03). Vdose (from V5 to V50) and MLD were generated from the lung volume outside PTV. Univariate and multivariate logistic regression analysis was used to evaluate the association between the dose parameters outside PTV to RP2. We employed area under the curve (AUC) for the receiver operating characteristic curve (ROC) to assess prediction accuracy for the single or multi-variate model. 26 out of 184 lung cancer patients (14.1%) developed RP2 within 3 months after the end of IMRT treatment. In univariate logistic regression, although none of the clinical parameters was significantly associated with RP2, female gender (P=0.051) and chemotherapy (P=0.151) had a trend of correlation. V5 (P=0.007), V10(P=0.012) V20 (P=0.004), V30 (P=0.003) and MLD (P=0.004) were significantly associated with RP2 incidence. From ROC curve, the largest AUC of 0.67 was generated from V30, which showed a better predictive value compared with other dosimetric factors. Multivariate logistic regression analysis showed the only significant dosimetric factor is V30 (P=0.021). Combining gender and chemotherapy factors, V30 has an AUC of 0.71 which is the largest among all the other dosimetric factors. For IMRT treated lung cancer patients, V30 generated from lung volume outside PTV may predict RP more accurately than traditional dosimetric parameters.

P1.17-20 Excluding PTV From Lung Volume May Better Predict Radiation Pneumonitis For IMRT Treated Lung Cancer Patients

Lung dose-volume histogram(DVH) could be calculated from multiple normal lung definitions. These dose differences have a direct impact on lung cancer radiotherapy treatment planning. Earlier study from 3D conformal radiation therapy suggested dose computation from total normal lung excluding gross tumor volume (GTV) may be more accurate than that of excluding planning target volume (PTV). It is unclear which definition should be used to more accurately predict radiation pneumonitis (RP) in lung cancer patients treated with intensity-modulated radiation therapy (IMRT). We aim to determine a superior normal lung volume to more accurately predict symptomatic RP in lung cancer patients treated with IMRT. This is a retrospective study. All patients treated with IMRT with at least 3 months follow-up are eligible. The normal lungs are defined by total lung volume excluding GTV, PTV or directly using the total lung volume. V5, V20, and MLD have been extracted for all three definitions. RP was diagnosed and graded according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events, version 4.03. The primary endpoint was grade 2 or higher RP (RP2). Correlation between RP2 and dose parameters were analyzed by logistic regression. We compared RP prediction performance of each lung volume using area under the receiver operating characteristic curve (AUC). A total of 184 consecutive patients treated between January 2014 and October 2017 were eligible, 26 patients (14%) developed RP2 within 3 months after treatment. Significant dosimetric difference was found between any 2-paired lung volumes (Ps<0.0001). All dose parameters from Lung-PTV method had significant correlation with RP2, with greater AUCs than the other two definitions. The best RP prediction performance was found in Lung-PTV volume MLD (AUC=0.649), which is significantly better than Lung-GTV volume MLD (AUC=0.611, P=0.006). There were significant dosimetric differences from various normal lung definitions. Excluding PTV method may accurately predict acute symptomatic radiation pneumonitis for IMRT treated lung cancer patients.

Impact of Tumor Size on Local Control and Pneumonitis After Stereotactic Body Radiation Therapy for Lung Tumors

PurposeStereotactic body radiation therapy (SBRT) is commonly used to treat primary or oligometastatic malignancies in the lung, but most of the available data that describe the safety and efficacy of SBRT are for smaller tumors. The purpose of this study was to evaluate the impact of tumor size, among other factors, on local control (LC) and radiation pneumonitis (RP) in patients who received lung SBRT. Methods and materialsThis retrospective study included 144 patients with 100 primary (57.1%) and 75 metastatic (42.9%) lung tumors treated with SBRT between 2012 and 2018. Measurements of tumor size, treatment volume, histology, and radiation dose were evaluated for association with LC. Additional factors evaluated for association with the development of symptomatic RP included volume of the lung, heart, and central airway exposed to relevant doses of radiation. ResultsThe median follow-up time was 15.0 months (interquartile range, 8.0-26.0 months). LC rates at 12 and 24 months posttreatment were 95.1% and 92.7%, respectively. LC at 1 year was higher for tumors <5 cm in diameter than for tumors >5 cm in diameter (98.2% vs 79.8%, respectively; P < .01). On univariate analysis, LC was associated with a smaller gross tumor volume (GTV) diameter (P < .01), GTV volume (P < .01), planning target volume (PTV) diameter (P < .01), PTV volume (P < .01), and larger PTV-to-GTV ratio (P = .04). Tumor histology and treatment intent were not correlated with LC. RP was associated with a higher ipsilateral lung mean lung dose (P = .02), V2.5 (P = .03), V5 (P = .02), V13 (P = .03), V20 (P = .05), V30 (P = .02), V40 (P = .02), and V50 (P = .03), and several similar total lung dose parameters and heart maximum point dose (P = .02). The optimal mean ipsilateral lung dose cutoff predictive of RP was 8.6 Gy. ConclusionsA larger tumor size and smaller PTV-to-GTV ratio was associated with local recurrence of lung tumors treated with SBRT, but ipsilateral lung doses were most associated with symptomatic RP.

Short-term clinical efficacy and adverse events of volumetric modulated arc therapy in patients with locally advanced non-small cell lung cancer

Objective To evaluate the short-term clinical efficacy and adverse events of volumetric modulated arc therapy (VMAT) in the treatment of locally advanced non-small cell lung cancer (NSCLC). Methods From January to December 2016, 58 patients (47 male and 11 female) with unresectable locally advanced NSCLC received concurrent or sequential chemoradiotherapy. The radiation dose was ranged from 38 Gy to 66 Gy. The radiation dose was equal or higher than 56 Gy in 53 patients (92%). The median radiotherapy fraction was 30, 1.8 Gy to 3.0 Gy for each fraction. Twenty-eight patients (48%) received concurrent chemoradiotherapy. Results The median follow-up time was 9 months. The 1-year overall survival (OS) rate was 84% and the 1-year progression-free survival (PFS) rate was 48%.Eleven patients (19%) suffered from symptomatic radiation pneumonitis and one of them died of radiation pneumonitis. Within 6 months after radiotherapy, 31 patients (53%) developed asymptomatic local pulmonary fibrosis on CT images. Seventeen patients (29%) suffered from grade Ⅱ esophagitis. Ten cases (17%) had ≥ grade Ⅲ adverse events and 9 of them presented with leucopenia. Conclusions VMAT yields high short-term clinical efficacy and tolerable adverse events in the treatment of locally advanced NSCLC, which does not increase the risk of pneumonitis. Key words: Lung neoplasm/volumetric modulated arc therapy; Treatment outcome; Radiation pneumonitis

(P39) Novel Use of Machine Learning for Predicting Radiation Pneumonitis in Locally Advanced Stage II-III Non-Small Cell Lung Cancer

Radiation pneumonitis (RP) is a common and radiotherapy dose-limiting toxicity for locally-advanced non-small cell lung cancer (LA-NSCLC). Prior studies have proposed relevant dosimetric constraints in order to limit this toxicity. We incorporate machine learning techniques in order to perform additional in-depth analyses of contributing factors to the development of RP in order to uncover previously unidentified criteria, establish more discrete and robust dosimetric criteria, and the elucidate the relative importance of individual factors. Utilizing a cohort of 203 consecutive stage II-III LA-NSCLC patients treated with definitive chemoradiation at our institution from 2008-2016, we evaluated 32 continuous and categorical features per patient grouped into risk factors, comorbidities, pretreatment imaging, stage, histology, radiation treatment, chemotherapy, and dosimetry utilizing a novel machine learning algorithm to identify predictive features for the development of RP. Univariate analysis was performed using optimally trained decision stumps to determine statistically significant features and their corresponding RP thresholds. Multivariate analysis was carried out using Mediboost for feature selection. MediBoost is a novel patient stratification tool that builds decision trees with optimal accuracy comparable to less-interpretable ensemble methods commonly used in the literature. Patients were treated to a median dose of 66.6 Gy in 1.8 Gy fractions. 17.7% patients developed grade ≥3 RP. On univariate analysis, lung dosimetric factors of lung mean, lung V10, and lung V20 were found to be the significant RP predictors with the greatest balance of specificity and sensitivity. On multivariate analysis, using the MediBoost algorithm, esophagus max (61.5%) and lung V20 (30.5%) were the two most common primary differentiators of RP, with lung mean and esophagus mean important secondary RP differentiators. We highlight the utility of a novel machine learning algorithm and demonstrate its ability to both identify known and novel predictors for the development of symptomatic RP. We provide interpretable decision trees using MediBoost that can aid clinicians in decision optimization regarding mitigation of RP and demonstrate the potential utility of our machine learning techniques for future studies.

Influence of respiratory motion management technique on radiation pneumonitis risk with robotic stereotactic body radiation therapy.

Purpose/ObjectivesFor lung stereotactic body radiation therapy (SBRT), real‐time tumor tracking (RTT) allows for less radiation to normal lung compared to the internal target volume (ITV) method of respiratory motion management. To quantify the advantage of RTT, we examined the difference in radiation pneumonitis risk between these two techniques using a normal tissue complication probability (NTCP) model.Materials/Method20 lung SBRT treatment plans using RTT were replanned with the ITV method using respiratory motion information from a 4D‐CT image acquired at the original simulation. Risk of symptomatic radiation pneumonitis was calculated for both plans using a previously derived NTCP model. Features available before treatment planning that identified significant increase in NTCP with ITV versus RTT plans were identified.ResultsPrescription dose to the planning target volume (PTV) ranged from 22 to 60 Gy in 1–5 fractions. The median tumor diameter was 3.5 cm (range 2.1–5.5 cm) with a median volume of 14.5 mL (range 3.6–59.9 mL). The median increase in PTV volume from RTT to ITV plans was 17.1 mL (range 3.5–72.4 mL), and the median increase in PTV/lung volume ratio was 0.46% (range 0.13–1.98%). Mean lung dose and percentage dose–volumes were significantly higher in ITV plans at all levels tested. The median NTCP was 5.1% for RTT plans and 8.9% for ITV plans, with a median difference of 1.9% (range 0.4–25.5%, pairwise P < 0.001). Increases in NTCP between plans were best predicted by increases in PTV volume and PTV/lung volume ratio.ConclusionsThe use of RTT decreased the risk of radiation pneumonitis in all plans. However, for most patients the risk reduction was minimal. Differences in plan PTV volume and PTV/lung volume ratio may identify patients who would benefit from RTT technique before completing treatment planning.

Risk factors for radiation pneumonitis after stereotactic radiation therapy for lung tumours: clinical usefulness of the planning target volume to total lung volume ratio.

To identify risk factors for symptomatic radiation pneumonitis (RP) after stereotactic radiation therapy (SRT) for lung tumours. We retrospectively evaluated 68 lung tumours in 63 patients treated with SRT between 2011 and 2015. RP was graded according to the National Cancer Institute-Common Terminology Criteria for Adverse Events version 4.0. SRT was delivered at 7.0-12.0 Gy per each fraction, once daily, to a total of 48-64 Gy (median, 50 Gy). Univariate analysis was performed to assess patient- and treatment-related factors, including age, sex, smoking index(SI), pulmonary function, tumour location, serum Krebs von den Lungen-6 value(KL-6), dose-volume metrics (V5, V10, V20, V30, V40 and VS5), homogeneity index of the planning target volume (PTV), PTV dose, mean lung dose (MLD), contralateral MLD and V2, PTV volume, lung volume and the PTV/lung volume ratio (PTV/Lung). Performance of PTV/Lung in predicting symptomatic RP was also analysed using receiver operating characteristic (ROC) analysis. The median follow-up period was 21 months. 10 of 63 patients (15.9%) developed symptomatic RP after SRT. On univariate analysis, V10, V20, PTV volume and PTV/Lung were significantly associated with occurrence of RP≥Grade 2. ROC curves indicated that symptomatic RP could be predicted using PTV/Lung [area under curve(AUC): 0.88, confidence interval (CI:0.78-0.95), cut-off value: 1.09, sensitivity: 90.0% and specificity: 72.4%]. PTV/Lung is a good predictor of symptomatic RP after SRT. Advances in knowledge: The cases with high PTV/Lung should be carefully monitored with caution for the occurrence of RP after SRT.

Yttrium-90 Radioembolization of the Right Inferior Phrenic Artery in 20 Patients with Hepatocellular Carcinoma

PurposeTo address the feasibility of infusion of yttrium-90 (90Y) glass microspheres directly through the right inferior phrenic artery (RIPA). Materials and MethodsFrom November 2015 to May 2017, 20 patients underwent 90Y radioembolization through the RIPA. When the systemic-to-pulmonary shunt was demonstrated on C-arm computed tomography (CT) of the RIPA, prophylactic embolization by polyvinyl alcohol (PVA) particles was performed prior to infusion of 90Y glass microspheres. Follow-up CT scans were retrospectively reviewed for pulmonary complications. Tumor response was determined by the modified Response Evaluation Criteria in Solid Tumors. ResultsNine (45%) patients had systemic-to-pulmonary shunts on C-arm CT images of the RIPA. The feeder of the systemic-to-pulmonary shunt was the azygoesophageal branch (n = 7) and the anterior branch (n = 2). The mean activity of 90Y glass microspheres infused into the RIPA was 0.49 GBq (range, 0.19–1.55 GBq). No patient had symptomatic radiation pneumonitis or cutaneous complications during follow-up. Seven patients had focal atelectasis (n = 5), focal ground-glass opacity (n = 2), and/or a small amount of pleural effusion (n = 2) on follow-up image. Best tumor response fed by the RIPA was complete response (n = 4), partial response (n = 9), stable disease (n = 2), progressive disease (n = 4), and unevaluable (n = 1). ConclusionThe administration of 90Y glass microspheres through the RIPA may be safe after embolization of a systemic-to-pulmonary shunt identified on C-arm CT.

Differences in lung injury after IMRT or proton therapy assessed by 18FDG PET imaging

Background and purposeTo compare lung injury among non-small cell lung cancer (NSCLC) patients treated with IMRT or proton therapy as revealed by 18F-FDG post-treatment uptake and to determine factors predictive for clinically symptomatic radiation pneumonitis. Material and methodsFor 83 patients treated with IMRT or proton therapy, planning CT and follow up 18F-FDG PET-CT were analyzed. Post-treatment PET-CT was aligned with planning CT to establish a voxel-to-voxel correspondence between PET and planning dose images. 18F-FDG uptake as a function of radiation dose to normal lung was obtained for each patient. PET image-derived parameters as well as demographic, clinical, treatment and dosimetric patient characteristics were correlated with clinical symptoms of pneumonitis. ResultsThe dose distributions for the two modalities were significantly different; V5 was higher for IMRT, whereas V60 was higher for protons. The mean lung dose (MLD) was similar for the two modalities. The slope of linear 18F-FDG-uptake – dose response did not differ significantly between the two modalities. The MLD, slope, and 95th percentile of SUV were identified as three major factors associated with radiation pneumonitis. ConclusionsDespite significantly different dose distributions for IMRT and for protons, the slope of the SUV–dose linear regression line previously shown to be associated with RP did not differ between IMRT and protons. Patients who developed radiation pneumonitis had statistically significantly higher MLD and higher slope regardless of treatment modality.

Posttreatment Immune Parameters Predict Cancer Control and Pneumonitis in Stage I Non–Small-Cell Lung Cancer Patients Treated With Stereotactic Ablative Radiotherapy

PurposeStereotactic ablative body radiotherapy (SABR) represents an exciting, tolerable, and highly effective form of radiotherapy. Ongoing investigations into the interactions between radiotherapy and the immune system have uncovered new mechanisms that can be exploited to improve efficacy. We determined whether baseline or posttreatment immune parameters could predict disease control and toxicity in stage I non–small-cell lung cancer (NSCLC) patients treated with SABR. Patients and MethodsPeripheral blood samples were collected from 62 patients 24 hours before treatment and within 4 weeks after treatment for lymphocyte subset count analysis. All peripheral blood samples were analyzed by flow cytometry. Associated parameters were evaluated to determine their association with progression-free survival (PFS) and symptomatic radiation pneumonitis (grade 2 or higher). The survival rates were estimated with Kaplan-Meier and multivariable analyses using binary logistic regression analysis or a Cox proportional hazards model. ResultsAt a median follow-up time of 36.0 months, the PFS rates for years 1, 2, and 3 were 91.0%, 82.5%, and 48.9%, respectively. The multivariable logistic regression analysis showed that only proportion of lung receiving 20 Gy of radiotherapy (odds ratio = 1.41; 95% confidence interval, 1.05-1.87; P = .023) and mean lung dose (odds ratio = 2.02; 95% confidence interval, 1.16-3.53; P = .016) were associated with symptomatic radiation pneumonitis (grade 2 or higher). Moreover, the immune parameters had no predictive value. In the multivariable Cox regression analysis, an elevated posttreatment cytotoxic CD8+ T-cell level was an independent prognostic factor for longer PFS in stage I NSCLC (hazard ratio, 1.16; 95% confidence interval, 1.01-1.28; P = .01). ConclusionA higher posttreatment cytotoxic CD8+ T-cell level was predictive of better PFS in stage I NSCLC patients receiving SABR. Thus, enhancing tumor antigen-specific cellular immunity by combining radiotherapy and immunotherapy might be a crucial strategy for improving survival in these patients.

Exclusion of emphysematous lung from dose-volume estimates of risk improves prediction of radiation pneumonitis

BackgroundThe risk factors for radiation pneumonitis (RP) in patients with chronic obstructive pulmonary disease (COPD) are unclear. Mean lung dose (MLD) and percentage of irradiated lung volume are common predictors of RP, but the most accurate dosimetric parameter has not been established. We hypothesized that the total lung volume irradiated without emphysema would influence the onset of RP.MethodsWe retrospectively evaluated 100 patients who received radiotherapy for lung cancer. RP was graded according to the Common Terminology Criteria for Adverse Events (version 4.03). We quantified low attenuation volume (LAV) using quantitative computed tomography analysis. The association between RP and traditional dosimetric parameters including MLD, volume of the lung receiving a dose of ≥2 Gy, ≥ 5 Gy, ≥ 10 Gy, ≥ 20 Gy, and ≥30 Gy, and counterpart measurements of the lung without LAV, were analyzed by logistic regression. We compared each dosimetric parameter for RP using multiple predictive performance measures including area under the receiver operating characteristic curve (AUC) and integrated discrimination improvement (IDI).ResultsOf 100 patients, RP of Grades 1, 2, 3, 4, and 5 was diagnosed in 24, 12, 13, 1, and 1 patients, respectively. Compared with traditional dosimetric parameters, counterpart measurements without LAV improved risk prediction of symptomatic RP. The ratio of the lung without LAV receiving ≥30 Gy to the total lung volume without LAV most accurately predicted symptomatic RP (AUC, 0.894; IDI, 0.064).ConclusionIrradiated lung volume without LAV predicted RP more accurately than traditional dosimetric parameters.

CBCT-Derived Radiosensitivity Marker Associated with Radiation Pneumonitis

Dose escalation of non-small cell lung cancer is limited by increasing risk of severe adverse events, including radiation pneumonitis (RP). Recent studies have demonstrated a relationship between a cone beam computed tomography (CBCT) derived marker (CDM) and lung density changes on follow-up imaging. This study investigates the relationship between the CDM and symptomatic radiation pneumonitis in a new dataset. The CDM was defined as the proportion of normal lung tissue voxels receiving > 20 Gy that demonstrated an intensity increase beyond an expected noise threshold as previously described in [Radiother Oncol 2015;117:17-22]. CDMs were defined for both the tenth (CDM10) and twentieth (CDM20) fractions. CDMs were extracted for NSCLC patients treated definitively (>54 Gy) with fractionated (1.8-2 Gy/fraction) radiotherapy at the Princess Margaret Cancer Centre between 2011 and 2015. The exclusion criteria included patients without CBCT or dose objects available for analysis, patients receiving neoadjuvant radiotherapy, patients with previous radiation treatment in the thorax, and patients who had an in-thorax recurrence or were lost to follow-up within 1 year without evidence of pneumonitis. Images were registered into a common volume using an intensity-based deformable image registration algorithm in the Elastix toolbox. Image registration accuracy was manually checked. All other image analysis was implemented in Matlab 2013. RP was determined from prospective clinical records scored by the treating oncologists at follow-up visits as per CTCAE v 4.0, and reviewed retrospectively. Correlation of dosimetric parameters (mean lung dose (MLD), V20) and the CDMs to RP events was assessed by logistical regression. Fourteen percent of patients had image registration failure due to large deformations. CDMs were extracted in the remaining 84 patients. The prescription dose range was 54-74 Gy, mean lung dose range was 2.2-26 Gy and V20 range was 3.4–36%. Fifty-four percent of patients had concurrent chemotherapy with cisplatin or carboplatin and etoposide. Symptomatic RP (≥ Grade 2) occurred in 26.1% of patients of these patients. Univariate logistic regression of the CDM20 was significantly correlated with symptomatic RP (P < 0.01), while MLD, V20 and CDM10 were not significantly correlated. Multivariate logistical regression with CDM20 and V20 was significant for both (P < 0.05). This study suggests a relationship exists between symptomatic RP and a CBCT response marker initially derived to predict density changes in follow-up images. CBCT is regularly acquired as part of routine clinical care, and a CBCT derived marker may allow for modifications to treatment including reductions in dose, closer monitoring, and earlier initiation of steroid treatment. Future work is needed to improve the CBCT image quality and the deformable image registration accuracy.

The Predictive Value of Exhaled Nitric Oxide in Symptomatic Radiation Pneumonitis after Thoracic Radiation Therapy

The Predictive Value of Exhaled Nitric Oxide in Symptomatic Radiation Pneumonitis after Thoracic Radiation Therapy

Measurement of exhaled nitric oxide and serum surfactant protein D levels for monitoring radiation pneumonitis following thoracic radiotherapy

The present study aimed to examine the role of exhaled nitric oxide (eNO) and serum surfactant protein D (SP-D) level in the determination of radiation pneumonitis (RP) after thoracic radiotherapy (RT). The study included 34 treatments for 33 patients, including 16 three-dimensional conformal and 18 stereotactic body RT treatments. eNO levels were measured prior to RT, immediately subsequent to RT, every week during the RT course and at 1, 3, 6, 9 and 12 months following the treatment. The therapy reduced the eNO from 24.3±12.8 ppb prior to RT to 19.0±10.4 ppb immediately subsequent to RT (P=0.04). A total of 5 patients (14%) developed symptomatic RP of grade 2 or higher 3–5 months later, and exhibited an eNO elevation of 2.1±0.68-fold the minimum value, whereas the RP- group exhibited 1.4±0.6-fold elevation (P=0.02). The sensitivity of a cut-off of a 1.4-fold increase in the eNO ratio at the onset of RP was 100%; however, the specificity was 52%, and no predictive alterations to eNO levels were observed prior to the onset of RP. RT was associated with an elevated serum SP-D level at 3–6 months after RT. There was a statistically significant difference in the initial serum SP-D level between RP+ and RP- patients. In conclusion, obtaining the eNO ratio was a useful RP monitoring tool but did not predict RP occurrence in the present setting, whereas serum SP-D level may be a potential predictor for the detection of RP risk.

Abstract 4745: Circulating cytokine levels predictive of Grade≥3 radiation pneumonitis: Preliminary secondary analysis of a randomized controlled trial of definitive chemoradiation in locally advanced NSCLC

Abstract PURPOSE: Host immune activation is believed to be a major player of radiation pneumonitis (RP). Several cytokine and angiogenic factors (CAFs) have been studied as correlative markers and therapeutic targets for RP; however, studies are sparse in the setting of prospective trials and high-grade toxicity (Grade≥3) endpoints. We examined the predictive value of several CAFs in combination with clinical factors for RP in the context of a Phase II, prospective randomized study of intensity modulated RT (IMRT) versus proton therapy for locally advanced NSCLC (n=178) as well as a prospective laboratory cohort (n=43). METHODS: From July 2009 to April 2014, 221 patients were treated with proton therapy or IMRT to doses of 60-74 Gy equivalents with concurrent platinum-doublet chemotherapy. Primary endpoints were symptomatic RP (Grade≥2) and RP requiring intervention (Grade≥3). Plasma circulating levels of IL-6, IL-10, IL-8, IL-17, IL-2, IL-1β, and IL-1α were measured at baseline and post-treatment (median time 48 days post-RT) by multiplex electrochemiluminescence immunoassay. Clinical characteristics were evaluated for associations with Grade≥3 RP: histology, age, smoking status, mean lung dose (MLD), chemotherapy, stage, performance status, and RT technique. CAFs with &amp;gt;50% undetectable samples were removed from analysis, and samples below the lower limit of quantitation (LLQ) were transformed to the mean of zero and the LLQ. Predictive values of clinical and cytokine factors were evaluated in univariate and multivariate analyses via Cox proportional hazards modeling. RESULTS: Of the 221 patients, 42 (19.0%) developed Grade 2 RP, and 22 (9.95%) developed Grade≥3 RP. Both IL-1α and IL-1β had &amp;gt;50% of undetectable samples and were removed from analysis. Pre-treatment level of IL-6 ≥4.00 pg/mL was associated with Grade≥3 RP (HR 2.487; p=.048), as was post-treatment level of IL-10 ≥0.50 pg/mL (HR 2.931; p=.020). On multivariate analysis, the factors associated with Grade≥3 RP development were post-treatment level of IL-10 ≥0.50 pg/mL (HR 3.332; p=.015) and MLD ≥20 Gy (HR 5.864; p&amp;lt;.001). CONCLUSIONS: In this preliminary analysis of prospectively collected CAFs, post-radiation IL-10 level was significantly associated with Grade≥3 RP and, if validated, may serve as a predictor of this toxicity in combination with MLD. IL-10 plays an important role in the inflammatory response and is potentially targetable, warranting further investigation. Citation Format: Matthew S. Ning, Ting Xu, Daniel Gomez, Hai T. Tran, Ritsuko Komaki, Xiong Wei, Steven H. Lin, Stephen Hahn, Eric Prado, Jianjun Zhang, John V. Heymach, Zhongxing Liao. Circulating cytokine levels predictive of Grade≥3 radiation pneumonitis: Preliminary secondary analysis of a randomized controlled trial of definitive chemoradiation in locally advanced NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4745. doi:10.1158/1538-7445.AM2017-4745

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.

Neutrophil-lymphocyte ratio and a dosimetric factor for predicting symptomatic radiation pneumonitis in non-small-cell lung cancer patients treated with concurrent chemoradiotherapy.

To identify the factors that predict the progression of radiological radiation pneumonitis (RP) to symptomatic RP, and to evaluate the usefulness of the neutrophil-lymphocyte ratio (NLR) as a marker of RP severity and prognosis in stage III non-small cell lung cancer (NSCLC) patients treated with definitive concurrent chemoradiotherapy (CCRT). We retrospectively reviewed 61 patients treated between January 2010 and December 2015. Patients' demographic characteristics, clinical data, laboratory findings and treatment parameters were analyzed to determine the predictive factors associated with progression from radiological RP to symptomatic RP. Forty-seven patients (77%) exhibited radiological RP at a median of 78 days after radiation therapy (RT) completion, and 15 (32%) of these patients developed symptomatic RP. The interval between RT completion and radiological RP presentation was shorter in patients who progressed to symptomatic RP (P = .001); progression was highly probable if this latency period was ≤2 months (P = .002). Stage and RT technique correlated with symptomatic RP development (P = .046 and P = .046, respectively). Among dosimetric factors, a V20 (defined as the lung volume receiving ≥20 Gy) of >30% was the most significant predictor of symptomatic RP (P = .001). The NLR and C-reactive protein level at radiological RP were higher in patients who developed symptomatic RP (P = .067 and P = .012, respectively). On multivariate analysis, a V20 >30% and an NLR at radiological RP >6 were associated with symptomatic RP development. The NLR at radiological RP is a useful biomarker for predicting symptomatic RP development after CCRT in stage III NSCLC patients.

Prognostic Value of Radiation Pneumonitis After Stereotactic Body Radiotherapy: Effect of Pulmonary Emphysema Quantitated Using CT Images

BackgroundThe aim of this study was to determine the prognostic factors of radiation pneumonitis (RP) after stereotactic body radiotherapy (SBRT). Patients and MethodsA total of 50 patients (36 male and 14 female) were treated with SBRT for 42 primary lung cancers and 8 metastatic lung cancers. SBRT was performed with 48 Gy in 4 fractions to the isocenter or with 40 Gy in 4 fractions covering 95% of the planning target volume. Percentage of low attenuation area (%LAA) was defined as percentage of the lung area with attenuation of −860 Hounsfield units (HU) or lower (%LAA-860) or of −960 HU or lower (%LAA-960). The dosimetric parameter of V20 Gy, which means percentage volume of the lung receiving 20 Gy or more, was recalculated. RP was assessed using Common Terminology Criteria for Adverse Events version 4.0. ResultsThe median follow-up period was 39.0 months (range, 7.2-94.5 months). RP of Grade 0, Grade 1, and Grade 2 to 3 was diagnosed in 11, 29, and 10 patients, respectively. Multivariate analyses (MVA) for Grade 1 showed that higher %LAA-860 and higher %LAA-960 were significantly associated with a lower rate of Grade 1 RP. MVA for Grade 2 to 3 showed that lower Brinkman index and lower lung V20 Gy were significantly associated with a lower rate of Grade 2 to 3 RP, and, in contrast, %LAA-860 and %LAA-960 had no association with Grade 2 to 3 RP. ConclusionThis result suggests that high %LAA is associated with radiological changes (Grade 1) but that %LAA has no correlation with Grade 2 to 3 RP because symptomatic RP might also be affected by other factors.

Prognostic analysis of radiation pneumonitis: carbon-ion radiotherapy in patients with locally advanced lung cancer

BackgroundCarbon-ion radiotherapy (CIRT) is a promising treatment for locally advanced non-small-cell lung cancer, especially for patients with inoperable lung cancer. Although the incidence of CIRT-induced radiation pneumonitis (RP) ≥ grade 2 ranges from 2.5 to 9.9%, the association between CIRT-induced RP and dosimetric parameters is not clear. Herein, we identified prognostic factors associated with symptomatic RP after CIRT for patients with non-small-cell lung cancer.MethodsClinical results of 65 patients treated with CIRT between 2000 and 2015 at the National Institute of Radiological Sciences were retrospectively analyzed. Clinical stage II B disease (TNM classification) was the most common stage among the patients (45%). The median radiation dose was 72 Gy (68–76) relative biological effectiveness (RBE) in 16 fractions. In cases involving metastatic lymph nodes, prophylactic irradiation of mediastinal lymph nodes was performed at a median dose of 49.5 Gy (RBE). The median follow-up was 22 months.ResultsGrade 2 and grade 3 RP occurred in 6 and 3 patients (9 and 5%), respectively. No patients developed grade 4 or 5 RP. Using univariate analysis, vital capacity as a percentage of predicted (%VC), forced expiratory volume in 1 s (FEV1), mean lung dose (MLD), volume of lung receiving ≥5 Gy (RBE) (V5), V10, V20 and V30 were determined to be the significant predictive factors for ≥ grade 2 RP. The receiver operating characteristic (ROC) analysis revealed the cutoff values for %VC, FEV1, MLD, V5, V10, V20 and V30 for ≥ grade 2 RP, which were 86.9%, 1.16 L, 12.5 Gy (RBE), 28.8, 29.9, 20.1 and 15.0%, respectively. In addition, the multivariate analysis revealed that %VC <86.9% (odds ratio = 13.7; p = 0.0041) and V30 ≥ 15% (odds ratio = 6.1; p = 0.0221) were significant risk factors.ConclusionsOur study demonstrated the risk factors for ≥ grade 2 RP after carbon-ion radiotherapy for patients with locally advanced lung cancer.