Irradiated Lung Volume Research Articles

Daily Adaptive vs. Non-Adaptive External Beam Radiation Therapy with Concurrent Chemotherapy for Locally Advanced Non-Small Cell Lung Cancer (NSCLC): A Prospective Randomized Trial of an Individualized Approach for Toxicity Reduction (ARTIA-Lung)

Radiotherapy (RT) with concurrent chemotherapy is a standard treatment for Stage III NSCLC. However, radiation pneumonitis incidence increases rapidly with volume of lung irradiated, and esophagitis increases with dose to the esophagus. Both conditions can have adverse impacts on patients' quality of life. Daily online adaptive RT (ART) may allow for reduced normal tissue doses due to smaller margins around the target, as well as target size reduction with tumor response. This prospective, randomized controlled trial tests the hypothesis that the proportion of study participants who experience score ≥3 PRO-CTCAE cough, dyspnea, or dysphagia will be at least 20% lower with daily ART than with non-adapted RT. Enrollment goals are 244 subjects at up to 10 cancer centers worldwide. Eligibility criteria include stage IIIA-IIIC (AJCC v8) NSCLC; baseline grade 0-2 dyspnea, cough, and dysphagia; and no contralateral hilar or supraclavicular/cervical lymph node involvement. Subjects will be randomized (1:1) to CBCT-based daily ART or non-adapted RT using IMRT or VMAT delivering 60-66 Gy in 30-33 fractions with concurrent platinum doublet chemotherapy. Adjuvant immunotherapy with durvalumab is permitted. Follow-up for study participants will be for 1-year post-completion of chemoRT. Study endpoints include: frequency of PRO-CTCAE score ≥3 cough, dyspnea, or dysphagia from randomization to 30 days post-chemoRT; patient-reported quality of life (FACT-L and EQ-5D-5L questionnaires); percentage of lung receiving ≥20 Gy; mean doses to lung, heart, and esophagus; primary tumor response on CT or PET-CT (RECIST v1.1); local disease progression; and incidence of grade ≥2 pneumonitis within 1 year. Stratification factors are the treating institution and the presence of contralateral mediastinal lymph node metastases (associated with increased volume of irradiated lung). Interim analyses for futility and superiority will be performed when the primary endpoint data have been collected for 50% of evaluable participants. This study opened to enrollment on 20 October 2022 and is expected to be completed in approximately 3 years. This prospective, randomized clinical trial rigorously evaluates the impacts of daily online ART on radiation pneumonitis, esophagitis, and quality of life in patients with advanced NSCLC. It will collect standard tumor response and disease progression metrics to assure that reduced margins do not have an adverse impact on outcomes. Online ART is emerging as an innovative approach enabling increased sparing of normal tissues. The results of this clinical study will support evidence-based clinical decisions around ART technologies.

Incidence, outcomes, and risk factors of acute immune checkpoint inhibitor (ICI) pneumonitis post-chemoradiation with durvalumab for patients with locally advanced non-small cell lung cancer (LA-NSCLC): A population-based multicenter study.

8561 Background: The PACIFIC trial has drastically changed the LA-NSCLC treatment paradigm and improved survival outcomes with consolidation durvalumab post-chemoradiotherapy. Despite these promising results, real-world practice has demonstrated that ICI pneumonitis can have significant clinical complications and terminate consolidation therapy prematurely. This study aimed to identify clinical predictors, outcomes, and healthcare utilization in ICI pneumonitis in LA-NSCLC patients who received consolidation durvalumab in real-world practice. Methods: Using the Alberta Immunotherapy Database, we retrospectively evaluated all NSCLC patients who received durvalumab in Alberta, Canada from January 2018 to December 2021. Pneumonitis cases were identified based on radiographic changes and oncologists’ clinical assessments. We examined incidence and predictive values of severe pneumonitis (≥grade 3), with secondary outcomes of overall survival (OS) and time-to-treatment failure (TTF). Exploratory multivariate analyses were performed to identify predictive values to developing severe pneumonitis and worse OS/TTF. Results: Of 189 total patients, most were ECOG 0-1 (91%) and had partial response from chemoradiation (85%) prior to durvalumab. 49% received full year of therapy (n = 93). Median TTF was 11.2 months, and median OS of 19.7 months with 1-year OS 64% (n = 121). 26% (n = 49) developed any grade of pneumonitis. 9% (n = 17) had severe pneumonitis. Corticosteroids were administered to 86% of the pneumonitis patients (n = 42); 53% (n = 26) required admission. 13% (n = 9) of deaths were attributed to pneumonitis. Male gender and pre-existing autoimmune condition were associated with severe pneumonitis whereas V20 (percentage of irradiated lung volume ≥20Gy) was associated with developing any grade pneumonitis. In multivariable analysis, male gender and V20 was significantly associated with worse OS whereas older age, smoking status, pneumonitis, and male gender with lower TTF. Pneumonitis development was found to be an independent risk factor for worse OS (p = 0.038) and TTF (p = 0.007). Conclusions: We report a pneumonitis incidence comparable to prior retrospective studies and higher rate of severe pneumonitis compared to PACIFIC trial. Our results corroborate that V20, a previously established risk factor for durvalumab associated pneumonitis, is a significant predictor for developing pneumonitis and worse OS. In contrast to smaller retrospective studies, we observed male gender and pre-existing autoimmune conditions appear to predict severe durvalumab associated ICI pneumonitis. These results affirm the importance of careful patient selection for safe completion of consolidation durvalumab in real-world LA-NSCLC population.

A Prospective Study of Differences in the Incidence of Radiation Pneumonitis in Elderly Patients between Volumetric Arc Modulated Therapy and Step-and-Shoot Intensity-Modulated Radiation Therapy

<h3>Purpose/Objective(s)</h3> Studies have shown that the incidence of radiation pneumonitis in elderly patients with thoracic tumor radiotherapy is high, and there is a significant correlation with smoking, pulmonary dysfunction, combined chemotherapy, radiation dose and radiation site. VMAT is considered a large-scale low-dose radiation therapy modality, while Step and Shot's IMRT is a small-scale low-dose radiation therapy modality. To test whether these two radiotherapy modalities have different incidences of radiation pneumonitis in elderly lung cancer patients, we conducted this prospective randomized controlled study. <h3>Materials/Methods</h3> A total of 50 elderly patients with non-small cell lung cancer (NSCLC) diagnosed from January 2019 to January 2020 were included and randomly divided into the VMAT group and the IMRT group according to the ratio of 1:1. We collected all irradiated lung volumes from 5 to 75 Gy at the interval of 5 Gy. The occurrence of radiation pneumonitis within six months after treatment was followed up. Fisher's exact test was used to analyze the incidence of radiation pneumonitis between the two groups. In addition, linear regression was used to analyze the fitting situation of radiation pneumonitis in the two groups with an interval of 5 Gy. <h3>Results</h3> The average age was 69 yrs, lung volume was 3310±837 ml, radiation dose was 68.8±8.3 Gy. The I to V levels of radiation pneumonitis were 12, 10, 2, 1, 0 in VMAT and 10, 12, 3, 0,0 in IMRT, respectively, P=0.610 with Fisher`s exact test. Judging from the coefficient of determination (R2) of the fitted model, no matter which grouping, the dose and the inflammatory ratio were linearly correlated and negatively correlated. From the distribution of the scatter plot, the fitting degree of IMRT is higher, and the scatter points are more concentrated on both sides of the curve, while VMAT is more diffuse. The IMRT fitting model is Y=42.19-3.14x, and the VMAT fitting model is Y=36.48-2.91x. The β coefficient (3.14) of the former is greater than that of the latter (2.91), indicating that with the increase of radiation dose, The inflammatory ratio decreased more rapidly. <h3>Conclusion</h3> In this small prospective pilot experiment, we did not directly find a difference in the incidence of radiation pneumonitis between the two radiation therapy modalities. However, in further analysis of the dose distribution in the lungs, we found that the trend of pneumonia incidences in the IMRT group was lower than that in the VMAT group as the dose increased. This study warrants further conduct in elderly patients to demonstrate which radiotherapy modality is more appropriate.

Analysis of normal lung irradiation in radiosurgery treatments: a comparison of lung optimized treatment (LOT) on cyberknife, 4D target volume on helical tomotherapy, and DIBH on linear accelerator.

Quantitative retrospective analysis of the normal lung irradiation due to the variations of the ITV volume based on the techniques used for upper lobe (UL), mid lobe (ML), and lower lobe (LL) lung tumours when used with 2-view, 1-view, 0-view based LOT technique on Cyberknife, AveIP on Helical Tomotherapy, and DIBH on VMAT systems. In the treatment of lung tumours, patients medically inoperable or those who are unwilling to undergo surgery have the option to be treated using radiation therapy. There are many motion control techniques available for the treatment of the moving target, such as movement encompassment, respiratory gating, breath-hold, motion reduction, and tumour monitoring. ITV generation is dependent on technique and hence the volume of the PTVs will differ based on the technique used. This study aimed to determine the influence of these ITVs on the irradiated normal lung volume for UL, ML, and LL lung tumours for 23 patients. The mean difference in the PTV volumes generated with the 0-view technique was significant with that of 2-view and DIBH techniques (p-value < 0.04). The mean difference in the PTV volumes generated by 2-view and DIBH was small for UL, ML, and LL tumours. V5 of the combined lung with the 0-view method was 5% compared to the 2-view method for UL tumours (p-value = 0.04) and the same was 9.5%, and 16.8% for ML and LL tumours (p-value < 0.04). In contrast to all other techniques, lung volume parameters V5, V10, V20, and V30 for the 0-view technology were consistently higher irrespective of the tumour location in the lung. The observed maximum mean lung dose (MLD) was 6.2Gy ± 2.7Gy with the 0-view technique and the minimum was 3.85Gy ± 1.75Gy with the DIBH technique. The difference in MLD between DIBH and 2-view was negligible (p-value = 0.67). The MLD increased for LL tumours from 4Gy to 6.5Gy from the 2-view to 0-view technique (p-value = 0.009). There was a significant increase in MLD for LL tumours with the 0-view technique compared to AveIP (1.9Gy, p-value = 0.04) and DIBH (2.0Gy, p-value = 0.003) technique. For ML and UL tumours, except for 0-view and 1-view, the difference in the MLD between the rest of the methods was not significant (p-value > 0.11). In the treatment of lung tumour patients with SBRT, this study has demonstrated 2-view with Cyberknife and DIBH with VMAT treatment techniques have optimal normal lung tissue sparing. There was a significant increase in the average lung volume receiving 5%,10%, 20%, and 30% dose when comparing the 1-view, 0-view, AveIP, and DIBH techniques to the 2-view technique. However, DIBH with VMAT was dosimetrically advantageous for ML and LL tumours, while providing significantly shorter treatment times than any other technique studied.

Proton beam therapy reduces the risk of severe radiation-induced lymphopenia during chemoradiotherapy for locally advanced non-small cell lung cancer: A comparative analysis of proton versus photon therapy

HypothesisWe investigated differences in severe radiation-induced lymphopenia (SRL) after pencil beam scanning proton therapy (PBSPT) or intensity-modulated (photon) radiotherapy (IMRT) for patients with locally advanced non-small cell lung cancer. MethodsWe retrospectively reviewed 223 patients who received definitive concurrent chemoradiotherapy with PBSPT (n = 29) or IMRT (n = 194). SRL was defined when ≥2 events of absolute lymphocyte counts (ALCs) of <200 cells/μL were observed in weekly laboratory tests conducted during treatment. Stepwise multivariate logistic regression with 10-fold cross-validation was performed to identify predictive values of SRL. Furthermore, 1:2 propensity score matching (PSM) analysis was performed between the PBSPT and IMRT groups. ResultsBaseline ALC was comparable between the PBSPT and IMRT groups (median, 2130 vs. 2040 cells/μL; p = 0.983). Lung volumes receiving ≥ 5–20 GyE and the mean dose were significantly lower in patients receiving PBSPT than those receiving IMRT (p < 0.001). Among 72 (32.3%) patients with SRL; 69 (95.8%) and 3 (4.2%) patients were treated with IMRT and PBSPT, respectively. After multivariable analysis, PBSPT reduced SRL compared to IMRT (odds ratio [OR] 0.13, p = 0.003). Specifically, lung V5Gy were identified as the strongest predictor of SRL before (OR 1.11) and after PSM (OR, 1.07) (p < 0.05). With a median follow-up of 23.0 months, the 2-year overall survival in patients with SRL was worse than that those without SRL (63.4% vs. 79.9%; p = 0.003). ConclusionsReduced irradiated lung volumes of PBSPT consequently reduced SRL. In addition, lung V5Gy contributed to the SRL. Reduction of SRL through the optimized RT might be essential to improve the outcomes.

Changes in Pulmonary Function and Development of Clinical Radiation Pneumonitis in Breast Cancer Patients following Post Mastectomy Radiation Therapy

Background: Lung is the main organ at risk for radiation induced injury while treating breast cancers with Post Mastectomy Radiotherapy (PMRT). Restrictive lung changes are usually seen in spirometry which tends to normalize by 1 year. Central Lung Distance (CLD) is shown to correlate well with the percentage of ipsilateral lung volume irradiated. Aims and Objectives: Spirometric changes following Radiation Therapy (RT) to chest wall in breast cancer patients using conventional fractionation and its correlation with acute radiation pneumonitis. Materials and Methodology: Thirty Breast cancer patients who received RT to chest wall +/- supraclavicular fossa and axilla, following Modified Radical Mastectomy (MRM) and neoadjuvant or adjuvant chemotherapy using tangential beams with Co60 teletherapy to a dose of 50 Gray in conventional fractionation were included and followed up till 6 months post RT. Baseline chest X-ray and spirometry done pre-RT were compared with those taken at 1, 3 and 6 months after completion of RT. Patients were evaluated at each visit for signs and symptoms of radiation pneumonitis, when present were graded as per Radiation Therapy Oncology Group (RTOG) criteria. Results: There was a significant fall in Forced Vital Capacity (FVC) by the end of 3 months (p value &lt;0.01) which improved by 6 months without any active intervention in 95% of the patients. Mean baseline FVC was 83% which decreased to 70% by the end of 3 months and 79% at 6 months. Forced Expiratory Volume in first second (FEV1) and FEV1/FVC did not show any significant change compared to baseline. Spirometric changes correlated with reversible restrictive lung changes. One out of 30 patients developed symptomatic acute radiation pneumonitis (5%) of grade 3 severity who had moderate restrictive lung disease. Conclusion: Significant decrease in FVC of the lungs is present following PMRT in carcinoma of breast patients in the initial 3 months which tends to normalize by 6 months. 5% of the patients develop symptomatic acute lung toxicity which can be further reduced by minimizing the irradiated lung volume.

Late Intervention with Radiation-Induced Lung Fibrosis - Comparing Pamrevlumab Anti-CTGF Therapy vs. Pirfenidone vs. Nintedanib as Mono-, Dual- and Triple-therapy Combinations

Radiation-induced lung fibrosis (RILF) is a major late side effect of radiotherapy of thoracic malignancies. The severity of RILF depends on irradiated lung volume and prescribed dose/fractionation scheme. In contrast to acute and subacute pneumonitis that are responsive to steroids, RILF is a dose-limiting factor for curative treatment of tumors and is an unmet medical need for potential anti-fibrosis therapy. We investigated the impact of pamrevlumab (FG-3019), an anti-CTGF antibody, and compared it to approved IPF (idiopathic pulmonary fibrosis) drugs, pirfenidone and nintedanib, or to their combinations. Late intervention, after fibrosis begins (15-16-week post radiation in mice), is challenging for anti-fibrotic treatment. Therefore, we evaluated if dual or triple combinations of the antifibrotic drugs may elicit superior effects. C57Bl/6 mice received single dose 14.5 Gy whole thoracic irradiation (RT) and the antifibrotic treatments started 16 weeks after RT, when lung remodeling was evident by CT, for 8 weeks. Pamrevlumab or placebo IgG were administered IP 2/wk at 40 mg/kg. Pirfenidone or nintedanib were administered PO at a daily target dose of 300 or 100 mg/kg, either formulated into chow or by gavage. Lung density changes were assessed by CT, and lung function was assessed by blood gas analysis. Gene expression changes were assessed by RNAseq. Pamrevlumab was the only monotherapy to inhibit lung remodeling and to normalize a substantial number of RT-altered transcripts when the IPF drugs were administered in chow. Interestingly, pirfenidone appeared to antagonize some of the benefits of pamrevlumab, which was also supported by transcriptome analysis. Based on the known short plasma half-life of pirfenidone and nintedanib and their possible insufficient exposure in chow, both drugs were administered by gavage for the next experiments to ensure that mice received a full daily dose. Neither drug was tolerable at the full dose, so the daily doses were divided into two parts and administered 2/d. With gavage administration, both pirfenidone and nintedanib inhibited lung remodeling measured by CT (p< 0.05), but pamrevlumab remained the superior monotherapy (p< 0.001). Combining pirfenidone with pamrevlumab did not appear to alter the benefit of pamrevlumab, but the combination of nintedanib with pamrevlumab significantly decreased lung remodeling at 24 weeks after RT compared to pamrevlumab alone (p< 0.01). Pamrevlumab was the only monotherapy to significantly increase median survival (p< 0.01). Addition of pirfenidone or nintedanib to pamrevlumab resulted in non-significant changes of median survival. At late stage RILF development, pamrevlumab monotherapy exhibits potent antifibrotic activity that warrants further clinical evaluation.

Optimal Management of Radiation Pneumonitis: Preliminary Findings of an International Delphi Consensus Study

Radiation pneumonitis (RP) is a dose-limiting toxicity for patients undergoing radiotherapy (RT) and systemic therapy for lung cancer; however, the optimal practice for diagnosis, management and follow-up remains unclear. We sought to establish expert consensus recommendations for RP management. Following literature review on RP, 9 open-ended questions related to knowledge, risk-reduction, diagnosis and treatment were generated for this first round of a consensus-building Delphi process. International leaders in multidisciplinary thoracic oncology were invited to participate (n = 31). Key statements regarding RP diagnosis and management were generated from responses to produce statements for Round 2. Participants will be solicited regarding agreement/disagreement with statements using a 5-point Likert scale. Subsequent rounds will seek consensus in areas that remain unresolved. For Round 1, a 74% response rate (n = 23; 12 radiation oncologists, 5 clinical oncologists, 6 respirologists) was achieved. Eighty-three percent of respondents were not aware of any guidelines for management of RP and 17% used local guidelines or expert review articles. Clinical history, exam and lab criteria (13 respondents) and imaging (15 respondents) were cited as used for diagnosis, and RTOG (9 respondents) and CTCAE grading (14 respondents) for assessment. Radiation-specific factors predictive of RP included irradiated lung volume (especially V20), dose, RT technique and location. The majority of clinical and radiation oncologists used motion management, image guidance and IMRT planning to achieve dosimetric constraints and minimize normal lung dose. Systemic therapy-related RP predictive factors included adjuvant or concurrent chemotherapy, immunotherapy (IO), and use of other pulmonotoxic medications. Patient-related predictive factors included lung function, autoimmune disease, age, performance status and smoking status. Majority of clinicians use risk stratification of patients in order to mitigate RP. Respondents uniformly agreed that steroid therapy is the mainstay of treatment for moderate to severe RP, with variability in the dosing and tapers used. A multidisciplinary management approach was favored by all, including radiation and medical oncologists, respirologists, thoracic radiologists and/or infectious disease or rheumatology specialists if indicated. The majority believe that IO will add complexity in identifying RP. Regarding additional measures to prevent RP in IO patients, respondents were split, with 50% taking additional measures and 50% not, though majority favored monitoring by oncologists during IO cycles and counseling patients on increased RP risk. Responses from international thoracic oncology experts highlight areas lacking consensus in the diagnosis and management of RP. These data will inform the next round of Delphi questions, with an aim of reaching consensus on this common issue.

Lung Density Changes Following SBRT: Association with Lung Dose and Clinical Pneumonitis

Radiation pneumonitis is an inflammation of the lungs that can develop following radiation therapy, the cause of which is not fully understood. The hypothesis of this study is that radiation induced lung changes are associated with radiation dose to the lung and pneumonitis. This work investigates the relationship between lung dose and the development of radiographic lung changes following stereotactic body radiotherapy (SBRT). In addition, the lung dose and radiographic changes were investigated for their ability to predict the development of clinical grade ≥2 radiation pneumonitis (RP≥2). Regions of consolidation (dense) and ground-glass opacities (hazy) were semi-automatically contoured on 262 3- and 6-month post treatment CT-scans for 145 subjects who underwent SBRT between 2008 and 2018 receiving 40-60 Gy in 3-10 fractions. 84% of the subjects received 48Gy in 4 fractions. RP≥2 was diagnosed in 9 patients (6%). The PTV volume, relative and absolute lung volumes irradiated within defined dose bins were extracted from the treatment plans. Volumes of dense and hazy radiographic changes, both absolute volumes in mL and volumes normalized by the PTV volume were assessed at 3- and 6-months. Correlations for all 3- and 6-month hazy and dense volumes with PTV volumes, relative and absolute lung volumes in defined dose bins, and treatment technique (3D conformal radiotherapy (3DCRT), static intensity modulated radiotherapy (IMRT), or volumetrically modulated arc therapy (VMAT)) were established through Spearman correlation using Bonferroni correction. Univariate logistic models, using the Firth small sample bias correction, were developed for predicting RP≥2. PTV volume and relative lung dose bins between 25 and 40 Gy were significantly correlated with the hazy and dense volumes on both the 3 and 6 month images (p=<0.0001-0.0019). There was no significant difference in the hazy or dense volumes at either 3- or 6-months by the treatment technique. Subjects developing RP≥2 on average demonstrated a 2- to 4-fold increase in the hazy and dense absolute and normalized volumes at both 3- and 6-months (n.s.). The 3-month dense (p=0.03), 6-month dense (p=0.02), 6-month dense normalized (p=0.04), and 6-month hazy volumes (p=0.03) were significantly correlated with RP≥2 in univariate logistic models (AUC 0.64-0.67). Lung V20-40Gyappears to be correlated with radiographic changes following lung SBRT. While irradiated lung volumes were not correlated with RP≥2, the amount of dense volume present at 3 and 6 months in particular appears to be related to the development of RP≥2. This observation indicates that in addition to dose, demographic and clinical factors may influence the development of RP and need to be further investigated.

Increased Radiation Pneumonitis after Crizotinib and Concurrent Thoracic Radiotherapy in Patients with ALK-positive Non-small-cell Lung Cancer

Crizotinib, an inhibitor of anaplastic lymphoma kinase (ALK), was approved by Food and Drug Administration (FDA) for the treatment of patients with ALK-positive non-small cell lung cancer (NSCLC) and its administration has achieved considerable success. Preclinical studies have demonstrated crizotinib in combination with radiation could enhance the inhibitory effect on ALK-positive NSCLC. Radiation pneumonitis is a dose limiting toxicity of radiotherapy, affecting its therapeutic ratio. However, the impact of crizotinib when administered in combination with thoracic radiotherapy (TRT) on the risk of pneumonitis has not been described, including both the concomitant and sequential use of radiotherapy. Patients with ALK-driven NSCLC treated with crizotinib, with or without TRT, were identified at two institutions from 2013 to 2018. Pneumonitis was diagnosed by the treating investigator and graded in real time by using Common Toxicity Criteria for Adverse Events (version 4.0). Clinical, radiologic, and pathologic features of pneumonitis were collected. Receiving both treatments within 1 month was considered concurrent and any treatment up to 9 months apart was considered sequential. We identified 214 patients who had NSCLC with an oncogenic alteration in ALK receptor and were treated with crizotinib (15 with and 209 without TRT). Among the 15 patients treated with crizotinib and TRT, 4 received concurrent therapy and 8 received sequential therapy. All 4 patients in concurrent group developed grade 2 or 3 pneumonitis at some point during crizotinib therapy. Time to onset of pneumonitis ranged from 14 days to 61 days in concurrent group. Imaging analysis was strongly consistent with lung parenchyma changes in the irradiated lung volume receiving a total dose of 15-38 Gy. Pulmonary toxicity was manageable; however, interruption of crizotinib therapy was not necessary. Three (37.5%) experienced development of a grade 2 pneumonitis in sequential group. Pneumonitis in irradiated lungs did not aggravate after crizotinib therapy in sequential group. In conclusion, this is, to our knowledge, the first report of lung toxicity after treatment with crizotinib and TRT. We observed a high incidence of pulmonary toxicity when crizotinib and concurrent TRT were administered in patients with ALK-positive NSCLC. Careful consideration and monitoring for pneumonitis may be warranted in patients treated with crizotinib in concurrent with TRT. In addition, using other schedules (e.g., sequential as opposed to concurrent administration) may be safe and optimal strategies.

Deep inspiration breath-hold for left-sided breast irradiation: Analysis of dose-mass histograms and the impact of lung expansion

BackgroundThe aim of this study was to compare dose-volume histogram (DVH) with dose-mass histogram (DMH) parameters for treatment of left-sided breast cancer in deep inspiration breath-hold (DIBH) and free breathing (FB). Additionally, lung expansion and anatomical factors were analyzed and correlated to dose differences.MethodsFor 31 patients 3D conformal radiation therapy plans were retrospectively calculated on FB and DIBH CTs in the treatment planning system. The calculated doses, structures and CT data were transferred into MATLAB and DVHs and DMHs were calculated. Mean doses (Dmean), volumes and masses receiving certain doses (Vx, Mx) were determined for the left lung and the heart. Additionally, expansion of the left lung was evaluated using deformable image registration. Differences in DVH and DMH dose parameters between FB and DIBH were statistically analyzed and correlated to lung expansion and anatomical factors.ResultsDIBH reduced Dmean (DVH) and relative V20 (V20 [%]) of the left lung in all patients, on average by − 19 ± 9% (mean ± standard deviation) and − 24 ± 10%. Dmean (DMH) and M20 [%] were also significantly reduced (− 12 ± 11%, − 16 ± 13%), however 4 patients had higher DMH values in DIBH than in FB. Linear regression showed good correlations between DVH and DMH parameters, e.g. a dosimetric benefit smaller than 8.4% for Dmean (DVH) in DIBH indicated more irradiated lung mass in DIBH than in FB. The mean expansion of the left lung between FB and DIBH was 1.5 ± 2.4 mm (left), 16.0 ± 4.0 mm (anterior) and 12.2 ± 4.6 mm (caudal). No significant correlations were found between expansions and differences in Dmean for the left lung. The heart dose in DIBH was reduced in all patients by 53% (Dmean) and this dosimetric benefit correlated to lung expansion in anterior.ConclusionsTreatment of left-sided breast cancer in DIBH reduced dose to the heart and in most cases the lung dose, relative irradiated lung volume and lung mass. A mass related dosimetric benefit in DIBH can be achieved as long as the volume related benefit is about ≥8–9%. The lung expansion (breathing pattern) showed no impact on lung dose, but on heart dose. A stronger chest breathing (anterior expansion) for DIBH seems to be more beneficial than abdominal breathing.

Developing of predictive models for pneumonitis with forward variable selection and LASSO logistic model for breast cancer patients treated with 3D-CRT

Abstract Purpose: To develop a multiple logistic regression model as normal tissue complication probability model by least absolute shrinkage and selection operator (LASSO) technique in breast cancer patients treated with three-dimensional conformal radiation therapy (3D-CRT), we focused on the changes of pulmonary function tests to achieve the optimal predictive parameters for the occurrence of symptomatic radiation pneumonitis (SRP). Materials and methods: Dosimetric and spirometry data of 60 breast cancer patients were analyzed. Pulmonary function tests were done before RT, after completion of RT, 3, and 6 months after RT. Multiple logistic regression model was used to obtain the effective predictive parameters. Forward selection method was applied in NTCP model to determine the effective risk factors from obtained different parameters. Results: Symptomatic radiation pneumonitis was observed in five patients. Significant changes in pulmonary parameters have been observed at six months after RT. The parameters of mean lung dose (MLD), bridge separation (BS), mean irradiated lung volume (ILVmean), and the percentage of the ipsilateral lung volume that received dose of 20 Gy (IV20) introduced as risk factors using the LASSO technique for SRP in a multiple normal tissue complication probability model in breast cancer patients treated with 3D-CRT. The BS, central lung distance (CLD) and ILV in tangential field have obtained as 23.5 (20.9-26.0) cm, 2.4 (1.5-3.3) cm, and 12.4 (10.6-14.3) % of lung volume in radiation field in patients without pulmonary complication, respectively. Conclusion: The results showed that if BS, CLD, and ILV are more than 23 cm, 2 cm, and 12%, respectively, so incidence of SRP in the patients will be considerable. Our multiple NTCP LASSO model for breast cancer patients treated with 3D-CRT showed that in order to have minimum probability of SRP occurrence, parameters of BS, IV20, ILV and especially MLD would be kept in minimum levels. Considering dose-volume histogram, the mean lung dose factor is most important parameter which minimizing it in treatment planning, minimizes the probability of SRP and consequently improves the quality of life in breast cancer patients.

Endobronchial brachytherapy—A novel approach for the management of airway amyloidosis

PurposeAirway amyloidosis is an uncommon condition and may have variable clinical course. There is no proven systemic therapy, and the management mainly relies on local invasive treatments. Several reports have found external beam radiotherapy to produce durable responses. The optimal dose and fractionation has not been determined. Endobronchial brachytherapy (EBB) has never been reported to affect this disease. MethodsThe study includes a retrospective chart review of all patients with airway amyloidosis treated with EBB at the Davidoff Cancer Center. Data include symptoms, radiotherapy method and dose, treatment outcomes, and toxicities. ResultsThree patients were included. Patients were either symptomatic with extensive airway involvement or have undergone multiple local procedures with rapid recurrence of the amyloid deposits. Two patients had upper and 1 patient had lower airway involvement. Two were treated with external beam radiotherapy and EBB and 1 was treated with EBB only. All patients achieved rapid improvement of symptoms with visible improvement in followup bronchoscopies. EBB doses ranged from 7.5 to 10 Gy. Of the seven lesions treated with EBB, only one lesion recurred 6 months from treatment. No major toxicities were reported. ConclusionsEBB is effective and safe for the management of airway amyloidosis and can offer long-term control. This is the first report of EBB for this indication. EBB should be further explored as means of minimizing the irradiated lung volume.

Improved Overall Survival of Mice by Reducing Lung Side Effects After High-Precision Heart Irradiation Using a Small Animal Radiation Research Platform

The aim was to reduce radiation exposure of the lung in experimental models to increase overall survival of mice to study late radiation-induced heart disease. A new irradiation plan was established on the Small Animal Radiation Research Platformmachine for local heart irradiation of mice with single doses of 8 and 16Gy. Lung damage was analyzed 20, 30, 40, and 50weeks after irradiation by computed tomography scans and histology and compared with a sham-irradiated, age-matched, control group. The use of an 8×6-mm2 collimator enabled local heart irradiation whereby only 18% of the lung received any irradiation. The V10 and V16 of the lung were 14% and 7%, respectively. After a mean heart dose of 8 and 16Gy, mice survived for at least 50weeks after irradiation. Computed tomography images demonstrated increased cell densities in the irradiated lung volume 50weeks after irradiation. Concomitantly, histologic examination revealed fibrotic and inflammatory changes in the irradiated lung volume. In the heart, amyloid depositions and left ventricle hypertrophy were observed. High-precision heart irradiation with 8 and 16Gy using an 8×6-mm2 beam induced cardiac amyloidosis and hypertrophy, which did not lead to myocardial dysfunction despite the presence of radiation pneumopathy in the small V16 of the exposed lung. By using the improved irradiation plan (V16: 7%), long-term survival of the mice after heart irradiation can be achieved that allows clinically relevant experimental investigation of late radiation-induced heart disease effects.

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.

Pulmonary function after lung tumor stereotactic ablative radiotherapy depends on regional ventilation within irradiated lung

PurposeTo determine if regional ventilation within irradiated lung volume predicts change in pulmonary function test (PFT) measurements after stereotactic ablative radiotherapy (SABR) of lung tumors. MethodsWe retrospectively identified 27 patients treated from 2007 to 2014 at our institution who received: (1) SABR without prior thoracic radiation; (2) pre-treatment 4-dimensional computed tomography (4-D CT) imaging; (3) pre- and post-SABR PFTs <15months from treatment. We defined the ventilation ratio (VR20BED3) as the quotient of mean ventilation (mean Jacobian-based per-voxel volume change on deformably registered inhale/exhale 4-D CT phases) within the 20Gy biologically effective dose (α/β=3Gy) isodose volume and that of the total lung volume (TLV). ResultsMost patients had moderate to very severe COPD by GOLD criteria (n=19, 70.1%). Higher VR20BED3 significantly predicted worse change in Forced Expiratory Volume/s normalized by baseline value (ΔFEV1/FEV1pre, p=0.04); n=7 had VR20BED3>1 (high regional ventilation) and worse ΔFEV1/FEV1pre (median=−0.16, range=−0.230 to −0.20). Five had VR20BED3<1 (low regional ventilation) and improved ΔFEV1/FEV1pre (median=0.13, range=0.07 to 0.20). In a multivariable linear model, increasing VR20BED3 and time to post-SABR PFT predicted decreasing ΔFEV1/FEV1pre (R2=0.25, p=0.03). ConclusionsAfter SABR to high versus low functioning lung regions, we found worsened or improved global pulmonary function, respectively. If pre-SABR VR20BED3 is validated as a predictor of eventual post-SABR PFT in larger studies, it may be used for individualized treatment planning to preserve or even improve pulmonary function after SABR.

Changes of systemic immune response after stereotactic ablative radiotherapy (SABR) - first results of a prospective study in early lung cancer patients

INTRODUCTION Non‑small cell lung cancer (NSCLC) is the most common lung tumor. Conventional conservative treatment in medically inoperable patients with early stage NSCLC has poor outcome. To improve treatment efficacy, stereotactic ablative radiotherapy (SABR) has been developed, which enables the delivery of high‑dose radiation to the tumor. OBJECTIVES This prospective study was conducted to test the hypothesis that a sudden death of cancer cells after SABR may lead to changes in systemic immune response. PATIENTS AND METHODS We enrolled 89 treatment‑naive patients with stage T1/2aN0 NSCLC. All patients received SABR, in accordance with treatment standards at our department. Blood samples were collected 3 times: before treatment (n = 89), and then at 2 (n = 86) and 12 weeks (n = 75) after treatment completion to assess the proportion of CD4(+) and CD8(+) T cells, and the expression of T‑lymphocyte transcription factors: T‑bet, GATA‑3, ROR‑γt, and FoxP3. Serum C‑reactive protein (CRP) levels, absolute neutrophil count (ANC), absolute lymphocyte count, and white blood cell (WBC) count were measured to exclude the impact of nonspecific inflammatory reaction. The expression levels of lymphocyte antigens were measured by flow cytometry. RESULTS Serum CRP levels, ANC, and WBC count remained stable during the study. We observed slight lymphopenia, which correlated with irradiated lung volume. After SABR, the proportion of CD8(+), CD4(+), as well as the proportion of CD4(+) T cells expressing GATA‑3(+), T‑bet(+), or ROR‑γt(+) increased, while the number of CD4(+)FoxP3(+) cells (specific for regulatory T cells) decreased. CONCLUSIONS Our findings may suggest that SABR enhances the systemic immune response by increasing the proportion of proinflammatory T‑cell subpopulations.

Stereotactic body radiation therapy for early-stage primary lung cancer, is an active breath coordinator necessary? An audit from a tertiary cancer care center.

The hypofractionated stereotactic body radiation therapy (SBRT) has emerged as a safe and effective treatment modality for early-stage nonsmall cell lung carcinoma. An audit SBRT in primary lung cancer treated in our center with and without an active breath coordinator (ABC) was undertaken to evaluate its impact on target volumes and clinical outcomes. This was an observational study. Nine patients with lung carcinoma were treated from January 2014 to August 2016. Five patients were simulated using ABC and four patients with free breathing. Volumetric modulated arc therapy plans were generated using Monaco treatment planning software. Three patients were treated with a dose of 54 Gy in three fractions and six patients with a dose of 48 Gy in four fractions. The statistical analysis was performed using Kaplan-Meier survival. The mean planning target volumes (PTV) in ABC and free breathing groups were 42.19cc and 60.17cc, respectively. The mean volume of lung receiving 20, 10, and 5 Gy (V20, V10and V5) in ABC group were 5.37cc, 10.49cc, and 18.45cc whereas in free breathing 6.63cc, 12.74cc, and 20.64cc, respectively. At a median follow-up of 18 months, there were three local recurrences. No significant toxicity occurred in our series. Our initial results show that SBRT is well tolerated with good local control. Although the PTV volume and irradiated normal lung volume was higher in this group compared to ABC group, this did not translate to any added clinical toxicity.

Decreasing Irradiated Rat Lung Volume Changes Dose-Limiting Toxicity From Early to Late Effects.

Technological developments in radiation therapy result in smaller irradiated volumes of normal tissue. Because the risk of radiation therapy-induced toxicity generally depends on irradiated volume, changing volume could change the dose-limiting toxicity of a treatment. Recently, in our rat model, we found that early radiation-induced lung dysfunction (RILD) was closely related to irradiated volume dependent vascular remodeling besides inflammation. The exact relationship between early and late RILD is still unknown. Therefore, in this preclinical study we investigated the dose-volume relationship of late RILD, assessed its dependence on early and late pathologies and studied if decreasing irradiated volume changed the dose-limiting toxicity. A volume of 25%, 32%, 50%, 63%, 88%, or 100% of the rat lung was irradiated using protons. Until 26 weeks after irradiation, respiratory rates were measured. Macrovascular remodeling, pulmonary inflammation, and fibrosis were assessed at 26 weeks after irradiation. For all endpoints dose-volume response curves were made. These results were compared to our previously published early lung effects. Early vascular remodeling and inflammation correlated significantly with early RILD. Late RILD correlated with inflammation and fibrosis, but not with vascular remodeling. In contrast to the early effects, late vascular remodeling, inflammation and fibrosis showed a primarily dose but not volume dependence. Comparison of respiratory rate increases early and late after irradiation for the different dose-distributions indicated that with decreasing irradiated volumes, the dose-limiting toxicity changed from early to late RILD. In our rat model, different pathologies underlie early and late RILD with different dose-volume dependencies. Consequently, the dose-limiting toxicity changed from early to late dysfunction when the irradiated volume was reduced. In patients, early and late RILD are also due to different pathologies. As such, new radiation techniques reducing irradiated volume might change the dose-limiting toxicity of the radiation therapy treatment.

TU-F-CAMPUS-J-01: Dosimetric Effects of HU Changes During the Course of Proton Therapy for Lung Cancer

Purpose: To characterize the changes in Hounsfield unit (HU) in lung radiotherapy with proton beams during the course of treatment and to study the effect on the proton plan dose distribution. Methods: Twenty consecutive patients with non-small cell lung cancer treated with proton radiotherapy who underwent multiple CT scans including the planning CT and weekly verification CTs were studied. HU histograms were computed for irradiated lung volumes in beam paths for all scans using the same treatment plan. Histograms for un-irradiated lung volume were used as control to characterize inter-scan variations. HU statistics were calculated for both irradiated and un-irradiated lung volumes for each patient scan. Further, multiple CT scans based on the same planning CT were generated by replacing the HU of the lung based on the verification CT scans HU values. Using the same beam arrangement, we created plans for each of the altered CT scans to study the dosimetric effect using the dose volume histogram. Results: Lung HU decreased for irradiated lung volume during the course of radiotherapy. The magnitude of this change increased with total irradiation dose. On average, HU changed by −53.8 in the irradiated volume. This change resulted in less than 0.5mm of beam overshoot in tissue for every 1cm beam traversed in the irradiated lung. The dose modification is about +3% for the lung, and less than +1% for the primary tumor. Conclusion: HU of the lung decrease throughout the course of radiation therapy. This change results in a beam overshoot (e.g. 3mm for 6cm of lung traversed) and causes a small dose modification in the overall plan. However, this overshoot does not affect the quality of plans since the margins used in planning, based on proton range uncertainty, are greater. HU needs to change by 150 units before re-planning is warranted.