Mean Lung Dose Research Articles

A Dosimetric Study Comparing Different Radiotherapy Planning Techniques With and Without Deep Inspiratory Breath Hold for Breast Cancer.

To analyze whether deep inspiratory breath hold (DIBH) would be dosimetrically beneficial irrespective of radiotherapy planning techniques for patients with left breast cancers requiring adjuvant radiotherapy. Planning CT scans were taken in free-breathing (FB) as well as deep-inspiration breath hold (DIBH) for patients requiring adjuvant radiotherapy for left breast cancers. After registration, three radiotherapy plans - 3D-conformal radiotherapy (3DCRT), intensity modulated RT (IMRT), and volumetric modulated arc-therapy (VMAT) - were generated for both FB and DIBH scans for each patient. The dose-volume parameters were collected from the dose-volume histogram and analyzed. A paired t-test is used for statistical analysis of the parameters. The study was conducted on thirteen patients. The mean dose of the left lung was reduced with DIBH by 32%, 24%, and 6% (8.6 Gy, 6.6 Gy, and 6.4 Gy) with 3DCRT, IMRT, and VMAT, respectively. The mean heart dose was reduced by 3.3 Gy (2.2 vs 5.5 Gy), 2.2 Gy (7.5 vs 9.7 Gy), and 1.2 Gy (5.8 vs 7 Gy) with 3DCRT, IMRT, and VMAT with DIBH. Similarly, the left anterior descending artery (LAD) mean dose was relatively reduced by 80%, 34%, and 20% when compared with the FB scans for 3DCRT, IMRT, and VMAT respectively, with max dose in the 3DCRT plan. DIBH appears to have maximum benefit in achieving a better sparing of organs-at-risk for patients being considered for 3DCRT, and to a lesser extent with even IMRT and VMAT techniques.

Development and validation of a random forest model for predicting radiation pneumonitis in lung cancer patients receiving moderately hypofractionated radiotherapy: a retrospective cohort study

Radiation pneumonitis (RP) is a type of toxicity commonly associated with thoracic radiation therapy. We sought to establish a random forest (RF) model and evaluate its ability to predict RP in patients with non-small cell lung cancer (NSCLC) receiving moderately hypofractionated radiotherapy (hypo-RT). A total of 106 patients with stage II-IVa NSCLC who received moderately hypofractionated helical tomotherapy (2.3-3.0 Gy/fraction) at Zhongshan Hospital were included. All enrolled patients were divided chronologically into the training (67 patients) and validation (39 patients) groups. Higher than or equal to grade 2 RP was defined as the end point. Logistic regression and RF models were established and compared using the receiver operating characteristic (ROC) and a confusion matrix in the training and validation groups. The cumulative incidence of the end point was 25.4% and 17.9% in the training and validation groups, respectively. Logistic regression models were constructed by dosage parameters of total lungs, ipsilateral or contralateral lungs, respectively. ROC analysis revealed that the dosimetric factors of total lungs yielded a superior classification performance than did that of the ipsilateral or contralateral lungs [area under the curve (AUC) =0.920, AUC =0.701, and AUC =0.661, respectively]. Furthermore, the RF model yielded a better prediction capacity than did the traditional logistic model based on the dosimetric factors of the total lungs (accuracy: 88.06%; precision: 84.62%; sensitivity: 64.71%; specificity: 96.00%). Moreover, the RF identified mean lung dose [MLD; mean decrease gini (MDG) =5.74], V20 (MDG =4.62), and V35 (MDG =3.08) of total lungs as the most common primary differentiators of RP. Our RF model established based on the dosimetric parameters of the total lungs could accurately predict the RP risk in patients with NSCLC treated with moderately hypofractionated tomotherapy.

Predictors of Pneumonitis in Patients With Locally Advanced Non-Small Cell Lung Cancer Treated With Definitive Chemoradiation Followed by Consolidative Durvalumab

PurposeIn patients with locally advanced, unresectable non-small cell lung cancer (NSCLC), the standard of care is concurrent chemoradiation (CRT) followed by consolidative immunotherapy with durvalumab. Pneumonitis is a known adverse event of both radiation therapy and immune checkpoint inhibitors such as durvalumab. We sought to characterize pneumonitis rates and dosimetric predictors of pneumonitis in a real-world population of patients with NSCLC treated with definitive CRT followed by consolidative durvalumab. Methods and MaterialsPatients with NSCLC from a single institution who were treated with definitive CRT followed by consolidative durvalumab were identified. Outcomes of interest included pneumonitis incidence, type of pneumonitis, progression-free survival, and overall survival. ResultsSixty-two patients were included in our data set treated from 2018 to 2021 with a median follow-up of 17 months. The rate of grade 2+ pneumonitis in our cohort was 32.3%, and the rate of grade 3+ pneumonitis was 9.7%. Lung dosimetry parameters including V20 ≥30% and mean lung dose (MLD) >18 Gy were found to be correlated with increased rates of grade 2+ and grade 3+ pneumonitis. Patients with a lung V20 ≥30% had a grade 2+ pneumonitis rate at 1 year of 49.8% compared with 17.8% in patients with a lung V20 <30% (P = .015). Similarly, patients with an MLD >18 Gy had a grade 2+ pneumonitis rate at 1 year of 52.4% compared with 25.8% in patients with an MLD ≤18 Gy (P = .01). Moreover, heart dosimetry parameters including mean heart dose ≥10 Gy were found to be correlated with increased rates of grade 2+ pneumonitis. The estimated 1-year overall survival and progression-free survival of our cohort were 86.8% and 64.1%, respectively. ConclusionsThe modern management of locally advanced, unresectable NSCLC involves definitive chemoradiation followed by consolidative durvalumab. Pneumonitis rates were higher than expected in this cohort, particularly for patients with a lung V20 ≥30%, MLD >18 Gy, and mean heart dose ≥10 Gy, suggesting that more stringent radiation planning dose constraints may be needed.

Dosimetric Comparison of IMRT Versus 3DCRT for Post-mastectomy Chest Wall Irradiation: An Analytical Observational Study

Purpose: To compare the dose distribution of three-dimensional conformal radiation therapy (3DCRT) with intensity-modulated radiation therapy (IMRT) for post-mastectomy radiotherapy (PMRT) to left chest wall. Materials and Methods: 30 post-MRM female breast cancer patients with histologically confirmed infiltrating ductal carcinoma of unilateral left breast without evidence of distant metastasis or second malignancy were found eligible during January 2017 to December 2021. All patients received 45 Gy in 20 fractions. Planning target volume (PTV) parameters -D2, D98, Dmean, V95, and V107—homogeneity index (HI), and conformity index (CI) were compared. The mean doses of lung and heart, percentage volume of ipsilateral lung receiving 5 Gy (V5), 20 Gy (V20), and 49 Gy (V49) and that of heart receiving 5 Gy (V5), 25 Gy (V25), and 42 Gy (V42) were extracted from dose-volume histograms and compared. Results: PTV parameters were comparable between the two groups. CI was significantly improved with IMRT (1.118 vs. 1.224, p &lt; 0.04) but HI was similar (0.0951 vs. 0.0962, p = 0.125) compared to 3DCRT. IMRT in comparison to 3DCRT significantly reduced the high-dose volumes of lung (V20, 24.52% vs. 29.62%; V49, 3.56% vs. 6.42%; p &lt; 0.001) and heart (V25, 5.89% vs. 8.24%; V42, 1.64% vs. 6.12%; p &lt; 0.001); mean dose of lung and heart (10.21 vs. 11.96 Gy and 3.86 vs. 7.42 Gy, respectively; p &lt; 0.001).Conclusions: For left sided breast cancer, IMRT significantly improves the conformity of plan and reduce the mean dose and high-dose volumes of ipsilateral lung and heart compared to 3DCRT, but 3DCRT is superior in terms of low-dose volume.

Volumetric modulated arc therapy (VMAT) comparison to 3D-conformal technique in lung stereotactic ablative radiotherapy (SABR).

Stereotactic ablative radiotherapy (SABR) can be a curative option for non-small cell lung cancer (NSCLC) and oligometastatic lung disease. Volumetric modulated arc therapy (VMAT) has offered further advancements in terms of radiation dose shaping without compromising treatment times however there is potential for greater low-dose exposure to the lung. This study was to assess whether VMAT lung SABR would result in any increase to the dosimetry parameters compared with three-dimensional conformal radiotherapy (3D-CRT) that could confer increased risk of radiation pneumonitis. A total of 53 and 30 3D-CRT treatment plans of patients treated with 48 Gy in 4 fractions were compared. No statistically significant difference in planning target volumes between the VMAT 29.9 cc (range 12.4-58.5 cc) and 3D-CRT 31.2 cc (range 12.3-58.3 cc) P=0.79. The mean of total lung V5, ipsilateral lung V5 and contralateral lung V5 all showed a trend of being smaller in the VMAT treatment group- 14% versus 15.8%, 25.6% versus 30.4% and 1.6% versus 2.2%, respectively, but all were not statistically significant differences. Mean of the mean lung dose MLD, again showed a trend of being lower in the VMAT treatments but was also non-significant, 2.6 Gy versus 3.0 Gy, P=1.0. Mean V20 was the same in both cohorts, 3.3%. The dosimetry for 3D-CRT and VMAT plans were not significantly different including V5, and therefore we conclude that VMAT treatment is unlikely to be associated with an increased risk of radiation pneumonitis.

Pseudo-siamese network combined with dosimetric and clinical factors, radiomics features, CT images and 3D dose distribution for the prediction of radiation pneumonitis: A feasibility study

PurposeRadiation pneumonitis (RP)(grade ≥ 2) can have a considerable impact on patient quality-of life. In previous studies, the traditional method commonly used radiomics and clinical factors for RP prediction. This study aims to develop and evaluate a novel pseudo-siamese network (PSN) to assist radiologists predict RP before radiotherapy based on combination of dosimetric and clinical factors, radiomics features, CT (computed tomography) images, and dose distribution (hybrid model). MethodOne hundred and ten patients with lung cancer (19 RP ≥ 2) who received radiotherapy between 2016 and 2020 were retrospectively enrolled in this study. Dosimetric factors were calculated from DVH (dose-volume histogram), such as lung mean dose, lung V5, and prescription dose. Clinical characteristics were recorded, such as age, sex, smoking status, TN stage, and overall stage. A total of 1419 radiomics features were extracted. Cluster analysis was used for detecting radiomics features that associated with RP. Patients were randomly split into a training set (90 %, 85 non-RP, and 14 RP) and a validation set (10 %, 6 non-RP, and 5 RP). A PSN architecture was designed for combining 1D (dosimetric and clinical factors, radiomics) and 3D (CT images, 3D dose distribution) features. 5-fold cross-validation procedure for estimating the skill of the model on new data. ResultsFor cluster analysis, totally of 106 radiomics features with high correlation were selected. The accuracy was 0.727, 0.636, 0.545, and 0.727 for input dosimetric and clinical factors, dose distribution, CT images, and radiomics features, respectively. The accuracy of hybrid model was 0.818. The sensitivity of hybrid model was 0.800 (95 % confidence interval (CI) [0.299, 0.989]), and specificity was 0.833(95 % CI [0.364, 0.991]). The areas under the receiver operating characteristic curves (AUCs) result in 5-fold cross-validation was 0.77–0.90(mean AUC ± std was 0.85 ± 0.05). ConclusionThis study firstly propose method that the combination of high dimensional and low dimensional features for RP prediction. The results confirm the feasibility of multi-dimensional features predict RP.

Robustness assessment of clinical adaptive proton and photon radiotherapy for oesophageal cancer in the model-based approach

PurposeIn the Netherlands, oesophageal cancer (EC) patients are selected for intensity modulated proton therapy (IMPT) using the expected normal tissue complication probability reduction (ΔNTCP) when treating with IMPT compared to volumetric modulated arc therapy (VMAT). In this study, we evaluate the robustness of the first EC patients treated with IMPT in our clinic in terms of target and organs-at-risk (OAR) dose with corresponding NTCP, as compared to VMAT. Materials and MethodsFor 20 consecutive EC patients, clinical IMPT and VMAT plans were created on the average planning 4DCT. Both plans were robustly evaluated on weekly repeated 4DCTs and if target coverage degraded, replanning was performed. Target coverage was evaluated for complete treatment trajectories with and without replanning. The planned and accumulated mean lung dose (MLD) and mean heart dose (MHD) were additionally evaluated and translated into NTCP. ResultsReplanning in the clinic was performed more often for IMPT (15x) than would have been needed for VMAT (8x) (p = 0.11). Both adaptive treatments would have resulted in adequate accumulated target dose coverage. Replanning in the first week of treatment had most clinical impact, as anatomical changes resulting in insufficient accumulated target coverage were already observed at this stage. No differences were found in MLD between the planned dose and the accumulated dose. Accumulated MHD differed from the planned dose (p < 0.001), but since these differences were similar for VMAT and IMPT (1.0 and 1.5 Gy, respectively), the ΔNTCP remained unchanged. ConclusionFollowing an adaptive clinical workflow, adequate target dose coverage and stable OAR doses with corresponding NTCPs was assured for both IMPT and VMAT.

Volumetric-modulated arc therapy as an alternative to intensity-modulated radiotherapy for primary tumors of advanced non–small-cell lung cancer: A multicenter retrospective analysis based on propensity score matching

Purpose: To investigate the effect of volumetric-modulated arc therapy (VMAT) versus intensity-modulated radiotherapy (IMRT) for advanced non–small-cell lung cancer (NSCLC). &#x0D; Methods: Cases in which the primary tumors were treated with IMRT or VMAT as initial intervention in stages III and IV NSCLC patients from September 2008 to March 2020 were retrospectively analyzed. Propensity Score Matching (PSM) was used to assess the efficacy and toxicity of the two radiotherapy techniques. &#x0D; Results: A total of 637 patients were included, out of which 483 cases were treated with IMRT, while 154 received VMAT. A total of 308 patients were selected after PSM. Patients who were having acute radiation esophagitis and pneumonia treated with VMAT had a lower percentage than those treated with IMRT (p &lt; 0.05) before PSM. However, there was no significant difference in grades 3 - 4 toxicity (χ2 = 2.77, p = 0.096). There were also no significant differences in the primary endpoints between the two groups after PSM (p &gt; 0.05), while for secondary endpoints, all lung V5, and V20, mean lung dose and heart V30, heart V40, mean heart dose in all patients and stage N2 patients in VMAT after PSM were significantly lower than those of IMRT (p &lt; 0.05). &#x0D; Conclusion: Radiation therapy of A-NSCLC primary tumors using VMAT and IMRT seem to produce similar efficacy. The volume parameters of normal tissues and organs is significantly lower in VMAT, especially in patients with stage N2. Therefore, VMAT may be more beneficial for reducing radiation damage in normal tissues and organs.

Explainable Artificial Intelligence for Identification of Dosimetric Predictors of Radiation Toxicity: A Secondary Analysis of RTOG 0617

<h3>Purpose/Objective(s)</h3> Dosimetric predictors of toxicity in patients treated with definitive chemoradiation (CRT) for locally advanced non-small cell lung cancer have been identified, though these are often identified through trial and error or difficult to understand statistical methods. This study utilizes machine learning (ML) evaluated using explainable artificial intelligence (EAI) techniques to empirically characterize dosimetric predictors of toxicity in patients with LA-NSCLC treated with CRT as part of a prospective clinical trial. <h3>Materials/Methods</h3> A secondary analysis was performed to utilize ML EAI to identify dosimetric predictors of treatment-related toxicity in the RTOG 0617 trial. We trained a machine-learning based, gradient-boosted tree (GBT) models of ≥ grade 3 pulmonary, cardiac, and esophageal toxicities using Zubrod performance status, T stage, N stage, group stage, radiation technique, receipt of cetuximab, receipt of consolidative chemotherapy, and available dosimetric parameters. Shapley additive explanation (SHAP) values based on the GBT models were used to identify inflection points to select dosimetric thresholds. Identified thresholds were validated using univariate (UVA) and multivariable (MVA) logistic regression. <h3>Results</h3> Of the patients included on the trial, 471 patients had available dosimetry data. A total of 27 (5.7%), 56 (11.9%), and 45 (9.6%) patients experienced ≥ grade 3 pulmonary, esophageal, and cardiac toxicities, respectively. For pulmonary toxicities, using SHAP plots, lung V5≥57% and ≥82% were identified as an inflection points predictive of pneumonitis, which was validated using MVA, with odds ratios (OR) of 4.04 (p=0.004) and 5.11 (p=0.009), respectively. Upon inspection of lung V20, values ≥30% (OR: 3.23; p=0.011) and ≥39% (OR: 5.42; p=0.003) were predictive. Using mean lung dose, values ≥21 Gy were associated with increased toxicity (OR: 3.52; p=0.004). Use of 3DCRT was significantly associated with increased pneumonitis only in the V5 ≥57%, V5 ≥82%, V20 ≥39% MVAs. When assessing esophagitis, esophagus V20 ≥36% (OR: 4.76; p=0.010) and ≥74% (OR: 4.82; p=0.002) were associated with increased risk, as were mean values ≥21 Gy (OR: 4.66; p=0.004) and ≥32 Gy (OR: 3.30; p<0.001). In all of these analyses, radiation technique did not have a significant impact but receipt of consolidative chemotherapy was protective against esophagitis. On evaluation of cardiac dosimetric parameters, only heart V40 ≥57% (OR: 2.04; p=0.032) was predictive of cardiotoxicity. Only group stage was also significantly associated with cardiotoxicity. <h3>Conclusion</h3> Using validation with logistic regression, we demonstrated the feasibility of ML EAI approaches to identify dosimetric predictors of toxicity. Using this method, new dosimetric thresholds were identified, pending validation in larger datasets. Our findings support the utilization of ML EAI for empiric determination of radiation treatment planning considerations.

Cardiac and Pulmonary Dosimetric Parameters in Lung Cancer Patients Undergoing Post-Operative Radiation Therapy in the Real-World Setting

<h3>Purpose/Objective(s)</h3> The recently published Lung ART trial reported increased rates of cardiac and pulmonary toxicity in the post-operative radiation therapy arm. It remains unknown whether the dosimetric parameters reported in Lung ART are representative of real-world practice. The purpose of this study is to examine heart and lung dose exposure in patients receiving post-operative radiation therapy for non-small cell lung cancer (NSCLC) across a statewide consortium. <h3>Materials/Methods</h3> From 2012 to 2020, 377 patients at 27 academic and community centers within the Michigan Radiation Oncology Quality Consortium (MROQC) underwent surgical resection followed by post-operative radiation therapy for non-metastatic NSCLC. Demographic and dosimetric data were prospectively collected for these patients. Rates of 3D-CRT and IMRT use were analyzed. Mean heart dose (MHD), heart V5, heart V35, mean lung dose (MLD), lung V20, target volume and minimum dose to 95% PTV were calculated for these patients and the reported dosimetric parameters were stratified by treatment modality. <h3>Results</h3> 51% of patients in this cohort had N2 disease at the time of surgery, 18% had a positive margin. 65.8% of patients were treated with IMRT compared to 32.1% treated with 3D-CRT. Average MHD for all patients was 10.3 Gy, mean Heart V5 was 40.3% and mean heart V35 was 12.6%. Average MLD was 11.2 Gy and mean lung V20 was 18.9%. These dosimetric parameters did not significantly differ based on treatment modality, with MHD and MLD 9.9 Gy and 10.1 Gy, respectively, for patients treated with 3D-CRT compared to 10.6 Gy and 11.8 Gy for patients treated with IMRT. <h3>Conclusion</h3> Cardiac and lung dosimetric parameters for patients receiving post-operative radiation therapy for NSCLC are similar to the dosimetric characteristics reported in Lung ART. The mean heart and mean lung doses observed are slightly lower (MHD 10.3 Gy, MLD 11.2 Gy) compared to Lung ART (MHD 13 Gy, MLD 13 Gy), possibly owing to increased use of IMRT. These data support application of Lung ART's findings outside of the clinical trial setting.

Dosimetric Risk Factors for Radiation Pneumonitis in Patients with Prior Receipt of Immune Checkpoint Inhibitors: A Retrospective Study

<h3>Purpose/Objective(s)</h3> Dosimetric parameters (e.g., mean lung dose (MLD), V20, and V5) can predict radiation pneumonitis (RP). Constraints thereof were formulated before the era of combined immune checkpoint inhibitors (ICIs) and radiotherapy, which could amplify the RP risk. Dosimetric predictors of acute RP (aRP) in the context of ICIs are urgently needed because no data exist thus far. <h3>Materials/Methods</h3> All included patients underwent thoracic irradiation, previously received ICIs, and followed-up at least once. Logistic regression models examined predictors of aRP (including a priori evaluation of MLD, V20, and V5), and their discriminative capacity was assessed by receiver operating characteristic analysis. <h3>Results</h3> Median follow-up of the 40 patients was 5.3 months. Cancers were lung (80%) or esophageal (20%). ICIs were PD-1 (85%) or PD-L1 (15%) inhibitors (median 4 cycles). Patients underwent definitive (n=19), consolidative (n=14), or palliative (n=7) radiotherapy; the median equivalent dose in 2 Gy fractions (EQD2) was 60 Gy (IQR, 51.8-64 Gy). Grades 1-5 aRP occurred in 25%, 17.5%, 15%, 2.5%, and 5%, respectively. The only variables associated with any-grade aRP were V20 (p=0.014) and MLD (p=0.026), and only V20 with grade ≥2 aRP (p=0.035). Graphs were constructed showing the incrementally increasing risk of aRP based on V20 and MLD, V20=5.2% and MDL=4.0Gy would predict for a 50% risk of ≥ grade 1 pneumonia, and V20=19.3% would predict for a 50% risk for grade 2 pneumonia. <h3>Conclusion</h3> This is the first study illustrating that V20 and MLD may impact aRP in the setting of prior ICIs. If these results are validated by larger studies with more homogeneous populations, the commonly accepted V20/MLD dose constraints could require revision if utilized in the setting of ICIs.

Evaluation of Repeated Lung Stereotactic Body Radiotherapy Using a Radiotherapy Dose Accumulation Routine

<h3>Purpose/Objective(s)</h3> Repeated lung SBRT has been used for recurrent or metachronous non-small-cell lung cancer. Comprehensive evaluation of cumulative dose is essential for safe reirradiation to minimize the risk of pneumonitis and esophageal toxicity. We evaluated an in-house script named RADAR (Radiotherapy Dose Accumulation Routine) designed to provide accurate dose assessment that accounts for registration uncertainties, and improve the efficiency of clinical workflow. <h3>Materials/Methods</h3> In this pilot study, we analyzed a cohort of 20 patients who underwent 2-5 courses of repeated lung SBRT. Lung volume changed 8±8% between courses. Planning CT images from earlier treatment courses were registered onto the final course in two steps: first, a rigid registration based on alignment of spine and rib cage, then a deformable image registration (DIR) using a ‘demons' algorithm in a planning system. The resulting deformable vector fields were used by RADAR to transform voxels for automated dose accumulation. User can choose to output either physical dose or equivalent dose in 2Gy fractions (EQD2, α/β=3) with a discount factor (Paradis, ARO 2019). RADAR provides three approaches for dose accumulation: 1) direct sum that outputs voxel level dose summation; 2) unrestricted search that incorporates DIR uncertainty by conservatively assigning the maximum dose within a search radius (3mm) to the voxel of interest for dose accumulation; 3) restricted search, which performs the same dose accumulation as in 2) but imposes structure label matching in the search radius, therefore including only voxels within the same structure. Accumulated dose distribution was written back to the planning system for evaluation. We extracted mean lung dose (MLD) and esophagus D5cc (EsoD5cc) with respect to various accumulation approaches for comparison. <h3>Results</h3> MLD and EsoD5cc were significantly higher when accounting for DIR uncertainties (<i>p</i><0.001 two-tailed t-test). MLD has less uncertainty than EsoD5cc due to its averaging nature. For radiotherapy with >2 courses, RADAR considerably shortened the processing time by auto-accumulating dose from multiple courses simultaneously, as opposed to the cumbersome manual approach of creating plan sums iteratively. Typical time for dose accumulation and evaluation using RADAR is < 10 mins. <h3>Conclusion</h3> RADAR is a convenient and efficient tool to calculate and evaluate cumulative dose for lung reirradiation cases. It identifies higher OAR doses due to dose accumulation uncertainties, for example coming from the registration. Our study provides initial data to establish clinical guidance for design and optimization of repeated lung SBRT.

Evaluating Radiation-Related Risk Factors for Pneumonitis in Patients with Stage III NSCLC Receiving Durvalumab after Definitive Chemoradiation

<h3>Purpose/Objective(s)</h3> Concurrent chemoradiotherapy (CCRT) followed by durvalumab consolidation up to 12 mo became the standard of care for patients (pts) with stage III NSCLC after the publication of the PACIFIC trial. Both radiation pneumonitis (RP) and immune checkpoint inhibitor pneumonitis (ICI-p) are serious toxicities that can occur in this population, and radiation and ICI modality individually is known to contribute to pneumonitis risk; when combined, they could work synergistically or additively to increase this risk. We set out to evaluate radiation treatment specific risk factors for symptomatic pneumonitis in pts receiving CCRT followed by durvalumab. We hypothesize that adjuvant ICI (durvalumab) will increase the pneumonitis risk from CCRT predicted by current consensus guidelines. <h3>Materials/Methods</h3> We conducted a retrospective study of pts with stage III NSCLC treated with CCRT followed by durvalumab from 2018 -21. Median follow up time was 18.8 mo from the last day of RT to last contact. RT dose parameters were extracted from each treatment plan. Normal lung volume (NLV) was defined as total lung volume minus clinical target volume (Lung -CTV). Percentage of NLV receiving more than 5, 10, or 20 Gy (V5, V10, V20), and mean lung dose (MLD) were calculated. The primary endpoint was development of symptomatic pneumonitis (≥gr 2), assessed via clinical presentation and available imaging. The association between the % NLV of radiation and the probability of developing pneumonitis was analyzed using logistic regression, and odds ratios (OR) were estimated. <h3>Results</h3> Of the 80 patients included in this study, 21 (26.3%) developed symptomatic pneumonitis following durvalumab initiation. 69 (86.3%) received carboplatin-paclitaxel and 11 (13.8%) received cisplatin-etoposide chemotherapy. 73 (91.2%) had received standard RT dose of 60 Gy, while 7 (8.8%) received an additional 12-16 Gy SBRT boost to the primary tumor on a separate study. We found no significant association between symptomatic pneumonitis and RT dose or type of chemotherapy. However, smaller treatment volumes receiving 5 or 10 Gy were associated with lower pneumonitis risk: V10 < 40%, vs ≥ 40% (OR = 0.347, 95% CI 0.11-1.07, P=0.067) and V5 <65% vs ≥65% (OR = 0.42, 95% CI: 0.15-1.17, P = 0.096). Mean MLD was 14.9 Gy (3.9-21.9 Gy), Mean V20 was 25.7% (4.5-40.1%), both well below current consensus guidelines. We did not identify a notable association between pneumonitis and other known clinical risk factors. <h3>Conclusion</h3> This data is from our institution's first cohort of pts treated as in the PACIFIC study after durvalumab was approved by FDA for this indication. Our data suggest pts with a lower radiation treatment volume at 5 or 10 Gy (V5/V10) prior to durvalumab may have a lower risk of developing pneumonitis when other parameters (MLD, V20) are kept under the current recommended radiation tolerance without adjuvant ICI. Further research with larger study populations is needed to confirm this and inform guideline development.

Quality of Life Assessment in Patients with Breast Cancer Receiving Radiation Therapy: A Prospective Study

<h3>Purpose/Objective(s)</h3> Quality of life (QOL) is important for cancer patients while it is frequently neglected in clinical patient care as well as cancer research. The purpose of this study is to exam the changes of QOL status and the associated factors during the course of radiation therapy in patients with breast cancer. <h3>Materials/Methods</h3> Invasive breast cancer patients, aged 18-year-old and above requiring adjuvant radiation therapy were eligible. A self-addressed promise questionnaire according to NCI "promise" were used to assess the QOL. The Questionnaires were completed one day prior to and at the end of radiation. Patient, tumor and prior treatment factors were collected during the first visit of the treatment. The primary endpoint was QOL which included physical function, activities, anxiety, depression, fatigue, sleep disturbance and pain. Data are presented as mean ± SD unless otherwise specified. The computer adaptive testing algorithm present in these three PROMIS domains standardized T scores according to a reference population, providing a mean score of 50 and a standard deviation of 10. Statistical significance of QOL between pre-radiation and end-radiation were tested using paired t test. The factors affecting changes of QOL were analyzed by correlation of spearman for continuous variables, and the analysis of variance for categorical variables. P less than 0.05 was considered to be significant. <h3>Results</h3> Between July 2019 and June 2021, a total of 321 breast cancer patients enrolled this study. The mean age was 45 years old. 88.5% patients received hypofractionated radiation with 72.9% patients at stage II-III. All of them signed written consent forms and completed the QOL prospectively. There was no significant difference in the scores of fatigue, sleep disturbance, physical function, activities and pain between pre-radiation and end-radiation. After radiation, anxiety and depression were improved instead. T score of anxiety pre-radiation and end-radiation was 47.68 ± 8.64 and 44.96 ± 7.48 respectively (p = 0.023). The improvement of anxiety was significantly correlated with RT fractions, RT dose and integral dose of the total body (p values < 0.05), but not RT techniques, RT fields, mean lung dose, age, tumor subtypes, surgical approaches, stage and prior chemotherapy. T score of depression pre-radiation and end-radiation was 44.05 ± 5.86 and 42.65 ± 4.74 respectively (p = 0.041). The improvement of depression was significantly correlated with integral dose of the total body and anti-HER2 target therapy (p values < 0.05). <h3>Conclusion</h3> Most QOL measures were not significantly changed after radiation while anxiety and depression improved in patients with breast cancer. Future study with larger cohort shall be investigated to validate these finding. This is part of a prospective study of treatment toxicity, quality of life and biomarker in cancer patients (GCOG0001/NCT05061342).

Whole Tumor vs. FDG-Directed Dose Escalation in Patients with Locally Advanced NSCLC: Evaluation of Isotoxic Treatment Plans from the Randomized ARTFORCE PET-Boost Trial

<h3>Purpose/Objective(s)</h3> In the phase II ARTFORCE PET-Boost trial, two individualized dose escalation strategies, utilizing hypofractionation and functional imaging, were tested aiming to improve local control in patients with locally advanced non-small cell lung cancer (LA-NSCLC). Before randomization, plans for both arms were optimized and normalized to the mean lung dose, approximating isotoxicity. The purpose of this study is to assess the isotoxicity of the two treatment plans for each patient, by comparing planned dose to organs at risk (OAR). <h3>Materials/Methods</h3> The PET-Boost trial included patients with stage II-III NSCLC, with a large primary tumor >4cm. Patients received an escalated dose either to the primary tumor as a whole (arm A), or the FDG-avid areas within the primary tumor (>50% SUV_max) (arm B). Before randomization, two treatment plans were created for each patient, one for each arm, with equal mean lung dose (max 20 Gy). In both arms, the escalated dose was delivered in 24 fractions of 3.0-5.4 Gy, defined by OAR constraints. As the PET-subvolume is smaller than the whole tumor, the dose per fraction could be escalated further. Involved lymph nodes received 66 Gy (24 × 2.75 Gy) in both arms. In this analysis, dose metrics were compared for OARs in the whole tumor vs PET-subvolume arm for each patient. Difference was calculated as metric_armB – metric_armA. Wilcoxon sign rank tests were applied to assess intrapatient differences. <h3>Results</h3> Between 2010 and 2017, 107 patients were randomized in seven European centers. For 87 patients, data from both treatment plans was available for current analysis. The median (+IQR) differences in dose to OARs between arm A and B were as follows: lung Dmean EQD2_α/β=3 -0.3 Gy (-0.5 – 0; p<0.005), lung V5_physical +1.1% (0.2 - 2.7; p < 0.005), lung V20_physical +0.5% (0.1 – 1.3; p<0.005), esophagus Dmean EQD2_α/β=10 +0.1 Gy (-0.9 – 0.6; p = 0.76), esophagus V36_physical +0.1% (-0.7 – 1.2; p = 0.45), esophagus Dmax EQD2_α/β=10 -0.2 Gy (-2.85 – 0.8; p = 0.05), heart Dmax -0.5 Gy EQD2_α/β=3 (-2.1 – 0.6; p = 0.04), heart Dmean -0.1 Gy EQD2_α/β=3 (-1.5 – 0.1; p < 0.005), brachial plexus Dmax_physical -0.3 Gy (-2.1 – 0.1; p=0.01), and spinal cord Dmax_physical -0.4 Gy (-2.1 – 0.8; p=0.03). We found that outliers with larger differences tended to have either very large primary tumors, or relatively small (≤ 70 cm³) tumor volumes. <h3>Conclusion</h3> An international trial was performed which randomized LA-NSCLC patients between two dose-escalation strategies that aimed to be isotoxic. Though most statistically significance, we found generally small differences in dose to OAR between the two plans. Our results confirm by aiming at an equal mean lung dose, doses to heart, esophagus, brachial plexus and spinal cord were also to a large extent kept isotoxic. Analyses of dose volume histograms in relation to adverse events reported in the trial is ongoing. This study has the ClinicalTrials.gov identifier NCT01024829.

Single Institute Experience – Linear Accelerator Based Total Body Irradiation Using Volumetric Modulated Arc Therapy Planning in Standard Size Linear Accelerator Room

<h3>Purpose/Objective(s)</h3> To share experience of linear accelerator based total body irradiation (TBI) with volumetric modulated arc therapy (VMAT) in a standard size linear accelerator room <h3>Materials/Methods</h3> 30 patients aged 2-18 years (between 2018-2021) were treated with TBI as conditioning for bone marrow transplant (BMT)using VMAT based plan on our linear accelerator in a standard sized linear accelerator room. Indication of BMT was – acute lymphoblastic leukemia, acute myelogenous leukemia, chronic myeloid leukemia, myelodysplasia, aplastic anemia etc. Patient selection involved assessment regarding need of anesthesia, details of previous radiation, details of conditioning regimen for scheduling, organs dysfunction, adequate counselling and written consent from parents. With or without anesthesia, patients were immobilized using full body vacloc, head rest, brain orfit cast and knee rest. Position was supine, hands by side. Both head first (HF) and feet first (FF) scans were acquired if body length was more than 120 cm (for 120 cm, HF scan alone was acquired). A wire was placed on thigh to aid fusion of HF and FF scans for plan evaluation. Fiducials at three levels and optically stimulated luminescent dosimeter for dose monitoring were placed. Dose was 2-4 Gy single fraction and 12-13.2Gy/6 fractions (twice daily over 3 days, with 6 hours gap) based on chemotherapy conditioning regimen- delivered to 14 and 16 patients respectively. The planning objective was 90-100% coverage and dose max less than 120%. For multifraction plans, target was mean dose to lungs and kidney less than 10 Gy and 8Gy respectively. VMAT plans were generated with 3-5 iso-centers with fixed couch vertical and lateral values and changing longitudinal value, ensuring only longitudinal couch movement. Plan was made using 6MV energy and 5-9 arcs and 3 cm overlap between fields (avoid over joints to prevent effusion and over lungs to reduce lung dose) <h3>Results</h3> Mean PTV V95 – 93% (92-96%), Dmax – 115% mean (109%-120%). Mean lung dose (for 12-13.2Gy plans) was 9.4Gy/ (9-10 Gy), kidney mean dose was 7.8Gy (7.5-8 Gy). Mean monitor units in the plans were 1120 for complete arc and 690 for partial arcs. Treatment was delivered in strict aseptic precautions, under cover of steroids and antiemetics - in presence of radiation oncologist and physicist. Cone beam CT scan was used for position verification before and after treatment. The mean duration of treatment was 75 mins (range 60-90 minutes). 18 patients had grade 2 nausea and vomiting, one had knee joint effusion. No other side effects were reported. All transplants were successful except one reported graft versus host disease. <h3>Conclusion</h3> The procedure needs careful planning and delivery. It is feasible and possible to deliver TBI using VMAT in a standard sized linear accelerator room and should be offered to patients requiring the same.

Efficacy and Toxicity of Stereotactic Body Radiation Therapy Treatment of Multiple Lung Lesions

<h3>Purpose/Objective(s)</h3> As the role of SBRT in caring for patients with complex cancer presentations continues to expand, it is paramount to elucidate how many courses of lung SBRT are safe and what factors predict toxicity. Our study seeks to evaluate the dose-volume factors and associated toxicities for treatment of multiple lung tumors with SBRT. <h3>Materials/Methods</h3> This retrospective IRB approved study was conducted using our institutional database of patients who underwent SBRT for multiple lung lesions between 2012 to 2020. 64 patients underwent SBRT for multiple tumors for a total of 137 tumors treated. We compared dosimetry and clinical outcome parameters of these patients to a paired set of 50 randomly selected patients who received SBRT for a solitary lung lesion. Variables collected include patient age, gender, cancer stage, tumor histology, SBRT dose, dosimetric parameters, toxicities from SBRT, and progression-free survival (PFS). Acute toxicity was defined as any toxicity related to lung SBRT occurring <90 days from the start of SBRT and late toxicity was beyond 90 days from the end of SBRT. Statistical analysis was performed using statistical software. <h3>Results</h3> 137 pulmonary lesions in 64 patients (2+ lesions in every patient) were treated using SBRT at our institution. Of these 137 lesions, 122/137 (89.1%) were primary lung tumors and 15/137 (10.9%) were metastatic lesions. Out of the 137 lesions, 9.5% were classified as SCLC, 43.1% as adenocarcinoma, 36.5% as squamous cell carcinoma, and 10.9% as distant metastases. The mean prescription dose for multi-lesion patients was 50 Gy delivered in 3-5 fractions versus 50 Gy in 5 fractions in the single lesion group. The mean V5 (47.3% vs. 25.7%, p<0.05), V10 (26.8.3% vs. 15.4%, p<0.05), V20 (10.2% vs. 4.5%, p<0.05), and mean lung dose (10.05 Gy vs. 5.29 Gy, p<0.05) were significantly greater in multi-lesion patients compared to single lesion patients, respectively. Fatigue and dyspnea were the most commonly reported acute toxicities; 56.2% multi-lesion patients experienced fatigue and 18.8% experienced dyspnea while 22.0% of single lesion patients experienced fatigue and 12.0% experienced dyspnea (p=0.315). No late toxicities were documented. 126/137 (92.0%) of the lung lesions treated with multiple SBRT treatments demonstrated local control, while 11/137 (8.0%) had local recurrence. 1-year PFS was 92.2% in the multi-lesion group versus 84.0% in the single lesion group. There was no significant correlation between pulmonary toxicity and histology in the single lesion and multi-lesion groups. <h3>Conclusion</h3> Our results suggest that SBRT treatment of multiple pulmonary tumors is safe and feasible without increasing in acute or late pulmonary toxicity. While there is significant difference in all lung parameters between these two groups, it did not translate into increasing toxicity. Further studies are needed to understand the relation between radiation dose parameters and incidence of pulmonary toxicity.

Acute Toxicological Outcomes of Postmastectomy Radiotherapy in Node Positive Breast Cancer with or without Internal Mammary Nodal Irradiation: Preliminary Results of POTANTIAL Trial

<h3>Purpose/Objective(s)</h3> To report acute toxicological outcomes of an ongoing prospective, multicenter, phase III, randomized controlled trial (NCT04320979) designed to evaluate the safety and efficacy of internal mammary node irradiation (IMNI) after mastectomy for high-risk node-positive breast cancer. <h3>Materials/Methods</h3> Eligible patients were randomly assigned (1:1) to receive IMNI (IMNI arm) or not (no IMNI arm). The prescribed dose was either 50 Gy in 25 fractions (conventional fractionated radiotherapy, CFRT) or 43.5 Gy in 15 fractions (hypofractionated radiotherapy, HFRT) Acute toxicities were evaluated weekly during radiotherapy (RT) and at 1 week, 2 weeks, 3 months, 6 months after RT according to Common Toxicity Criteria for Adverse Events v3.0. Clinically significant toxicities were defined as ³ grade 3 dermatitis, esophagitis, myelosuppression and ³ grade 2 pneumonitis. The mean dose, maximum dose, and V10–V50 of ipsilateral lung and neighboring esophagus were evaluated. Chi-square test was performed to compare the differences between IMNI and no IMNI arms. <h3>Results</h3> Between May 8, 2020, and June 8, 2021, 219 patients treated in 14 centers were analyzed with minimum follow-up of 6 months. There were 114 (52.1%) and 105 (47.9%) patients in no IMNI and IMNI arm. Chest wall ± IMN was irradiated with intensity-modulated RT (IMRT) in 196 (89.5%) patients and electrons in 23 (10.5%) patients. Supra/infraclavicular ± axillary nodal regions were irradiated with IMRT technique in all patients. There were 147 (67.1%) patients treated with HFRT and 72 (32.9%) patients treated with CFRT. Among patients treated with HFRT and CFRT, the differences were significant in mean lung dose (13.1 Gy vs 13.4 Gy, p=.048 and 14.4 Gy vs 15.2 Gy, p=.009), V10 of lung (37.0% vs 37.9%, p=.024 and 39.0% vs 41.0%, p=.011), but not significant in mean esophagus dose (14.7 Gy vs 15.3 Gy, p=.447 and 16.9 Gy vs 18.8 Gy, p=.257), V10 of esophagus (58.0% vs 62.1%, p=.260 and 59.0% vs 77.4%, p=.059) between no IMNI and IMNI arm. There were no statistically significant differences in ³ grade 3 dermatitis (1.8% vs 1.0%, p = 1.000), ³ grade 3 esophagitis (0.9% vs 0.0%, p=1.000), or ³ grade 2 pneumonitis (3.8% vs 2.0%, p=.684) between no IMNI and IMNI arm. 108 (49.3%) patients had ≥ grade 3 myelosuppression, including 107 (48.9%) lymphopenia, 6 (2.8%) leucopenia, and no thrombocytopenia. The incidence of ≥ grade 3 myelosuppression were significantly higher in IMNI arm than no IMNI arm (56.2% vs 42.1%, p=.037). <h3>Conclusion</h3> IMNI caused acceptable dermatitis, esophagitis and pneumonitis in breast cancer after mastectomy. Higher risk of myelosuppression, mainly lymphopenia, was found in IMNI arm.

Incidence of Radiation Pneumonitis Among Patients Treated with Concurrent Thoracic Radiotherapy and Osimertinib for Metastatic Non-Small Cell Lung Cancer

<h3>Purpose/Objective(s)</h3> A case series from China published in 2020 reported a high rate of radiation pneumonitis (RP) among 11 patients treated with concurrent thoracic radiotherapy (TRT) and osimertinib, including 9% who developed a fatal complication. We analyzed the RP rates for patients at our institution who were also treated with a similar combination for metastatic non-small cell lung cancer (NSCLC). <h3>Materials/Methods</h3> This retrospective study was performed at a single academic medical center in the US. We identified all patients who were treated with concurrent TRT and osimertinib between June 2016 and December 2021. Baseline patient characteristics, tumor size and location, and dosimetric parameters were evaluated. The highest grade of RP that developed within 6 months of treatment was scored in accordance with CTCAE v5.0. Fisher's exact test and logistic regression were performed to investigate the association of pre-treatment factors with development of grade ≥2 and grade ≥3 RP. <h3>Results</h3> Sixteen patients with metastatic NSCLC were treated with concurrent TRT and osimertinib over the study time period. The treatment site of each patient's pulmonary metastases was as follows: peripheral in 4 (25%), central in 4 (25%) (within 1-2 cm of the proximal bronchial tree [PBT]), ultra-central in 7 (44%) (within 1 cm of the PBT), and mediastinal in 1 (6%). Two of 16 patients withheld osimertinib 24-48 hours before and after TRT, both of which had tumors in an ultra-central location. Patients were treated with a median dose of 50 Gy (11-65 Gy) in a median of 7.5 fractions (1-15 fractions); the median duration of TRT was 10 days (1-22 days). The median follow-up time was 13 months (1 – 61 months). Nine patients developed grade ≥2 RP (56%) with a median time to onset of 29 days (1-84 days). The severity of RP was grade ≥3 in 6 (37.5%) and grade 4 in 1 (6.3%); no patients had grade 5 RP. Of the 6 patients who developed grade ≥3 RP, 2 (33.3%) were treated with stereotactic body radiotherapy (SBRT) while 4 (66.6%) were treated with hypofractionated TRT. All patients who developed grade ≥3 RP were female. Tumor location for patients who developed grade ≥3 RP was central in 3 (50%), ultra-central in 2 (33%) and mediastinal in 1 (17%); no patients with peripheral tumors developed grade ≥3 RP. Both patients who withheld osimertinib before and after TRT did not develop RP. The association of female sex and non-peripheral tumor location with grade ≥3 RP was not statistically significant in the context of a small case series (p=0.23). RP was not associated with the use of SBRT vs hypofractionated TRT or mean lung dose. <h3>Conclusion</h3> TRT with concurrent osimertinib was associated with a high rate of RP, particularly when the site of pulmonary metastases was in a central, ultra-central, or mediastinal location. Withholding osimertinib 24-48 hours before and after TRT may mitigate this risk. These data raise safety concerns that are not currently listed in treatment guidelines. Further research is indicated to validate these findings in larger cohorts.

Definitive Proton Re-Irradiation for Locally Advanced Lung Cancer in the Immunotherapy Era

<h3>Purpose/Objective(s)</h3> Despite advances in the treatment of NSCLC and SCLC, locoregional recurrences or second primary tumors after irradiation (RT) remain a therapeutic challenge due to the toxicity of re-RT and limited efficacy of systemic therapy alone. We evaluated safety and efficacy of definitive intent re-RT with intensity-modulated proton therapy (IMPT). <h3>Materials/Methods</h3> In this single institution retrospective cohort study, consecutive patients with biopsy-confirmed recurrent or second primary NSCLC or SCLC received IMPT re-RT (dose in GyE) after initial definitive intent photon RT (dose in Gy). Univariate associations between variables of interest were examined with ANOVA for categorical variables and Pearson correlation coefficient for continuous variables. Time-to-event variables were estimated using the Kaplan-Meier method and associations modeled by Cox proportional hazards model and log-rank test. <h3>Results</h3> We identified 22 patients with recurrent or second primary NSCLC (n=20) or SCLC (n=2) treated from April 2019 to May 2021. Median initial RT dose was 60 Gy (range 45-70 Gy) with 10 patients (45%) receiving immunotherapy after initial RT. Re-RT started median 28.2 mo (range 8.8-172.9 mo) after initial RT. The median age at re-RT was 71 (range 54-85) with median ECOG performance status 1 (range 0-2). One patient had an actionable mutation and 5 patients had PD-L1 >1%. Most patients had locally advanced recurrences with 50% rT3-4 (n=11) and 59% rN1-3 (n=13). Median re-RT dose was 60 GyE (range 44-60 GyE) frequently in 30 fractions (n=9) or 15 fractions (n=7). With re-RT, 8 patients (36%) received concurrent chemotherapy. Four patients (18%) had immunotherapy after re-RT. Re-RT median lung V20 GyE was 8% (range 2%-26%), lung mean dose was 5.3 GyE (range 0.9-13.9 GyE), heart mean dose was 2.5 GyE (range 0-24.4 GyE), and esophagus mean dose was 6.6 GyE (range 0.2-24.2 GyE). With median follow-up 7.4 months after completion of re-RT, 1-yr OS was 68%, 1-yr PFS was 45%, 1-yr DMFS was 60%, and 1-yr LC was 80%. Higher re-RT and initial RT mean lung doses were significantly associated with worse OS, and there was trend for worse OS among patients with re-RT doses below 50 GyE (Table). Two patients (9%) developed grade 3 toxicities, 1 patient had grade 2 toxicity (5%), and 5 patients (23%) had Grade 1 toxicities. No grade 4 or 5 toxicities were observed. No significant dosimetric correlates were identified with toxicity. <h3>Conclusion</h3> Definitive IMPT re-RT for NSCLC and SCLC can prolong disease control with limited toxicity, particularly in the modern era with routine use of PD-L1 inhibitors. However, careful patient selection and planning are needed for optimal outcomes.