V20 Gy Research Articles

Multi-Criteria Optimization and RapidPlan for Improved Organs at Risk Sparing in Treatment Planning of Malignant Pleural Mesothelioma

Treatment planning for malignant pleural mesothelioma is complex and time-consuming owing to the large volume of the target as well as its overlap and proximity to critical organs. Knowledge-based planning (KBP) model using RapidPlan (RP) was previously developed and clinically tested at our institution for treatment planning of these cases that had undergone pleurectomy-decortication, and therefore had two intact-lungs. The aim of this work is to investigate if multi-criteria optimization (MCO) can further improve the RP model with respect to organ at risk (OAR) sparing without compromising target coverage. The RP model was trained with clinically accepted plans of 57 patients that used Volumetric Modulated Arc Therapy (VMAT) with 2 partial arcs and 6 MV photons. The dose volume histogram (DVH) estimation model was trained to estimate doses to the heart, ipsilateral lung, total lung, contralateral lung, stomach, esophagus, kidneys and liver. Clinical treatment plans for 12 patients were re-planned using RP as well as a combination of RP and MCO. Application of MCO was after RP and used tradeoff exploration to navigate to the improved dose distribution on a Pareto surface. Selection of a plan that further improved OAR sparing while maintaining coverage constraints of PTV D95 and V95 ≥ 94% was made. Dosimetric parameters for clinical plans (CP), plans using RP as well as plans generated with RP and MCO were all compared for 12 new validation cases. Wilcoxon sign-rank test was used for statistical significance testing. The mean heart dose was reduced from 20.9 Gy ± 3.2 Gy for CP to 17.1 Gy ± 4.2 Gy with RP and further to 13.8 Gy ± 3.3 Gy with RP and MCO. The heart V30 Gy was reduced from 23.7% ± 8% to 18.2% ± 9.4% with RP and further to 13.6% ± 5.7% with RP and MCO. The corresponding results for contralateral lung V5 Gy were 68.6% ± 14.1% with CP, 50% ± 26.3% with RP and 45.3% ± 22.8% with RP and MCO, while the mean esophagus dose was reduced from 26.5 Gy ± 3.1 Gy to 21.5 Gy ± 4.7 Gy with RP and further to 19.1 Gy ± 4.2 Gy with RP and MCO. All these dosimetric improvements were statistically significant (p<0.001). However, improvements with RP and MCO for the total lung mean and V20 Gy, liver mean, stomach mean and kidney V18 Gy were marginal over the RP. Sparing of ipsilateral lung V20 Gy was maintained at ≥ 50 cc on average for all plans. PTV D95 and V95 were both normalized at 94%. Combination of RP and MCO significantly improved sparing of the OARs, especially the heart, contralateral lung and esophagus without compromising coverage or doses to other structures. Since doses to the heart, and contralateral lung are known to correlate with incidence of radiation pneumonitis, it would be prudent to consider planning with both RP and MCO to help determine the optimal treatment plan for the individual patient's anatomy.

Effect of Contralateral Esophagus Sparing in Hypofractionated Radiotherapy for Ultra-Central NSCLC

Esophageal toxicity is a known complication of radiotherapy (RT) for ultra-central lung tumors, with ∼5 - 15% of patients developing grade ≥3 esophagitis. Despite increasing adoption of hypofractionated regimens, there are no consensus recommendations for reducing esophageal toxicity in these patients. We previously demonstrated the utility of a novel contralateral esophagus sparing technique (CEST) in a prospective trial of patients with locally-advanced NSCLC receiving concurrent chemoRT (70 Gy/7 weeks). Whether CEST is effective for hypofractionated RT is unknown. The aims of this study were to identify outcomes and toxicities associated with use of CEST in patients receiving definitive hypofractionated RT to ultra-central lung tumors. We retrospectively analyzed the records of consecutive patients with ultra-central NSCLC who received definitive RT to a dose of ≥60 Gy with fraction size ≥3 Gy per day, from 1/1/2015 to 6/30/2022. The esophageal wall contralateral to the tumor was contoured as an avoidance structure. VMAT planning was used to ensure steep dose fall-off across the esophagus while maintaining full tumor coverage. Treatment was delivered using daily cone-beam CT guidance. Toxicity was graded using CTCAE v 4.0. Descriptive statistics were used to analyze outcomes. The study was approved by the IRB. We identified 45 patients with ultra-central NSCLC treated with definitive RT, with median follow-up of 27.3 months. Median age was 74.5 years old [57.6 - 88.2]. Median ECOG PS was 2 [1 - 3]. Twenty-three patients had PTVs located within 1 cm of the esophagus. Median ITV and PTV volumes were 17 cc [1.6 - 154 cc] and 43.6 cc [8.4 - 292 cc], respectively. Median total dose was 60 Gy [60 - 67.5 Gy] in 20 [10 - 20] fractions. Median esophageal Dmax was 24 Gy [2 - 66.7 Gy] for all patients and 36 Gy [12.3 - 66.7 Gy] for patients with tumors located within 1 cm of the esophagus. For the CE, median Dmax, V20 Gy and V25 Gy were 35.7 Gy [17 - 45.2 Gy], 2.1 cc [0 - 6.7 cc] and 0.95 cc [0 - 3 cc], respectively. There were no episodes of grade ≥2 esophagitis (95% CI, 0-7.9%). The rate of grade 1 esophagitis was 13.3% (6.2 - 26.1%). Esophageal Dmax was higher in patients who developed esophagitis (44.5 vs. 26.1 Gy, t = 2.5, p = 0.038). Two patients developed grade 2 pneumonitis (4.4%, 95% CI 0 - 10.5%). There were no episodes of grade ≥3 pulmonary toxicity. There were 3 (6.7%) local recurrences, with 2-year local recurrence rate of 4.4%. Use of CEST to minimize esophageal dose for treatment of ultra-central NSCLC is associated with reduced rates of esophagitis compared with historical controls, without compromising local control. This technique is readily adaptable for clinical practice. More data are needed to refine the empirically derived CE dose-volume constraints, especially for tumors directly abutting the esophagus.

Intensity-Modulated Proton Therapy (IMPT) Offered Advantageous Dosimetry Compared to Volumetric Arc Therapy (VMAT) or Helical Tomotherapy (HT) in Patients with Synchronous Bilateral Breast Cancer

Radiotherapy of synchronous bilateral breast cancer poses some technical challenges with regards to dose coverage and sparing of organs at risk (OAR). In this study, we aimed to evaluate dosimetric characteristics of 3 different techniques, IMPT vs photon (VMAT and HT). We hypothesized that IMPT would result in lower doses to organs at risk, as compared to the other 2 techniques. A total of 10 patients with synchronous bilateral breast cancer who were treated with VMAT at our institution were retrospectively analyzed. Clinical target volume (CTV) included chest wall and regional nodes (supraclavicular fossa and internal mammary chain) and prescription dose was 40.05 Gy in 15 daily fractions. HT and IMPT plans were generated for each patient. Dose-volume statistics, including planning target volume (PTV) coverage and dose to OAR: lungs, heart, thyroid, spinal cord, brachial plexus and esophagus, were compared between modalities using a paired T-test. Mean age of patients was 61 years (43-84). Majority of the patients (80%) were ER+ PR+ and HER2-. 40% of patients underwent breast reconstruction following surgery. All 3 techniques provided adequate target volume distribution and OAR sparing. Compared to VMAT and HT plans, IMPT had better heart and lung sparing effects, resulting in lower mean and V25 Gy heart dose; mean, V20 Gy and V5 Gy lung dose (p<0.0001). There was no significant difference in VMAT and HT plans for mean heart and lung dose. VMAT plans showed significantly lower V25 Gy heart dose on average (p = 0.04). V5 Gy lung dose was slightly lower in HT compared to VMAT plans, approaching statistical significance (p = 0.08). PTV coverage was adequate for all 3 techniques. All techniques fulfilled cord, esophagus, thyroid and brachial plexus constraints. IMPT plans showed significantly better OAR sparing compared to photon techniques. All 3 techniques met OAR constraints, and resulted in adequate target volume coverage. As IMPT is significantly more costly than VMAT or HT techniques, appropriate patient selection is important to deliver treatment in the most resource-effective manner for patients who would derive the most benefit, for example those with young age or existing heart or lung comorbidities.

Dosimetric Impact of Setup Errors in Single-Isocenter VMAT Radiosurgery for Brain Metastases

In stereotactic radiosurgery (SRS) and fractionated stereotactic radiosurgery (fSRS) of brain metastases (BM) using single-isocenter VMAT, intra-fraction positioning errors may affect target coverage. This study aims to investigate geometric and dosimetric accuracy in single and multiple BM treatments. Seventy patients with single (n = 38) and multiple (n = 32) BM treated with 15-21 Gy in 1 (n = 59) or 27 Gy in 3 (n = 11) fractions using coplanar FFF-VMAT technique were analyzed. PTV was defined by a 2 mm isotropic GTV expansion. Pre-treatment setup errors were evaluated with CBCT and corrected with a robotic six degrees-of-freedom couch. For each fraction, intra-fractional errors were measured by post-treatment CBCT and applied to the planning CT. Plans involving translations and rotations (Fx-plan) were recalculated with Monte Carlo TPS. Original and Fx-plans were compared in terms of target and brain dose parameters, performing the Wilcoxon-Mann-Whitney test (alpha = 0.05). The relationships of the BM volume, maximum dimension, distance-to-isocenter (for multiple BM cases only) and barycenter shift with the difference in target coverage between the two plans were investigated. The median post-treatment 3D error and maximum rotational error over all 129 BM were 0.5 mm [0.1-2.7] and 0.3° [0.0-1.3], respectively. The resulting median BM barycenter shift was 0.5 mm [0.1-2.7]. The percentage of fractions in which at least one BM barycenter shifted by more than 2 mm from the planned position was 4% and 1% for single and multiple BM cases, respectively. The median single GTV volume was 0.27 cc [0.01-10.48], while the PTV had a median volume of 1.05 cc [0.12-17.05]. The median BM maximum dimension was 10.7 mm [2.9-34.1] and for multiple BM the median distance-to-isocenter was 5.15 cm [0.89-7.52]. For single BM patients, the GTV D95% was never reduced by > 5%, while PTV D95% reductions > 1% occurred in only 11 (29%) PTV. For multiple BM patients, the target statistics were slightly worse, with dose deficits larger than 5% and 1% occurring respectively in 2 BM and 34 (37%) PTV. Anyway, the majority of single and multiple BM had a loss of coverage for both GTV and PTV below 1% in Fx-plans. Larger than 5% brain V12 Gy (SRS) and V20 Gy (fSRS) increases were observed for only one single BM patient. None of the two dosimetric comparisons resulted statistically significant (p>0.05). The differences in target coverage showed a moderate-to-strong correlation only with the BM barycenter shift in both cases (R2 = 0.70-0.73 for single and R2 = 0.44-0.50 for multiple BM). Due to the optimal patient setup, as well as the full six degrees-of-freedom corrections, the safety PTV margin, and the fast beam delivery, the dosimetric effects of residual setup and patient motion errors for both single and multiple BM cases were negligible. These findings warrant a potential reduction in the PTV margin with this treatment technique.

Posterior Neck Coverage in Patients Receiving Regional Nodal Irradiation for Breast Cancer

Patterns-of-failure studies suggest the posterior neck (PN) may harbor microscopic disease in patients with locally advanced breast cancer. We compared target coverage, lung dose, and toxic effects in patients treated with either an anterior oblique field (AO) or opposed oblique fields (OO) to address the superior axillary and supraclavicular nodal (SCV) regions. We identified 119 consecutively treated patients who received regional nodal irradiation, including a "third field," to address the superior axillary and supraclavicular nodal regions with a monoisocentric technique in our institution. Coverage of the axillary clinical target volume (CTV), SCV CTV and PN CTV was determined based on the delivered treatment plan. Wilcoxon rank-sum test and Fisher's exact test were used to compare coverage of the axillary, SCV, and PN CTVs, lung dosimetry, and toxic effects (graded by the Common Terminology Criteria for Adverse Events v4.0) between patients receiving an AO or OO. There were 29 patients in the AO group and 80 in the OO group. All patients in the AO group received conventionally fractionated radiation versus 61% in the OO group. Modestly hypofractionated plans were delivered to 39% of the OO group. The body mass index and anterior-posterior separation at the matchline (measured at the center of the carotid artery) were similar in both groups. The median volume (%) of the SCV CTV receiving at least 90% of the prescription dose (V90%) was 91% (85, 99) in the AO group and 93% (91, 95) in the OO group (P = 0.2). The median V90% of the PN CTV was 30% (12, 49) in the AO group and 100% (100, 100) in the OO group (P<0.001). The median V90% in the axillary levels I, II and III CTVs were 98%, 95% and 90%, respectively, in the AO group and all 100% in the OO group (P<0.001). Maximum dose and heterogeneity in the SCV CTV were similar in both groups. Including only patients who received conventionally fractionated plans, the mean lung dose (cGy) was 1216 in the AO group and 1328 in the OO group (P = 0045). The lung V5 Gy, V10 Gy and V20 Gy were similar in both groups. Ipsilateral upper extremity lymphedema (all grade 1) was 3.4% in the AO group and 2.5% in the OO group (p>0.9). Moist desquamation in the neck was 0% in the AO group and 1.2% in the OO group (p>0.9). Pneumonitis (all grade 1) was 0% in the AO group and 1.2% in the OO group (p>0.9). Compared to a single anterior field, opposed oblique fields provide superior axillary and posterior neck coverage without increasing toxicity.

Radiation Induced Lumbar Plexopathy (RILP) in Patients of Cancer Cervix Treated by IMRT Technique: A Study of Dosimetry and Clinical Correlation

To assess the Dosimetric parameters of lumbo sacral plexus in carcinoma cervix patients treated with concurrent chemo-radiation by Intensity modulated radiotherapy (IMRT) technique & to clinically correlate these Dosimetric parameters with the lumbo sacral plexus toxicity. Total twenty-four patients were included in this study between December 2020 to December 2021. They were all treated by Intensity modulated radiotherapy (IMRT) technique. Radiotherapy dose delivered was 50Gy in 25 fractions at 2Gy/#, it was followed by 3 applications of intracavitary brachytherapy of 7Gy/ fraction each. The lumbo-sacral plexus was delineated according to guidelines given by Sun and Xi et al. No dose constraint was prescribed to the lumbo-sacral plexus prior to the treatment. Magnetic resonance imaging (MRI) of bilateral lumbo-sacral plexus test was done prior to the treatment and 12 months' post treatment. Dose received by the lumbo-sacral plexus was calculated DVH parameters was evaluated. The lumbo-sacral plexus toxicity was assessed by the 10-point questionnaire pre-treatment & post treatment and was compared. Assessment of toxicity was done by RTOG (Radiation Therapy Oncology Group) scoring criteria. Out of the 24 patients treated, 7 patients had gross nodes which were treated with a boost dose of 60 Gy. Out of these patients 9 patients (37.5%) developed signs and symptoms of radiation induced lumbar plexopathy (RILP). Among these patients, the most common symptom was weakness in the lower limbs followed by impaired leg movement and activities interfering daily activities such as walking, squatting and getting up from the chair. Other positive findings included stiffness, lower limb pain, lower back ache radiating the lateral aspect of the thigh and numbness of the lower limbs. Total prescribed dose to 95% of the planned target volume ranged from 49.2Gy - 61.9 Gy (median - 57 Gy). The mean volume of the LS plexus was 128 cc (range, 92- 143 cc). The mean of the D-max of LS plexus was 56.2 Gy (range, 43.2 Gy- 61.9 Gy). The V30 Gy was received by 84 % of LS plexus, whereas V40, V50, V60 was received by 64 %, 13 % and 4%. The most common significant findings on MRI post treatment were unilateral thickening of the nerve roots followed by hyperintensity in T2 weighted image and STIR sequencing. Mild contrast uptake and edema were present in the nerve roots. Radiation induced lumbar plexopathy (RILP) is one of the late complications after chemoradiotherapy in patients of carcinoma cervix, which is often misdiagnosed or missed on follow up. Therefore, lumbar plexus must be contoured in all pelvic malignancies which are treated by chemoradiotherapy with IMRT technique as it prevents dose dumping in that region. Further studies with longer follow up are needed.

Multitask AI Models for the Joint Prediction of Overall Survival, Progression-Free Survival, and Death without Progression as a Composite Endpoint for LA-NSCLC Patients Treated with Chemoradiotherapy

Prior methods model the risk of endpoints separately. Herein, we construct a composite AI model that considers multiple endpoints jointly, including overall survival (OS), progression-free survival (PFS), and death without progression (DWP). Our hypothesis is that the composite model potentially improves predictive performance for patients with locally advanced non-small cell lung cancer (LANSCLC) treated with chemoradiotherapy (CRT). A total of 335 LANSCLC patients treated with definitive CRT, including all evaluable patients accrued from Oct 2017 to Dec 2021, were randomly split into training/test subsets (n = 234/101). Cardio-pulmonary substructures (CPSs) were autocontoured, manually reviewed, and edited if necessary. A total of 1093 non-independent dosimetric parameters were extracted, including GTVp, GTVn, GTV, PTV, esophagus, lungs minus IGTV, left/right lung, 15 CPSs, and the overlapping volume of each OAR with PTV and the distance from each OAR to GTVp/GTVn. Other clinical parameters included age, consolidation immunotherapy (CI), ECOG score, Charlson comorbidity index, coronary heart disease, histology, PD-L1 expression, and clinical stage (AJCC 8). Within training, censored time-to-event data were imputed based on conditional event distributions derived from Kaplan-Meier estimators for casting survival analysis as a regression problem and training neural additive model (NAM) regressors. Features were selected by LASSO regression for a single endpoint (OS, PFS, DWP) and multi-task (MT) LASSO regression for four separate composite endpoints (OS-PFS, OS-DWP, PFS-DWP, OS-PFS-DWP). The performance of MT NAMs in the test set that jointly predicted the composite endpoints was evaluated using the C-index and compared to that of a single task (ST) NAM that predicted each endpoint separately. The best testing performance in predicting OS and DWP was attained by the MT NAM that jointly predicted all endpoints (c-index = 0.65, 95% CI 0.58-0.71 for OS; c-index = 0.78, 95% CI 0.69-0.87 for DWP). The best model to predict PFS was also MT between PFS and DWP (c-index = 0.59, 95% CI 0.52-0.65). The c-indices of all ST NAMs were less than 0.56. The best MT NAMs significantly outperformed ST NAMs in predicting OS (p = 0.001) and DWP (p = 0.01) except for PFS (p = 0.32). The best MT NAM in predicting OS and DWP included ECOG score, atria-PTV overlap volume, D75% [Gy] to the left atrium (LA), pulmonary arterial volume, histology (adenocarcinoma), D65% [Gy] to the descending aorta (DA), V10 Gy [%] of the LA and CI in order of overall importance. ECOG score consistently ranked as the most important feature for all four MT NAMs. An increase of ECOG score from 0 to 2 indicated a 6-month earlier risk of mortality and DWP. Atria-PTV overlap volume and D65% [Gy] to the DA were included in all four MT NAMs. MT AI models improved outcome prediction in patients with LANSCLC treated with CRT by jointly learning commonalities between the primary and auxiliary endpoints.

Temporospatial Feathering of Hot Spots for Computed Tomography-Guided Stereotactic Adaptive Radiotherapy (CT-STAR) for the Ultra-Central Thorax

SBRT to the ultra-central thorax is limited by potential toxicity. It has been demonstrated that exposing proximal bronchial tree or pulmonary arteries to high dose per fraction (fx) treatment may induce bronchopulmonary hemorrhage, amongst other serious complications. Online adaptive radiotherapy is a technique that adjusts a treatment plan to the anatomy-of-the-day and benefits have been demonstrated in ultra-central thoracic disease. In addition, feathering is a treatment planning technique that generates several plans to avoid consistent organ-at-risk (OAR) doses throughout treatment. With daily adaptation, it may be possible to adjust the position of a hot spot (>120% prescription (Rx)) within the tumor each fx (temporospatial feathering) while respecting hard OAR constraints. We investigated the feasibility and plan quality of using CBCT-guided stereotactic adaptive radiotherapy (CT-STAR) for ultra-central lung tumors with hotspot temporospatial feathering. Seven patients with ultra-central thoracic disease (6 patients with parenchymal tumors in contact with the trachea, proximal bronchial tree, great vessels, esophagus, or heart; 1 patient with a subcarinal lymph node) receiving standard of care radiotherapy were enrolled on an imaging study. An in-silico planning study first generated an SBRT plan (in silico Rx: 55 Gy in 5fx) that used a GTV_OPT (GTV minus OAR plus a safety margin) to optimize the location of the plan hotspot. Five spherical boost structures were manually created inside of the GTV_OPT structure. The same planning template was used except the boost structures were iteratively used in plan optimization instead of the GTV_OPT structure, to simulate the five CT-STAR fx hotspot temporospatially feathering. The five-plan composite was compared to the initial plan. All plans generated met strict OAR constraints. Table 1 shows the mean difference in PTV, GTV, and OARs percent coverage by various isodose levels. Feathering the hotspot had negligible impact on target coverage by 50 Gy and 55 Gy isodose lines as well as OAR doses compared to the base SBRT plan. The feathered plan sum resulted in 14.7% increase in V66 Gy of the GTV. One patient saw a decrease in V66 Gy coverage to all target structures, though V50 Gy and V55 Gy were not affected. We demonstrated the feasibility and utility of temporospatially adapting the hotspot for central lung SBRT, which safely increases the amount of tumor receiving more than 120% Rx.

Effect of Dose to the Heart and Cardiac Substructures on Cardiac Toxicity after Breast Cancer Radiation

Pre-existing cardiovascular disease, chemotherapy, and higher mean heart dose are known risk factors for cardiac toxicity after breast radiation therapy. However, the relationship between cardiac substructure radiation exposure and toxicity is not well understood. We hypothesized that mean heart dose is a surrogate for global cardiac radiation exposure but that more specific dosimetric thresholds for the heart and its substructures could be identified, which could be used to guide radiation planning for breast cancer patients in the future. In this cohort study, all breast cancer patients who received curative intent breast or chest wall radiotherapy at a single high-volume institution in 2014 and 2017 were included (n = 841). Baseline characteristics included hormone therapy, chemotherapy, menopausal status, diabetes, dyslipidemia, pre-existing cardiac toxicity, and age at diagnosis. Outcomes included any cardiac toxicity, arrhythmia, cardiomyopathy, ischemia, valvular, pericardial disease, and death. The heart and substructures, including left ventricle, right ventricle, left atrium, right atrium, aortic valve, pulmonic valve, mitral valve, tricuspid valve, and left anterior descending artery, were delineated on the simulation CT for each patient. Dosimetric variables, including mean dose, max dose, and V1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, and 70 Gy for the heart and substructures (in cc) were extracted. For each dosimetric variable, multivariable logistic regression was performed using baseline covariates in addition to the single dosimetric variable. Patients with missing data values were excluded. Results were combined and False Discovery Rate p-value correction was performed. Multiple cardiac substructure dosimetric variables were associated with increased risk of mortality on multivariable analysis (p < 0.05). For left atrium and right atrium, V2, 3, 4, and 5 Gy were all significant. For right ventricle, mean dose, V1, 2, 3, 4, 5, 10, 15, 20, 25, 30, and 35 Gy were significant. For mitral valve, mean dose, max dose, V3, 4, and 5 Gy were significant. For tricuspid valve, mean dose was significant. For aortic valve, max dose, mean dose, V4, and V5 Gy were significant. For the whole heart, V1, 2, 3, 4, 5, 10, 15, 20, 25, 30, and 35 Gy were significant. We have identified multiple dosimetric variables for the heart and its substructures which were associated with increased risk of mortality after breast cancer radiation. In fact, for certain structures, there were multiple exposure thresholds which showed increased risk of toxicity, highlighting the complex relationship between substructure dose and outcomes. Further study into these relationships will identify the most critical cardiac substructure constraints that could be used in radiation treatment planning.

Association of Left Ventricular Myocardium Dose Exposure with Heart Failure in Lung Cancer Radiotherapy

The volume of left anterior descending (LAD) coronary artery dose receiving 15 Gy (LAD V15 Gy) has been associated with major adverse cardiac events (MACE; a composite endpoint of unstable angina, heart failure hospitalization/urgent visit, myocardial infarction, coronary revascularization, and cardiac death) and mortality in patients with locally advanced non-small cell lung cancer (LA-NSCLC) following radiotherapy (RT). With growing evidence supporting specific cardiac substructure dose exposure with distinct pathophysiologic cardiac endpoints, our objective was to assess whether RT dose to the left ventricular myocardium (LVM) was associated with the specific cardiac endpoints of heart failure (HF) vs. overall MACE. Retrospective analysis of 701 patients with LA-NSCLC treated with RT between 2003 and 2014. LAD was segmented manually, while LVM (excluding blood pool) was segmented using an open-source deep learning-based automated algorithm (TotalSegmentator; Wasserthal et al, 2022) and dosimetric parameters (mean, max, and VX Gy in 5 Gy increments) collected. HF was defined as any grade ≥3 Common Terminology Criteria for Adverse Event (CTCAE) HF or cardiomyopathy. Receiver operating curve and cut-point analyses estimating HF were performed. Fine and Gray and Cox regressions, adjusting for preexisting cardiovascular (CV) risk factors and other prognostic factors, were calculated. Of 701 patients, the median age was 65 years (interquartile range [IQR], 57-73), 51% were men. At a median follow up of 20 months (IQR, 8-45) following RT, there were 64 HF events. The median time to HF was 20 months (IQR, 9-43), with a 2-year cumulative incidence of 5.2%. The optimal cut-point for the LVM dose variable with the highest C-index predicting HF was LVM V10 Gy ≥10% (.58). By LVM V10 Gy cut point ≥10% vs <10%, the 2-year HF cumulative incidence was 7.2% vs 4.0% (p = .005). Adjusting for baseline CV risk, there was an increased risk of HF with LVM V10 Gy ≥10% (vs. <10%) (subdistribution hazard ratio [SHR] 2.81; 95% confidence interval [CI], 1.02-7.70; p = .045), but not LAD V15 Gy ≥10% (p>.3). Conversely, adjusting for baseline CV risk, there was an increased risk of MACE with LAD V15 Gy ≥10% (SHR = 19.70; 95% CI = 2.57-151.35; p = 0.004), but not LVM V10 Gy ≥10% (p>0.3). On all-cause mortality analysis, adjusting for CV and other prognostic factors, LAD V15 Gy ≥10% (HR = 1.4; 95% CI = 1.02-1.80; p = 0.036), but not LVM ≥10% (p>0.5), remained significantly associated with mortality. Left ventricular myocardium V10 ≥10%, is associated with the specific endpoint of HF, but not overall MACE, while LAD V15 ≥10% remained strongly associated with MACE and all-cause mortality, but not HF. These findings underscore the need to study the interaction between RT dose to specific substructures (i.e., myocardium) and pathophysiologically relevant cardiac endpoints (i.e., HF).

Comparison of Plan Quality Metrics after Left Anterior Descending Coronary Artery Sparing in VMAT Esophageal Radiotherapy

Cardiotoxicity is a significant late effect of esophageal radiotherapy (RT). Mean heart dose has been implicated with major adverse cardiac events (MACE) and emerging evidence increases MACE association with left anterior descending (LAD) coronary artery specific dose. This retrospective planning study investigates the dosimetric impact of including the LAD as an OAR-sparing objective for VMAT-based plan optimization in patients previously treated for esophageal cancers. A retrospective cohort was identified of patients who underwent neoadjuvant RT for esophageal cancers between 2017-2020 without intentional LAD sparing. Treatment planning was performed using Eclipse™ treatment planning system. Doses were calculated using Acuros® XB algorithm or anisotropic analytical algorithm with a 2-2.5mm calculation grid. For each patient, the LAD was delineated and the treated VMAT plan was re-optimized to reduce the dose to the LAD receiving 15 Gy to less than 10%, when possible. Re-plans were performed such that 95% of the PTV received the prescription dose. Institutional constraints were used to minimize the dose to the heart, lung, and spinal cord (Table 1). A paired t-test was used to compare the dose between the original VMAT plan used for treatment (Esophagus Original) against those re-optimized (Esophagus + LAD), with significance of p<0.05. A total of 19 patients were identified. Of those treated, 12 of 19 original plans (63%) exceeded the LAD constraint (V15<10%) with a mean V15 Gy of 47.1%. Plan re-optimization accounting for the LAD allowed for 66.7% (9/12) of cases to meet LAD V15 constraints. Aside from increased sparing of the mean heart dose, there were no statistically significant impacts on target coverage and OAR doses otherwise, including to that of the lung and spinal cord (Table 1). Accounting for LAD dose in treatment planning may help reduce future MACE risks. LAD dose can be significantly reduced without compromising PTV coverage or having significant effects on other OAR dose sparing.

Association of Left Anterior Descending Coronary Artery Calcium Progression and Radiation Dose with Major Adverse Cardiac Events in Breast Cancer

Coronary artery calcium (CAC) is associated with increased risk of major adverse cardiac events (MACE). Accelerated CAC progression has been observed in patients with breast cancer after radiotherapy (RT) and there is a relationship between left anterior descending (LAD) coronary artery RT dose and the risk of coronary events. However, there is lack of consensus on LAD dose constraints for breast RT and limited data on the extent and impact of CAC progression. Our objective was to evaluate the association of LAD dose exposure and CAC progression with the risk of MACE in patients with breast cancer following RT. Retrospective analysis of 181 patients with breast cancer treated with RT between 2008 and 2019. CAC was manually measured on RT planning and follow-up CTs (with at least one-year interval) using the Agatston method. Coronary arteries were segmented using a deep learning-based automated algorithm and dosimetric parameters collected. MACE cumulative incidence was estimated, and Fine and Gray regressions performed, accounting for non-cardiac death as a competing risk. The median follow-up following RT was 70 months (interquartile range [IQR], 53-86). The median age was 63 years (IQR, 53-72), 43% had hypertension, 40% hyperlipidemia, 8% coronary heart disease (CHD). Most had pathologic stage I-II disease (76%). RT was targeted to breast/chest wall only in 60% and included regional nodes in 40% (internal mammary chain in 4%). The most common dose/fractionation was 48-50.4 Gy/25-28 fractions (67%) and 42.6-42.7 Gy/16 fractions (30%). At the time of RT, 68 (38%) had at least moderate CAC burden (CAC >100; statin-therapy indicated), but only 29 (43%) were on statin therapy. At a median interval of 44 months (IQR, 26-63), 55% (n = 84) had CAC progression, with a median increase of 52%/year (IQR, 18-193). The median time to MACE was 68 months (IQR, 53-85), with a 5-year cumulative incidence of 7.3% (15 MACE overall). Accounting for age and CHD, there was an increased risk of MACE with LAD CAC progression (subdistribution hazard ratio [SHR] 1.02/10 CAC points; 95% confidence interval [CI] 1.01 = 1.03; p = .007) and the volume of LAD receiving 15 Gy (LAD V15 Gy; SHR 1.03/%; 95% CI, 1.01-1.06; p = .004). There was no association between mean heart dose, chemotherapy, or Her2 therapy exposure and MACE (p>.05). LAD CAC progression and LAD V15 Gy dose exposure were associated with an increased risk of MACE following RT. Accelerated CAC progression was commonly observed, however most patients were under-optimized for cardiovascular (CV) risk, with less than half of statin-eligible patients with at least moderate CAC burden on statin therapy. Together, these data support more aggressive cardiac risk mitigation approaches, including guidelines-based CV risk factor modification and optimized sparing of LAD radiation dose.

Investigating Dosimetry and Imaging Biomarkers for Prediction of Major Adverse Cardiac Events Following Locally Advanced Non-Small Cell Lung Cancer Radiotherapy

Thoracic radiotherapy (RT) may confer major adverse cardiac events (MACE) following treatment. Mean heart dose positively associates with MACE and recent studies show cardiac substructure dosimetry improves MACE prediction. Use of imaging biomarkers with cardiac substructure dose has not been studied for prediction of MACE. We sought to develop an integrated model for cardiac substructure dose and baseline coronary artery calcium (CAC) scoring and establish its relationship to MACE. A retrospective cohort analysis was performed of consecutive patients with locally advanced non-small cell lung cancer (NSCLC) treated with definitive RT from 2006-2018 at a single institution. Demographics, medical history, cardiac events, and treatments received were recorded. Cardiac substructures were contoured, including the left descending artery (LAD), left main coronary artery (LMCA), left circumflex (LCX), right coronary artery (RCA), TotalLeft (LAD+LMCA+LCX), and TotalCor (TotalLeft+RCA). Doses were measured in 2 Gy equivalent dose. CAC was scored by visual assessment and compared to established automated Agatston scoring. Primary endpoint was MACE incidence. Receiver operating characteristic (ROC) curves assessed dose and CAC metric model performance. Threshold modeling was conducted using the log rank statistic with 95% confidence intervals measured using bootstrap resampling with 1000 iterations. Competing risk models adjusted for death were used to measure cumulative incidence of MACE as well as in univariable and multivariable risk regression modeling. Pearson correlations were used to validate CAC scoring. P-values were two tailed and considered significant at P≤0.05. Of 233 eligible patients, 61.4% were male with a 68.1 years (range 34.9-90.7) median age. Median follow-up was 73.7 months (range 1.6-153.9). Median overall survival was 34.8 months. Following RT, 22.3% experienced at least one cardiac event at a median time of 21.5 months (range 1.7-118.9). Visual CAC scoring showed significant correlation with automated Agatston scoring (r = 0.72, P=1e-5). While left sided coronary arteries (TotalLeft), mean heart dose (MHD) and CAC scores individually predicted for MACE (AUC = 0.56-0.59), a multivariable model of TotalLeft CAC had the highest ROC analysis performance (AUC = 0.69). On univariable and multivariable competing risk regression analyses, TotalLeft V15 Gy >2.53 cc and CAC score >5 independently associated with MACE (P<0.05). A model incorporating age, TotalLeft CAC>5 and V15>2.53cc, showed incrementally higher MACE incidences for low (9.3%), intermediate (18.4%), and high-risk groups (27.7%) (P<0.01). RT-induced MACE occurs in >20% of those undergoing thoracic RT in a median time of <2 years. We validate significant associations between TotalLeft RT dose and MACE and establish CAC as a predictive risk factor. These findings may serve to inform personalized RT and future cardiac risk in locally advanced NSCLC.

Cardiopulmonary Toxicity from Intensity Modulated Proton Therapy for Thymic Malignancies

Use of radiation therapy for thymic malignancies is limited by excess dose to organs at risk (OARs) including heart, lung, and esophagus. Intensity Modulated Proton Therapy with Pencil Beam Scanning (IMPT/PBS) allows the conformality benefits of volumetric modulated arc therapy (VMAT) combined with dosimetry benefits of protons making it an exciting tool to treat thymic tumors. Very limited clinical data are reported with the use of IMPT/PBS to treat thymic malignancies. This study evaluates the incidence of acute and delayed toxicities among patients who underwent IMPT/PBS for thymic tumors. Our single center retrospective study identified 27 patients with diagnosis of either thymic carcinoma or thymoma who received IMPT/PBS between 2015 and 2022. Patient demographics, IMPT treatment details and clinical outcomes (toxicity, recurrence, and survival) were recorded. Frequency distributions are described for primary endpoints of acute (≤ 90 days) and late (>90 days) toxicity graded using CTCAE version 5.0. Specific toxicities assessed were dermatitis, esophagitis, pneumonitis, pulmonary fibrosis, and cardiac toxicity. Recurrence and survival data were analyzed as secondary endpoint using Kaplan-Meier method. Median follow-up was 22 months. Median age of the patients was 59 years (range, 30-87), predominantly female (55%), and white (66%), and stage ¾ (72%). Histologically showed mainly thymoma (59%) and Masaoka stage ¾ (70%). Surgery prior to IMPT was performed in 19 (70%) patients; of whom 5 patients had positive margins. Chemotherapy was used in 12 (44%) patients. Median IMPT dose was 50.4 GyE. Patients were primarily planned with 2 or 3 fields (81%), coplanar distribution (74%), using SFO technique (70%). Robust planning was performed accounting for 5 mm margin and 3.5-5% range uncertainty. All patients required use of range shifter ranging from 2-5 cm. Median of Heart-mean (10.3 GyE), Heart-max (54 GyE), Lung-mean (8.1 GyE), Lung V20 Gy (16.1%), Lung-V30 Gy (11.4%), Esophagus-mean (10.3 GyE) and Cord-Max (1.4 GyE). QACT was performed in 21 (77%) patients with replan needed in 5 of them. Only 1 (3.7%) patient had a grade 3+ acute toxicity (dermatitis) and only 2 (7.4%) patients had a grade 3+ late toxicity (both pulmonary). No patients had any acute or delayed cardiac-related adverse effects following PBT treatment. One (3.7%) patient had an infield recurrence of malignancy and 6 had out-of-field metastatic failure. Local control and overall survival were 74.1% and 85.2%, respectively. In this largest single-institution analysis of IMPT/PBS experience, we note extremely low incidence of grade 3+ acute or late toxicity with excellent local control and overall survival. No marginal failures were noted. In a patient population at high risk of cardiopulmonary radiation toxicities, IMPT/PBS should be strongly explored as a possible treatment option.

Dosimetric Comparison of Nodal Clinical Target Volume for Locally Advanced Non-Small Cell Lung Cancer: Options for Geometric Expansion vs. Lymph Node Stations

We investigated whether dosimetric differences existed in nodal clinical target volume (CTV) using options for geometric expansion and lymph node stations based on the European Society for Radiotherapy and Oncology (ESTRO) guideline for locally advanced non-small cell lung cancer (NSCLC). With treatment planning computed tomographic images in 17 patients who underwent radiotherapy for cT4N2M0 NSCLC from 2017 to 2022 at our institution, we retrospectively contoured nodal CTVs based on the guideline's options of: (1) geometric expansion, CTV including the nodal gross tumor volume plus 5 mm margin: (2) lymph node stations, CTV including the affected lymph node stations. The 5 mm margins for planning target volume (PTV) were added to the nodal and primary tumors' CTVs. Treatment planning of 60 Gy in 30 fractions to the PTV D50% was performed using volumetric modulated arc therapy; Dn% was irradiated dose to n% of volume of the structure; VnGy was percentage of volume of the structure at least irradiated n Gy. We compared dose-volume parameters between the two options using Wilcoxon rank sum test. Primary tumors were located in the right and left lobes in 12 and five patients, and in the upper and lower lobes in 13 and four patients, respectively. Median PTV size/D95% of the options for geometric expansion and lymph node stations were 569 cc (range, 149-2005 cc)/58.2 Gy (range, 57.5-58.7 Gy) and 635 cc (range, 184-2109 cc)/58.1 Gy (range, 57.5-58.7 Gy), respectively. Median mean dose of the esophagus/heart in the two options were 12.2 Gy (range, 6.6-24.9 Gy)/3.3 Gy (range, 0.6-19.1 Gy) and 16.1 Gy (range, 13.6-30.5 Gy)/4.6 Gy (range, 0.7-18.9 Gy), respectively. Median V20 Gy/mean dose of the lungs in the options for geometric expansion and lymph node stations were 20.5% (range, 14.8-33.9%)/12.2 Gy (range, 8.7-18.4 Gy) and 24.0% (range, 15.1-36.7%)/13.5 Gy (range, 9.5-19.4 Gy), respectively. In the eight patients (47%) with lymph node metastases in stations 2 or 3, a significant dosimetric difference between the two options existed on V20 Gy of the lungs; median values of the difference were 2.8% and 0.5% with and without lymph node metastases in stations 2 or 3, respectively (p = 0.027). Of the ESTRO guideline for the nodal CTV, using the option for geometric expansion might be able to reduce V20 Gy of the lungs in patients with lymph node metastases in stations 2 or 3.

Comparison of Early Outcomes of Stereotactic Accelerated Partial Breast Irradiation vs. Volumetric Modulated Arc Therapy-Based FAST-FORWARD Whole Breast Irradiation for Breast Cancer

Despite evidence supporting APBI from 8 published prospective randomized trials enrolling over 10,000 women, the uptake of APBI in clinical practice is surprisingly low. This is being exacerbated by a new, convenient, and safe shortened WBI schedule. Here, we report the dosimetric and early outcome analyses of the first >1000 patients treated at our institution since the first adoption of stereotactic APBI and the ultra-hypofractionated WBI regimen. From 2016 to 2022, 801 women with breast cancers in the suitable or cautionary categories according to the ASTRO APBI consensus panel guidelines, received 30 Gy in 5 fractions (92%) either using a robotic stereotactic radiation system (83%) or stereotactic volumetric-based arc therapy (VMAT, 17%). Between 2020 and 2022, 468 women, who were not candidates for APBI and not undergoing any regional irradiation received 26 Gy in 5 fractions using VMAT to the whole breast with the addition of cardiac sparing technique in left-sided breast cancer patients. Tumor bed boosts were delivered in 99% of FF-WBI patients. We evaluated dose-volume histogram parameters for target volumes and organs-at-risk and radiation-related toxicities during RT or within 6 months after the end of RT. Target volume coverage was acceptable in both groups, with mean 96% of the target volumes receiving 95% of the prescribed doses and 0 cm3 within target volumes exceeding 105% of the prescribed doses. S-APBI resulted in small, but statistically significant, reductions in the radiation dose delivered to the ipsilateral breast, contralateral breast, lungs, heart, and coronary artery compared with FF-WBI. Comparing WBI to APBI, the mean contralateral breast dose, ipsilateral lung V20 Gy, mean contralateral lung dose, and mean heart dose, were reduced by 89%, 78%, 73%, and 29%, respectively. With median follow-up periods of 32 months for s-APBI and 19 months for FF-WBI, acute toxicity was assessable in all patients. The risks of any grade acute toxicity were 21% for s-APBI and 25% for FF-WBI (p = .117). Among them, grade 2 rates were 1.3% in both groups and no severe toxicity has been reported. We found s-APBI and VMAT-based FF WBI were associated with favorable dosimetric and acute toxicity profiles. However, considering significantly less irradiated volume in the breast, lungs, and heart, APBI with advanced available technique options should be considered over any WBI-based approach for patients at low risk for local recurrence.

Toxicity of Patients with Ultra-Central Thoracic Tumors Treated with Stereotactic Body Radiotherapy (SBRT) with Dose of 50 Gy in 5 Fractions

The ideal regimen for stereotactic body radiotherapy (SBRT) in ultra-central lung tumors is still to be defined, mostly due to the risk of unacceptable or fatal toxicity. There is not much information on outcomes after SBRT for this group of patients. We summarize here our experience with ultra-central lung cancer patients treated with the dose of 50 Gy delivered in 5 fractions. This study is a retrospective review of all cases of ultra-central thoracic tumors treated with SBRT with the dose of 50 Gy in 5 fractions, delivered every other day, at our institution. In all cases, as we defined ultra-central lung tumor, the PTV overlapped or touched one or more of the following structures: bronchial tree, trachea, great vessels, heart, and esophagus. Metastatic and primary lung lesions were included. The volumes of treatment were defined by 4D-CT to consider breathing motion. Normal organs constraints followed the recommendations of the RTO 0813 trial as follows: Spinal cord: max 30 Gy. Lung right or lung left: V13 Gy[cc] < 1500. Esophagus: max 52 Gy and nonadjacent esophagus: V27.5 Gy[cc] < 5. Heart: V32 Gy[cc] < 15; max 52 Gy. Great vessels: max 52 Gy and non-adjacent great vessels V47 Gy[cc] < 10. Trachea plus bronchus: max 52 Gy and non-adjacent V18 Gy[cc] < 4. Follow-up, at the discretion of the treating MD, included periodic CT scans of the thorax after SBRT and assessment of radiation-induced toxicity scored with CTCv3.0. Between December 2015 and February 2022, 86 patients were eligible for this review. Median follow-up was 17 months (range: 1-76 months); the median age was 74 years (range: 37-98 years). Histology was as follows: 50 patients had biopsy proved NSCLC, 16 had no biopsy, and 20 had metastatic non-lung primaries. Overlapped structures were as follows: with great vessels in 46 cases, heart in 20 cases, trachea/branchial tree in 18 cases, and esophagus in 2 cases. In 16 patients the overlap was present in more than one structure. Overall, 68.6% did not report acute toxicity. The most common acute side effects were fatigue (15.1%), coughing (8.1%), shortness of breath (6.9%), esophagitis (2.3%), and dysphagia (1.1%). No grade 3 or more significant toxicity was described. As acute side effects, many patients had exacerbations of the previous condition, such as shortness of breath (16 pts) or coughing (4 pts) during follow-up. Pneumonitis was found as a late side effect in four cases. One patient had empyema associated with a fistula in the non-irradiated lung, where the patient had previous surgery, but in the irradiated lung no severe complication was detected. There were no deaths attributed to the SBRT treatment. 67.5% of 86 patients were alive at the time of the review; 87.2% had local control, and 65.1% had metastases-free survival. In this cohort of patients, no death or even severe acute or chronic toxicity was attributed to SBRT. SBRT seems safe for ultra-central lesions using the regimen of 50 Gy in 5 fractions with the constraints of the RTOG 0813 trial.

Knowledge Based Planning Evolution: Multi-Criteria Optimization of Prostates. Is There Always a Better Model?

The current paradigm of radiotherapy Knowledge Based Planning (KBP) utilizes dose volume relationships on previously treated plans and may be insensitive to clinician plan preferences. To improve KBP models, incorporation of plan quality metrics and optimization weightings can be achieved using Clinical Scoring Metrics (CSM) and Multi-Criteria Optimization (MCO) respectively. A combination of KBP, MCO and CSM may result in higher quality plan output with potential to improve all prospective clinical plans. This study assesses the benefit of MCO, using CSM, and its application in the evolution of the KBP model. A retrospective Dose Volume Histogram (DVH) parameter review was undertaken for 40 intact prostate radiotherapy cases. Following analysis, these cases were used to develop the CSM system to reflect clinician preferences and departmental protocol. Hypofractionated plans containing simultaneous integrated boost (SIB) and urethral sparing were originally planned using a clinically approved KBP model (Model A). Model A was then refined using MCO, improving the 40 individual model plans to form Model B. A further 20 prostate patients, who were excluded from KBP development, were planned using both models to compare plan quality using the CSM system. Using a single optimization, Model A resulted in a median plan score of 134.1 (92.4-151.5), compared to the median Model B score of 145.1 (114.5-175.1) out of a possible score of 200 points. A Wilcoxon rank sum test was conducted and found the model score difference was significant (p = 0.014). Organ At Risk (OAR) doses, including Rectum V30 Gy, were found to significantly (p = 0.019) decrease, with Model A resulting in a median of 22.1 Gy (9.3-39.0), compared to the Model B median of 16.3 Gy (6.8-35.7). PTV coverage metric V57 Gy, resulted in no significant differences (p = 0.47) with a median score of 98.4% (97.2% - 99.9%) and 98.4% (96.9% - 99.2%) for model A and B, respectively. The application of MCO was used to influence and produce higher quality KBP models, as supported by a CSM system. OAR doses were found to significantly decrease, with no effect on target coverage. As a result, existing plan objectives were tightened through the utilization of KBP models, even with a single optimization resulting in higher scoring plans. The future development of this work may increase the efficiency of planning operations and allow the clinician to accurately anticipate planning goals for not only prostate, but all disease sites.

Extended Field Radiosurgery of Spinal Metastases with MRI-Guided Adaptive Planning: A Dosimetric Study

Spinal metastases occur in ∼40% of cancer patients. Stereotactic body radiotherapy (SBRT) precisely delivers high doses of RT to enhance local control and reduce chronic pain. Eligibility for spine SBRT can depend on number of spine vertebrae involved. For example, RTOG 0631 was limited to two contiguous levels due to concerns about spinal cord (SC) tolerance when aligning to long targets in the mobile spine. The purpose of this study was to determine whether adaptive replanning on an MRI-Linear Accelerator could permit SBRT of longer spinal segments. We randomly selected ten patients treated in the abdomen on a 0.35T MRI-Linac with MRI including L2-T8. For each patient, their simulation MRI was used to generate six distinct plans starting at 2 spinal levels incrementing to 7 spinal levels. Coverage was 90% at 16 Gy to the entire vertebrae including processes and TG-101 constraints were used for SC and other nearby organs at risk (OAR). Each plan was then rigidly fused in 6-dimensions to a treatment MRI obtained on another day (non-adaptive) and evaluated. An adaptive plan was then generated for each non-adaptive plan. Target coverage between non-adaptive and adaptive techniques was compared using paired t tests. McNemar's tests were used to compare proportions of dose objective failures for OAR between sets. The target-coverage and number of patients meeting V10 Gy <0.35 and Dose max <14 Gy are shown in the table below with respective p-values. Statistically significant p-values (<0.05) were obtained for all criteria analyzed, especially above 4 vertebral body (VB) levels. This dosimetric analysis suggests that adaptive replanning using a hybrid MR/Linac platform has the potential to safely extend spine SRS beyond the currently accepted practice of 2-3 consecutive VB levels. Future directions include applying this innovative approach in a clinical trial.

Optimizing Radiation Therapy for Brain Metastasis Patients: A Comparative Study of Knowledge-Based Treatment Planning with HyperArc

The purpose of this study is to examine the benefits of using a knowledge-based treatment planning (KBP) model in treating brain metastasis patients with HyperArc (HA) automated non-coplanar stereotactic radiosurgery (SRS). Treatment plans of the 113 patients with either single or multiple brain metastases treated with HA were enrolled in the study. The eighty-two treatment plans with 190 metastatic brain lesions were used to construct the training model using the DVH estimation algorithm. The model was then validated on the remaining 31 patients' treatment plans with 56 metastatic brain lesions. Two corresponding HA plans were manually generated for these 31 patients using the two optimization algorithms (SRS NTO and ALDO). The SRS NTO plan generates a rapid dose falloff and prevents dose bridging of adjacent disparate targets, while the ALDO plan can cover the target with the prescribed dose but may create a high inhomogeneous dose within the target. The dosimetric outcomes were compared between the KBP, SRS NTO, and ALDO plans. The KBP, SRS NTO, and ALDO plan consistently showed CTV and PTV coverage levels of over 99%. The KBP plans resulted in similar doses to the organs at risk compared to the SRS NTO plans, but significantly reduced doses to the brainstem and optic apparatus (lens, eyes, optic nerves, and optic chiasma) by 17% to 67% compared to the ALDO plans (P = 0.003 for brainstem and P < 0.001 for optic apparatus). The mean brain dose was not significantly different between the three plans (P = 0.694 for KBP vs. SRS NTO and P = 0.381 for KBP vs. ALDO). However, the ALDO plans showed a statistically better brain V12 Gy than the KBP plans (P = 0.009), with a difference of less than 2 c.c. that was deemed not clinically significant. The ALDO plans also had a significantly better intermediate dose spillage, gradient radius, and conformity index than the KBP plans. The KBP plans showed a significantly faster gradient index and intermediate dose spillage compared to the SRS NTO plans. This study demonstrates the ability of the KBP model (RapidPlan) to generate accurate DVH predictions for use with HA in generating SRS plans that achieve optimal sparing of organs at risk while maintaining dose falloff. The KBP plans showed balanced dosimetric results compared to the SRS NTO and ALDO optimization algorithms.