PTV Size Research Articles

Efficacy and Low Toxicity of Normo-Fractionated Re-Irradiation with Combined Chemotherapy for Recurrent Glioblastoma—An Analysis of Treatment Response and Failure

Background: Glioblastoma is the most common malignant brain tumor in adults. Even after maximal safe resection and adjuvant chemoradiotherapy, patients normally relapse after a few years or even months. Standard treatment for recurrent glioblastoma is not yet defined, with re-resection, re-irradiation, and systemic therapy playing key roles. Usually, re-irradiation is combined with concurrent chemotherapy, harnessing the radiosensitizing effects of alkylating agents. Methods: A retrospective analysis of 101 patients with recurrent glioblastoma treated with re-irradiation was conducted, evaluating the survival impact of concurrent chemotherapy regimens, as well as prior resection. Patients were subcategorized according to concurrent chemotherapy (temozolomide vs. CCNU vs. combination of both vs. none) and details are given regarding treatment toxicity and patterns of relapse after first- and second-line treatment. Results: Patients were treated with normo-fractionated re-irradiation (with prescription dose of ~40 Gy to the PTV), resulting in a moderate cumulative EQD2 (~100 Gy). The mean overall survival was 11.3 months (33.5 months from initial diagnosis) and mean progression free survival was 9.5 months. Prior resection resulted in increased survival (p < 0.001), especially when gross total resection was achieved. Patients who received concurrent chemotherapy had significantly longer survival vs. no chemotherapy (p < 0.01), with the combination of CCNU and TMZ achieving the best results. Overall survival was significantly better in patients who received the CCNU + TMZ combination at any time during treatment (first or second line) vs. monotherapy only. The treatment of larger volumes (mean PTV size = 112.7 cm3) was safe and did not result in worse prognosis or increased demand for corticosteroids. Overall, the incidence of high-grade toxicity or sequential radionecrosis (5%) was reasonably low and treatment was tolerated well. While second-line chemotherapy did not seem to influence patterns of relapse, patients who received TMZ + CCNU as first-line treatment had a tendency towards better local control with more out-field recurrence. Conclusions: Normo-fractionated re-irradiation appears to be safe and is accompanied by good survival outcomes, even when applied to larger treatment volumes. Patients amenable to undergo re-resection and achieving concurrent systemic therapy with alkylating agents had better OS, especially when gross total resection was possible. Based on existing data and experiences reflected in this analysis, we advocate for a multimodal approach to recurrent glioblastoma with maximal safe re-resection and adjuvant second chemoradiation. The combination of TMZ and CCNU for patients with methylated MGMT promoter yielded the best results in the primary and recurrent situation (together with re-RT). Normo-fractionated RT enables the use of more generous margins and is tolerated well.

Integrating Deep Learning-Based Dose Distribution Prediction with Bayesian Networks for Decision Support in Radiotherapy for Upper Gastrointestinal cancer.

Selecting the better techniques to harbor optimal motion management, either a stereotactic linear accelerator delivery using TrueBeam (TBX) or Magnetic Resonance (MR)-guided gated delivery using MRIdian (MRG), is time-consuming and costly. To address this challenge, we aimed to develop a decision-supporting algorithm based on a combination of deep learning-generated dose distributions and clinical data. We retrospectively analyzed 65 patients with liver or pancreatic cancer who underwent both TBX and MRG simulations and planning process. We trained three-dimensional U-Net deep learning models to predict dose distributions and generated dose volume histograms (DVHs) for each system. We integrated predicted DVH metrics into a Bayesian network (BN) model incorporating clinical data. The MRG prediction model outperformed the TBX model, demonstrating statistically significant superiorities in predicting normalized dose to the PTV and liver. We developed a final BN prediction model integrating the predictive DVH metrics with patient factors like age, PTV size, and tumor location. This BN model an area under the receiver operating characteristic curve index of 83.56%. The decision tree derived from the BN model showed that the tumor location (abutting vs. apart of PTV to hollow viscus organs) was the most important factor to determine TBX or MRG. We demonstrated a decision-supporting algorithm for selecting optimal RT plans in upper gastrointestinal cancers, incorporating both deep learning-based dose prediction and BN-based treatment selection. This approach might streamline the decision-making process, saving resources and improving treatment outcomes for patients undergoing RT.

Prognostic factors for patients with breast cancer brain metastasis after stereotactic radiotherapy.

e13109 Background: Breast cancer (BC) is the most common cancer in females and BC brain metastasis (BCBM) is considered as the second most frequent brain metastasis. Numerous prognostic factors are associated with survival for patients with BCBMs. Here we investigated the clinical factors associated with overall survival (OS) and distant intracranial control (DIC) after stereotactic radiotherapy (SRT) for BCBM. Methods: The records of BCBM patients treated with SRT were collected from electronic database in Cancer Center, Union Hospital, Tongji medical college, Huazhong University of Science and Technology Hospital. Based on the univariate and multivariate Cox regression analysis, the prognostic significance of available variables was assessed. The nomogram was created from Cox models and internally validated by use of bootstrap and cross-validation. Model discrimination was measured by calibration plots and the concordance index, and the clinical benefits were evaluated through clinical decision curve analysis (DCA). Results: 101 BCBM patients receiving SRT were analyzed in this study, and 5 patients were excluded with other primary malignancies or missing data. Median observation time was 15.0 months, and median OS was 22.0 months. OS rate was 71.5% in 1 year, 45.8% in 2 years, and 32.8% in 3 years. DIC was 49.8% in 1 year, 26.6% in 2 years, and 18.3% in 3 years. Multivariable analysis identified prognostic factors for OS including number of the brain metastasis, molecular subtypes type, brain metastasis as the first metastasis site, Karnofsky performance status (KPS), and receiving systemic therapy after SRT. KPS<80, triple-negative subtype, the existence of extracranial metastases, the existence of lung metastases were associated with decreased DIC. Selected by the Akaike information criterion (AIC), the nomogram model contains age, KPS, histological subtype, number of brain metastases, brain metastasis as first metastasis site, PTV size, liver metastases, albumin and neutrophils. The calibration curve for probability of survival showed high consistencies between prediction by nomogram and actual observation. The C-index of the nomogram for predicting survival was 0.823, and the bias-corrected C-index generated by bootstrap validation with 1,000 resamples was 0.772, which was statistically higher than the C-index values of the other systems: Recursive partitioning analysis (RPA) (0.627), Graded prognostic assessment (GPA) (0.637), Breast-specific Graded Prognostic Assessment (breast-GPA) (0.699). BCBM patients receiving SRT were divided into four risk groups: I group (risk score < 150), II group (150≤risk score< 220), III group (220≤risk score<290) and IV group (risk score≥290). The Kaplan‐Meier OS curves showed great discrimination among the four risk groups. Conclusions: The proposed nomogram resulted in a more-accurate prognostic prediction for BCBM patients receiving SRT.

Determining The Optimal Time To Apply Adaptive Radiotherapy Plan For Head And Neck Cancer Patients

Background: Head and neck cancer (HNC) patients may have considerable anatomical alterations with IMRT and VMAT. Maintaining dosage precision and minimizing tissue damage using adaptive radiotherapy (ART) improves patients' quality of life. However, the optimal time to initiate ART in HNC patients remains undetermined. Objective: This research aimed to identify the optimal time to start ART in HNC patients using a novel method to evaluate anatomical modifications. Materials and Methods: The research included 48 people with HNC who had undergone dynamic IMRT. The size of the patient's PTV was used to divide them into different groups. Both the ER of the original PTV and the ER of the revised PTV were determined. ER differences (dER) were correlated with volume decrease percentage (%dV). Pre-treatment CT images were taken, and then again at fractions 7, 14, and 21 throughout therapy. Results: The PTV volume distributions were verified to be expected. Small, medium, and high ER volumes showed statistically significant variations between the first and second phases (p<0.001). Fraction 14 was the optimum time to administer ART in cases with a PTV of less than <100cc, whereas fractions 7 and 21 were best for cases with a PTV of 100cc to 500cc. Conclusions: The optimal time to begin PTV-based adaptive radiotherapy in HNC patients has been determined. The ER technique improves the clarity of presenting the gap between the reference isodose volume and the PTV, which is valuable information for ART.

A convolution-superposition fluence model for the Siemens HD120 multi leaf collimator with application to a 3D VMAT dose engine

Purpose. To construct a fast-calculating fluence modelfor the Siemens HD120 multi leaf collimator (MLC) using convolution-superposition techniques, and to develop a 3D VMAT dose engine using this fluence model. This work offers analternative to time-consuming open-source Monte Carlo simulations for thosedeveloping in-house dose-calculating software for research or clinical needs.Methods. EPID-acquired images of sweeping-window and sweeping-checker field profiles were used to commission transmission, 2 Dinterleaf leakage, and tongue-and-groove maps specific to the HD120 MLC. These maps, along with a 2D head-scattermodel were incorporated into a convolution-superposition algorithm to provide a fluence model for the HD120 MLC. This fluence model was used to develop a 3D VMAT dose engine, where 3D pre-computed 6MV dose kernels (EGSnrc) and a 3D fluence curvature-correction map were incorporatedto calculate 3D VMAT doses in a 22 cm diameter cylindrical phantom. Four VMAT patient plans witha large range of PTV sizes (36 cc to 604 cc) were chosen to test the fluence model and dose engine. Results. Excellent agreement was observed between the simulated commissioning fields and measured EPID-responses. 2D 2%/2 mm gamma analysis yielded a 98.9% pass rate for 1 cm, 2 cm, and 4 cm sweeping-window fields. 2D 2%/2mm gamma analysis for outer/inner MLC leaves yielded 89.1%/77.0% and 95.2%/91.1% pass rates from 1 cm and 2 cm sweeping-checker fields. Mean 3%/3 mm gamma analysis showed excellent agreement between our dose engine and Eclipse (Acuros) regardless of PTV size: 98.7% pass rate, with 95.1% pass rate in the high-dose volume. Fluence calculation times were13.6 seconds per dynamic MLC field and 1.4 minutes/arc for 3D VMAT dose on a standard PC. Conclusions. A fast-calculating convolution-superposition fluence model has been commissioned for the Siemens HD120 MLC and incorporatedinto a 3D VMAT dose engine. This work can be used to facilitate the development of fast in-house dose-calculating software.

How much rotational error is clinically acceptable for single-isocenter/two-lesion lung SBRT treatment on halcyon ring delivery system (RDS)?

SBRT treatment of two separate lung lesions via single-isocenter/multi-target (SIMT) plan on Halcyon RDS could improve patient comfort, compliance, patient throughput, and clinic efficiency. However, aligning two separate lung lesions synchronously via a single pre-treatment CBCT scan on Halcyon can be difficult due to rotational patient setup errors. Thus, to quantify the dosimetric impact, we simulated loss of target(s) coverage due to small, yet clinically observable rotational patient setup errors on Halcyon for SIMT treatments. Seventeen previously treated 4D-CT based SIMT lung SBRT patients with two separate lesions (total 34 lesions, 50Gy in five fractions to each lesion) on TrueBeam (6MV-FFF) were re-planned on Halcyon (6MV-FFF) using a similar arc geometry (except couch rotation), dose engine (AcurosXB algorithm), and treatment planning objectives. Rotational patient setup errors of [±0.5⁰ to ±3.0⁰] on Halcyon were simulated via Velocity registration software in all three rotation axes and recalculated dose distributions in Eclipse treatment planning system. Dosimetric impact of rotational errors was evaluated for target coverage and organs at risk (OAR). Average PTV volume and distance to isocenter were 23.7 cc and 6.1cm. Average change in Paddick's conformity indexes were less than -5%, -10%, and -15% for 1°, 2°, and 3°, respectively for yaw, roll, and pitch rotation directions. Maximum drop off of PTV(D100%) coverage for 2° rotation was -2.0% (yaw), -2.2% (roll), and -2.5% (pitch). With ±1° rotational error, no PTV(D100%) loss was found. Due to anatomical complexity: irregular and highly variable tumor sizes and locations, highly heterogenous dose distribution, and steep dose gradient, no trend for loss of target(s) coverage as a function of distance to isocenter and PTV size was found. Change in maximum dose to OAR were acceptable per NRG-BR001 within ±1.0° rotation, but were up to 5Gy higher to heart with 2° in the pitch rotation axis. Our clinically realistic simulation results show that rotational patient setup errors up to 1.0° in any rotation axis could be acceptable for selected two separate lung lesions SBRT patients on Halcyon. Multivariable data analysis in large cohort is ongoing to fully characterize Halcyon RDS for synchronous SIMT lung SBRT.

Predictors of toxicity after curative reirradiation with intensity modulated radiotherapy or proton therapy for recurrent head and neck carcinoma: new dose constraints for pharyngeal constrictors muscles and oral cavity.

Our study aims to identify predictive factors of moderate to severe (grade ≥ 2) late toxicity after reirradiation (reRT) of recurrent head and neck carcinoma (HNC) and explore the correlations between dose organs at risk (OAR) and grade ≥ 2toxicity. Between 09/2007 and 09/2019, 55patients were re-irradiated with IMRT or proton therapy with curative intent for advanced HNC. Our study included all patients for whom data from the first and second irradiations were available. Co-variables, including interval to reRT, size of re-irradiated PTV, and dose to OAR, were analyzed as potential predictors for developing moderate to severe long-term toxicity with death as acompeting risk. Receiver-operator characteristics (ROC) analysis assessed the association between dose/volume parameters and the risk of toxicity. Twenty-three patients participated in our study. After amedian follow-up of 41months, 65% of the patients experienced grade ≥ 2late toxicity. The average dose to pharyngeal constrictor muscles (PCM) at the time of reRT showed an association with the risk of grade ≥ 2dysphagia: AUC = 0.78 (95% CI: 0.53-1), optimal cut-off value = 36.7 Gy (sensitivity 62%/specificity 100%). The average dose to the oral cavity at the time of reRT showed an association with the risk of grade ≥ 2dysgeusia: AUC = 0.96 (0.89-1), optimal cut-off value = 20.5 Gy (sensitivity 100%/specificity 88%). Our analysis depicted an association between the dose to OAR and the risk of developing moderate to severe dysphagia and dysgeusia and proposed new dose constraints for PCM (36.7 Gy) and oral cavity (20.5 Gy).

Comparison of Changes in Pulmonary Function After Stereotactic Body Radiation Therapy Versus Conventional 3-Dimensional Conformal Radiation Therapy for Stage I and IIA Non-Small Cell Lung Cancer: An Analysis of the TROG 09.02 (CHISEL) Phase 3 Trial

The [Anonymized for Review] trial compared conventional radiotherapy (CRT) with stereotactic body radiation therapy (SBRT) in patients with inoperable early-stage non-small cell lung cancer. Patients randomised to SBRT had less local failure and improved overall survival. This analysis reports differences in pulmonary function tests (PFTs) and the six-minute walk test (SMWT) between patients who received SBRT and those who received CRT. We analyzed the PFTs and SMWT of all patients recruited to the [Anonymized for Review] trial. During this trial, patients underwent serial PFTs. Linear regression models were used to compare parameters between SBRT and CRT at 3 and 12-months post-treatment. 101 patients were enrolled, 33 patients were treated with CRT, 61 with SBRT and 7 did not receive treatment. Primary tumor size was similar between arms, SBRT 25mm (SD 9mm) and CRT 28mm (SD 9mm). On regression analysis, at 3 and 12 months, there was no evidence of a difference between arms in PFT decline or distance walked in the SMWT. PTV size was significantly larger in the CRT arm, 142.79 cc (SD 61.14cc) compared to the SBRT group 46.15 cc (SD 23.39 cc). The mean Biological Equivalent Dose (BED) received by the target was significantly larger in the SBRT group 125.92 Gy (SD 21.58 Gy) compared to CRT 65.49 Gy (6.32Gy). Mean dose to the lungs - iGTV was 8.9 Gy (SD 2.34 Gy) in the CRT group and 4.37 Gy (SD 1.42 Gy) in the SBRT group. Despite the considerably higher biologically effective doses delivered to the tumor in SBRT, there was no difference in decline in respiratory function observed between the two groups.

Intra-fraction motion of pelvic oligometastases and feasibility of PTV margin reduction using MRI guided adaptive radiotherapy.

This study assesses the impact of intra-fraction motion and PTV margin size on target coverage for patients undergoing radiation treatment of pelvic oligometastases. Dosimetric sparing of the bowel as a function of the PTV margin is also evaluated. Seven patients with pelvic oligometastases previously treated on our MR-linac (35 Gy in 5 fractions) were included in this study. Retrospective adaptive plans were created for each fraction on the daily MRI datasets using PTV margins of 5mm, 3mm, and 2mm. Dosimetric constraint violations and GTV coverage were measured as a function of PTV margin size. The impact of intra-fraction motion on GTV coverage was assessed by tracking the GTV position on the cine MR images acquired during treatment delivery and creating an intra-fraction dose distribution for each IMRT beam. The intra-fraction dose was accumulated for each fraction to determine the total dose delivered to the target for each PTV size. All OAR constraints were achieved in 85.7%, 94.3%, and 100.0% of fractions when using 5mm, 3mm, and 2mm PTV margins while scaling to 95% PTV coverage. Compared to plans with a 5mm PTV margin, there was a 27.4 ± 12.3% (4.0 ± 2.2 Gy) and an 18.5 ± 7.3% (2.7 ± 1.4 Gy) reduction in the bowel D0.5cc dose for 2mm and 3mm PTV margins, respectively. The target dose (GTV V35 Gy) was on average 100.0 ± 0.1% (99.6 - 100%), 99.6 ± 1.0% (97.2 - 100%), and 99.0 ± 1.4% (95.0 - 100%), among all fractions for the 5mm, 3mm, and 2mm PTV margins on the adaptive plans when accounting for intra-fraction motion, respectively. A 2mm PTV margin achieved a minimum of 95% GTV coverage while reducing the dose to the bowel for all patients.

A novel dose fall-off index and preliminary application in brain and lung stereotactic radiotherapy.

Stereotactic radiotherapy (SRT) has been widely used for the treatment of brain metastases and early stage non-small-cell lung cancer (NSCLC). Excellent SRT plans are characterized by steep dose fall-off, making it critical to accurately and comprehensively predict and evaluate dose fall-off. A novel dose fall-off index was proposed to ensure high-quality SRT planning. The novel gradient index (NGI) had two different modes: NGIx V for three-dimensions and NGIx r for one-dimension. NGIx V and NGIx r were defined as the ratios of the decreased percentage dose (x%) to the corresponding isodose volume and equivalent sphere radii, respectively. A total of 243 SRT plans at our institution between April 2020 and March 2022 were enrolled, including 126 brain and 117 lung SRT plans. Measurement-based verifications were performed using SRS MapCHECK. Ten plan complexity indexes were calculated. Dosimetric parameters related to radiation injuries were also extracted, including the normal brain volume exposed to 12 Gy (V12 ) and 18 Gy (V18 ) during single-fraction SRT (SF-SRT) and multi-fraction SRT (MF-SRT), respectively and the normal lung volume exposed to 12 Gy (V12 ). The performance of NGI and other common dose fall-off indexes, gradient index (GI), R50% and D2cm were evaluated using Spearman correlation analysis to explore their correlations with the PTV size, gamma passing rate (GPR), plan complexity indexes and dosimetric parameters. There were statistically significant correlations between NGI and PTV size (r = -0.98, p < 0.01 for NGI50 V and r = -0.93, p < 0.01 for NGI50 r), which were the strongest correlations compared with GI (r = 0.11, p = 0.13), R50% (r = -0.08, p = 0.19) and D2cm (r = 0.84, p < 0.01). The fitted formulas of NGI50 V = 23.86V-1.00 and NGI50 r = 113.5r-1.05 were established. The GPRs of enrolled SRT plans were 98.6 ± 1.7%, 94.2 ± 4.7% and 97.1 ± 3.1% using the criteria of 3%/2 mm, 3%/1 mm and 2%/2 mm, respectively. NGI50 V achieved the strongest correlations with various plan complexity indexes (|r| ranged from 0.67 to 0.91, p < 0.01). NGI50 V also showed the highest r values with V12 (r = -0.93, p < 0.01) and V18 (r = -0.96, p < 0.01) of the normal brain during SF-SRT and MF-SRT, respectively and V12 (r = -0.86, p < 0.01) of the normal lung during lung SRT. Compared with GI, R50% and D2cm , the proposed dose fall-off index, NGI, had the strongest correlations with the PTV size, plan complexity and V12 /V18 of the normal tissues. These correlations established on NGI are more helpful and reliable for SRT planning, quality control and reducing the risk of radiation injuries. This article is protected by copyright. All rights reserved.

Analysis of the interplay effect in lung stereotactic ablative radiation therapy based on both breathing motion and plan characteristics

Abstract Introduction: Stereotactic ablative radiotherapy (SABR) is susceptible to challenges for tumours affected by intrafraction organ motion. This study aims to investigate the effect of breathing characteristics and plan complexity on the interplay effect. Methods: A patient-specific interplay effect evaluation was performed using in-house software with an alpha version of the treatment planning verification software Verisoft (PTW-Freiburg, Germany) on VMAT plans. The OCTAVIUS 4D phantom was used to acquire the static dose distribution, and the simulation approach was utilised to generate the moving dose distribution. The influence of plan complexity, PTV size, number of breaths, and motion amplitudes on the interplay effect were examined. The dose distribution of two extreme phases—end-inhale and end-exhale—was considered using the gamma criteria of 2%/2 mm for the interplay effect evaluation. Results: A strong correlation was found between the motion amplitude (p &lt; 0.001) and the NBs (p &lt; 0.001) with the gamma-passing rate. No correlation was found between the gamma-passing rate and the PTV size or plan complexity. Conclusion: The simulation tool allowed the analysis of a large number of breathing traces, demonstrating how free-breathing patients, suspected of high interplay, could be selected for other motion management solutions. The simulated cases showed strong interplay effects for long breathing periods with extended motion amplitudes in a small group of patients.

Impact of fractionated stereotactic radiotherapy on activity of daily living and performance status in progressive/recurrent glioblastoma: a retrospective study

BackgroundThe prognosis of recurrent glioblastoma (GBM) is poor, with limited options of palliative localized or systemic treatments. Survival can be improved by a second localized treatment; however, it is not currently possible to identify which patients would benefit from this approach. This study aims to evaluate which factors lead to a lower Karnofsky performance status (KPS) score after fractionated stereotactic RT (fSRT).MethodsWe retrospectively collected data from patients treated with fSRT for recurrent GBM at the Institut de Cancérologie de Lorraine between October 2010 and November 2017 and analyzed which factors were associated with a lower KPS score.Results59 patients received a dose of 25 Gy in 5 sessions spread over 5–7 days (80% isodose). The median time from the end of primary radiotherapy to the initiation of fSRT was 10.7 months. The median follow-up after fSRT initiation was 8.8 months. The incidence of KPS and ADL impairment in all patients were 51.9% and 37.8% respectively with an adverse impact of PTV size on KPS (HR = 1.57 [95% CI 1.19–2.08], p = 0.028). Only two patients showed early grade 3 toxicity and none showed grade 4 or late toxicity. The median overall survival time, median overall survival time after fSRT, median progression-free survival and institutionalization-free survival times were 25.8, 8.8, 3.9 and 7.7 months, respectively. Initial surgery was associated with better progression-free survival (Hazard ratio (HR) = 0.48 [95% CI 0.27–0.86], p = 0.013).ConclusionsA larger PTV should predicts lower KPS in the treatment of recurrent GBM using fSRT.

Safety and Efficacy of Dose-Escalated Radiotherapy with a Simultaneous Integrated Boost for the Treatment of Spinal Metastases

<h3>Purpose/Objective(s)</h3> Dose-escalated radiotherapy (RT) using a spinal simultaneous integrated boost (SSIB) has been recently utilized for treatment of metastatic lesions not amenable to spine stereotactic radiosurgery (SSRS). Prior reports have utilized small sample sizes with short follow-up times. Our goal was to characterize the long-term efficacy and safety of this technique in a large cohort of patients with long term follow-up. <h3>Materials/Methods</h3> We reviewed 58 patients with 63 spinal metastatic sites that were treated with RT using a SSIB between 2012 and 2021. All patients received 30 Gy to the clinical tumor volume (CTV)and 40 Gy to the gross tumor volume, each delivered simultaneously in 10 fractions (GTV). Acute and late toxicities were noted for each patient. Local control (LC) was defined as having no progression on magnetic resonance imaging (MRI) at the SSIB-treated site. Overall survival (OS) was defined as the time from initiation of SSIB to death or last follow up, and was estimated using the Kaplan-Meier method. Multivariable Cox analysis was performed to identify associations with OS and LC. <h3>Results</h3> In our cohort, the median Karnofsky Performance Score (KPS) prior to RT was 80 (interquartile range [IQR], 80-90). Tumor histology was considered to be radioresistant in 81% of patients. Most patients had paraspinal involvement (65%) and epidural extension (82%). The median follow-up was 31 months with a median OS of 18 months (95% confidence interval [CI], 13-27 months). OS at 1, 2, and 3 years were 64%, 45%, and 24%, respectively. Actuarial LC was 98% (CI, 95-100%) and 95% (CI, 89-100%) at 1 and 2 years, respectively. The median GTV and CTV doses were 4123 cGy (range, 3400-4318 cGy) and 3641 cGy (range, 3302-4089 cGy), respectively. The mean cord dose was 2401 cGy (range 59-3168 cGy). The most commonly observed acute toxicities were fatigue (41%), pain (38%), esophagitis (8%), and nausea (8%). However, only one patient (2%) experienced Grade 3 or higher toxicity (pain). At last follow-up, no patients had developed myelopathy and all patients maintained ambulation. Following RT, pain improvement was achieved in 82% with a median pain score of 2 (IQR, 1-4) out of 10 from a pre-RT baseline of 4 (IQR, 3-6). Multivariable Cox analysis revealed that higher KPS score prior to RT (hazard ratio [HR], 0.40, 95%, CI, 0.20-0.84; <i>P</i>=0.016) was associated with longer OS, whereas increased size of PTV (HR 1.003, CI 1.001-1.005; <i>P</i>=0.017) was associated with shorter survival. <h3>Conclusion</h3> Our data show that the use of RT with SSIB provides favorable LC and OS with improved pain relief for selected patients that are not amenable for SSRS. Importantly, there were limited acute toxicities with no observed instances of radiation-induced myelopathy. Multi-institutional validation is warranted.

Retrospective Review of the Safety of Osimertinib with Thoracic Radiotherapy

<h3>Purpose/Objective(s)</h3> Tyrosine Kinase inhibitor [TKI] therapy is the backbone of treatment for patients who progress after definitive treatment for EGFR mutated non-small cell lung carcinoma [NSCLC], or those who are diagnosed with metastatic disease. Evidence from phase II and III clinical trials have suggested that ablative consolidation of oligometastatic or progressive sites leads to improved progression-free, and overall survival. For patients on TKI therapy, there is little information regarding the safety of combining therapy with radiation therapy [RT]. There are 5 FDA approved EGFR TKI's but simertinib is most used today and is the focus of this review. We present the risk of toxicity of concurrent simertinib and thoracic RT in a large institutional cohort. <h3>Materials/Methods</h3> A prospectively collected database of patients treated with simertinib from September 2014 through March of 2021 was reviewed to identify those who had RT at some point in their treatment. 206 individual patients were identified of whom 60 had treatment directed to a thoracic target. 13 patients were treated to 2 metachronous thoracic sites yielding 73 individual treatments. Patient records were retrospectively reviewed to identify practice patterns regarding sequencing of RT and TKI, and the incidence of toxicity. <h3>Results</h3> In these 73 targets, most volumes were treated with SBRT [3-5 fractions] 42(57%). Twenty-one targets (29%) were treated with hypofractionation [8-20 fractions; HFRT], 8(11%) were treated with conventional radiation, [200cGY per fraction; CFR] and 2 with quad shot fractionation [QS]. The median PTV size was 91.25cc (range 8.55cc – 767.95cc). In 43 treatments radiation was delivered concurrently with simertinib, drug was held for 20 radiation treatments, and 10 treatments were delivered before simertinib initiation. Of those tumors treated with continuous simertinib dosing, 28 tumors were treated with SBRT, 13 with HFRT, 1 CFR and 1 with QS. 24 patients were diagnosed with radiation pneumonitis following thoracic RT; 4/11(36%) tumors treated prior to TKI; 6/20(30%) treatments when medication was held; and 14/44(32%) tumors when simertinib was continued through radiation (p=0.14). Most cases of pneumonitis were grade 1-2 and only 2 patients developed grade 3 pneumonitis. Grade 3 pneumonitis was not associated with continuous simertinib dosing. The median PTV for any grade pneumonitis was 112.27cc. Institutional V20 planning constraints were met in all but 1 patient who was treated with CFR. Other toxicities reported included 7 events of esophagitis, and 4 events of dermatitis all of which were grade 1-2. <h3>Conclusion</h3> Patients receiving osimertininb concurrently with thoracic RT did not appear to have higher rates of pneumonitis relative to those who held drug during RT or initiated it after RT. This suggests it is safe to continue simertinib concurrently with thoracic RT when standard planning dose limits are followed.

Lymphocyte Nadir Following Radiation for Soft-Tissue Sarcoma: Defining Key Dosimetric Parameters and Outlining Clinical Significance

<h3>Purpose/Objective(s)</h3> Lymphopenia following radiotherapy (RT) is associated with worse oncologic outcomes in numerous cancers, but its incidence and effects are unknown in soft-tissue sarcomas (STS). Our goals were to determine the dosimetric parameters associated with development of lymphopenia and evaluate the impact of lymphopenia on overall survival (OS) and disease-free survival (DFS). <h3>Materials/Methods</h3> We retrospectively reviewed 51 patients who underwent either preoperative, postoperative, or definitive RT for STS at our institution between April, 2010 and May, 2021. Absolute lymphocyte count (ALC) nadir was defined as lowest lymphocyte value within one year after RT, and lymphopenia grading was by CTCAE v5.0. Dosimetric parameters were evaluated for associations with ALC nadir, including PTV size as well as mean and volumetric doses (V10, V20, V30) of body, bone, heart, and lung. <h3>Results</h3> Median follow-up was 1.9 years (range 0.3-9.7 years). Stage I cancer was present in 15.7%, Stage II in 11.8%, Stage III in 68.6%, Stage IV in 3.9% (for N1). Grade 1 disease was found in 6.5%, Grade 2 in 6.5%, Grade 3 in 78.4%, and unknown in 9.8%. Chemotherapy was delivered to 35.3%. Median RT dose was 50 Gy (range 45-78 Gy) and IMRT was used for 70.6%. Time to ALC nadir was within 6 months of RT for 86% of patients. Median ALC at baseline was 1400 cells/mm³ (range 600 to 3400 cells/mm³) and at nadir was 900 cells/mm³ (range 40 to 2400 cells/mm³). Strongest correlations with ALC nadir were body V10 (r_s = 0.435, p = 0.002), mean bone (r_s = 0.632, p = 0.001), bone V10 (r_s = 0.632, p <0.001), and bone V20 (r_s = 0.562, p <0.001). Significant but weaker correlations included mean body, body V20, body V30, and bone V30. Lung and heart parameters as well as total dose did not show significant correlations. On multivariable linear regression controlling for disease grade, surgical resection, and chemotherapy use, strongest correlations with ALC nadir were body V10 (β = 0.468, p < 0.001) and bone V10 (β = 0.479, p < 0.001). Distribution of lymphopenia was: grade 1 (17.6%), grade 2 (13.7%), grade 3 (19.6%), and grade 4 (5.9%). Grade 2-4 lymphopenia was associated with inferior OS (HR 5.82, p = 0.01) and DFS (HR 3.85, p=0.002). Lower ALC nadir was also associated with worse OS (HR = 1.95, p = 0.014) and DFS (HR = 1.15, p = 0.001). On multivariate regression, only Grade 3-4 lymphopenia remained associated with worse OS and DFS. <h3>Conclusion</h3> Lower ALC nadir and development of Grade 2-4 lymphopenia were associated with worse OS and DFS in STS. Despite the heterogenous location of STS presentation, lower ALC nadir showed strong correlations with increasing body V10 and bone V10, consistent with the known radiosensitivity of lymphocyte cell lines. Our study supports efforts to reduce treatment-related hematopoietic toxicity as a move to improve oncologic outcomes. This work also raises the hypothesis that radiation effects on lymphocyte progenitors in the bone marrow dominate those of circulating lymphocytes for treatments with minimal contribution to heart and lung.

High Dose Thoracic Re-Irradiation and Chemo-Immunotherapy for Centrally Recurrent NSCLC.

Simple SummarySince the early 1980s, there has been a trend towards escalating radiation doses in pulmonary tumor recurrences with the aim of improving survival. In this context, we performed a literature search in order to summarize the evidence of curative thoracic re-irradiation for centrally recurrent lung cancer. Tumor relapse in this specific situation poses a major problem because of the proximity to mediastinal organs. Of the initial 227 studies, 11 fulfilled the inclusion criteria for this analysis. The median overall survival (mOS) was 18.1 months (range 9.3–25.1), the median progression-free survival (mPFS) was nine months (range 4.5–16), and the median locoregional control (mLRC) was 12.1 months (range 6.5–20). The total re-irradiation dose correlated with both mLRC (p-value = 0.012) and mOS (p-value = 0.007). As large-scale prospective trials in the field are missing, this literature review is primarily based on retrospective data. In today’s age of enhanced long-term survival rates after chemoradiotherapy followed by immune checkpoint inhibition, the current analysis provides valuable insights into radiation treatment options for patients with loco-regional lung cancer recurrence.Introduction: Thoracic re-irradiation for recurrent lung cancer dates back four decades, when the first small series on 29 patients receiving palliative doses was published. With 5-year overall survival rates of 57% in PDL-1 positive patients after primary chemo-radio-immunotherapy, the number of patients who experience loco-regional relapse will increase in the near future. In this context, centrally recurring lung tumors pose a major treatment challenge. Hence, the aim of the current review is to compile the available evidence on curatively intended thoracic re-irradiation for this special clinical situation. Methods: A systematic literature search according to the PRISMA guidelines was performed. A study was included when the following criteria were met: (1) 66% of the patients had NSCLC, (2) a total dose of 50 Gy in the second course and/or a biologically effective dose of at least 100 Gy in both treatment courses was administered, (3) re-irradiation was administered with modern radiation techniques, (4) 50% or more of the patients had a centrally located relapse, (5) the minimum cohort size was 30 patients. Results: Of the initial 227 studies, 11 were analyzed, 1 of which was prospective. Median overall survival (OS) was 18.1 months (range 9.3–25.1), median progression free survival (PFS) was nine months (range 4.5–16), and median loco-regional control (LRC) was 12.1 months (range 6.5–20). Treatment-related mortality rates ranged from 2% to 14%. The total dose at re-irradiation correlated with both LRC (p-value = 0.012) and OS (p-value = 0.007) with a close relation between these two clinical endpoints (p-value = 0.006). The occurrence of acute toxicity grade 1 to 4 depended on the PTV size at re-irradiation (p-value = 0.033). Conclusion: The evidence regarding curative re-irradiation for centrally recurrent NSCLC is primarily based on scarce retrospective data, which are characterized by a high degree of heterogeneity. The OS in this clinically challenging situation is expected to be around 1.5 years after re-treatment. Patients with a good performance score, younger age, small tumors, and a longer interval to recurrence potentially benefit most from re-irradiation. In this context, prospective trials are warranted to achieve substantial advances in the field.

An analysis of a large multi-institutional database reveals important associations between treatment parameters and clinical outcomes for stereotactic body radiotherapy (SBRT) of oligometastatic colorectal cancer

PurposeIn recent years, stereotactic body radiotherapy (SBRT) has emerged as an effective treatment for oligometastatic cancers. Here, we report radiation treatment parameters and clinical outcomes for patients with oligometastatic colorectal cancer (CRC) treated with SBRT using a large multi-institutional database. MethodsPatients with extra-cranial oligometastatic CRC (≤5 lesions) treated with SBRT at six large academic cancer centers were included. The primary outcome was local recurrence while secondary outcomes included overall survival (OS) progression free survival, oligo-progression, and widespread progression. Survival outcomes were estimated using the Kaplan-Meier method. Univariable and multivariable analyses were performed to determine the relationship between patient and treatment characteristics and clinical outcomes. ResultsWe identified 235 patients with a total of 381 oligometastatic CRC lesions. The 1- and 5-year local recurrence rate was 13.6% and 44.3% respectively. The median OS was 49 months with a 2-and 5-year OS of 76.1% and 35.9%, respectively. On multivariable analysis, a BED10 of ≥120 Gy, and lung versus liver metastases were associated with a reduction in local recurrence. Larger total PTV size (≥17.5 cc) was associated with worse overall survival, progression free survival, and widespread progression. ConclusionThis large multi-institutional analysis found that the use of SBRT for oligometastatic colorectal cancer resulted in favorable overall survival. However, local recurrence is higher than expected for ablative radiation treatment. An increase in BED10 should be considered if feasible and safe.

Role of Stereotactic Body Radiotherapy (SBRT) in the Treatment of Oligo Metastatic Colorectal Cancer: Analysis of a Large Multi-Institutional Database

In recent years, stereotactic body radiotherapy (SBRT) has emerged as an effective local treatment for oligometastatic cancers. However, it has been suggested that colorectal cancers may represent a more radioresistant histology, even to the high doses used in SBRT. Here, we report local recurrence rates, progression free-survival, and overall survival of patients with oligometastatic CRC treated with SBRT using a large multi-institutional data-base.We collected data retrospectively from six cancer centers with a high volume of SBRT treatments from Jan 1 2008 to December 31, 2016. Our primary outcome was local recurrence while secondary outcomes included overall survival (OS), local recurrence free survival, progression free survival, oligo-progression, and widespread progression. Time-to event outcomes were estimated using the Kaplan-Meier method. Univariable regression analysis was performed to determine the relationship between patient, tumor and treatment variables and outcomes. Variables significant on univariable screen were entered into a multivariable model. All analysis was performed in R (R Foundation for Statistical Computing, version 4.0.2) RESULTS: We identified 235 patients with a total of 381 oligometastatic CRC lesions that were treated with SBRT. The mean age was 70.7 ± 12.2 years, 58% of patients were male with a median follow-up of 25.5 months. The most common site of metastasis was the lung (n = 133, 56.6%) with a total of 239 (62.7%) lesions. The median time to local recurrence was not reached with the 1- and 5-year local recurrence rate was 13.6% and 44.3% respectively. The median OS was 49 months with a 2-and 5-year probability of 76.1% and 35.9% respectively. On multivariable analysis, a BED10 of ≥100 Gy (HR 0.67, 95% CI 0.45-0.99) and the presence of lung (HR 0.53, 95% CI 0.34-0.82) or lymph node metastasis as opposed to liver metastasis (HR 0.31, 95% CI 0.13-0.74) were associated with improved local control. Larger total PTV size (≥17.5cc) was associated with worse overall survival (HR 2.62, 95% CI 1.45-4.72), progression free survival (HR 2.01, 95% CI 1.39-2.90) and widespread progression (HR = 2.82, 95% CI: 1.63-4.88). Use of prior systemic therapy before SBRT was also adversely associated with widespread progression (HR = 1.90, 95% CI: 1.22-2.95).This large multi-institutional analysis found that the use of SBRT for oligometastatic colorectal cancer resulted in favorable overall survival. However, local recurrence is appreciably lower than what has historically been demonstrated in other cancer primary sites. These results suggest that an increase in BED should be considered if feasible and safe, in order to optimize local control. Increased overall PTV size may also be an indicator for the need for systemic therapy in addition to SBRT.

Dosimetric Analysis of Intra-Fraction Motion Detected by Surface Guided Radiation Therapy During Linac Stereotactic Radiosurgery

Stereotactic radiosurgery (SRS) requires very sharp dose gradients, high conformality and typically uses minimal expansion margins. Immobilization with an open face mask is more comfortable and less invasive than frame-based immobilization but concerns about intra-fraction motion must be addressed. Surface guided radiation therapy (SGRT) is an attractive option for intra-fraction patient monitoring because it is continuous, has sub-millimeter accuracy and uses no ionizing radiation. The purpose of this study was to investigate the dosimetric consequences of uncorrected intra-fraction patient motion detected during frameless Linac-based SRS.All SRS patients (pts) were immobilized in an SRS-specific open face thermoplastic mask with bite plate and were monitored during treatment using SGRT with tolerances of 1 mm translations and 1° rotations; the treatment beam automatically turned off if these tolerances were exceeded. SRS pts received 18 or 21 Gy in 1 fraction or 27 Gy in 3 fractions based on tumor size and location. GTV to PTV margins ranged from 0 to 3 mm. Twelve pts were treated with circular cones and 13 were treated with MLC-based plans with the technique chosen based on PTV size. If the SGRT system detected motion greater than tolerance during treatment, conebeam CT(CBCT) was repeated and the necessary shifts were made prior to continuing treatment. For the 25 pts with intra-fraction 3D vector shifts of at least 1 mm, we offset the isocenter in the treatment planning system using the translational shifts from the repeat CBCT and re-calculated the plans with the planned MU to determine the dosimetric effect the shift would have caused had it not been detected. The GTV and PTV coverage and normal brain V12 for the shifted plans were compared to the planned values. Wilcoxon signed rank tests were used to compare planned and shifted dosimetric indices and median 2 sample tests were used to investigate these differences between cone and MLC plans.From the recalculated plans, the resulting median V12 increased by 0.24 cc (P = 0.006) and the median GTV and PTV coverage decreased 9% (P < 0.001) and 10.2 % (P < 0.001), respectively. PTV coverage decreased more for shifted cone plans than for shifted MLC plans (11.6% vs 4.7%, P = 0.011) but the median V12 differences were found to be significantly larger for MLC plans (-0.34 cc vs -0.01 cc, P = 0.011), due to the sharper dose gradients and higher conformality for the cone plans compared to the MLC plans. Differences in GTV coverage between cone and MLC plans were not statistically significant.SGRT detected clinically meaningful intra-fraction motion during frameless SRS, which could potentially lead to large underdoses and increased normal brain dose if not corrected. Dosimetric differences between planned and shifted plans were statistically significant.R.D. Foster: None. B.J. Moeller: Independent Contractor; Novant Health. Partner; SERO. Stock; Moderna. M. Robinson: None. M. Bright: SEAAPM.J.L. Ruiz: Stock; Obseva USA, Inc. C.J. Hampton: None. J.H. Heinzerling: Research Grant; Vision RT, Inc, AstraZeneca. Honoraria; Vision RT, Inc, AstraZeneca. Consultant; Vision RT, Inc.

Prospective Study of Surface Guided Radiation Therapy (SGRT) for Breath Hold SBRT Treatments of the Lung: Analysis of Reliability of Surface Guidance Alone for Internal Tumor Position During Breath Hold

<h3>Purpose/Objective(s)</h3> Respiratory motion management with breath hold (BH) is one technique to limit normal lung and other organ dose during SBRT treatments of the lung. Surface guidance (SGRT) has been utilized for BH in larger targets such as breast cancer, but its reliability in BH treatments of small targets has not been investigated. We report the initial results of the reliability of utilizing SGRT alone as a technique for BH during a prospective study of treatment of primary and metastatic lung tumors. <h3>Materials/Methods</h3> An IRB approved prospective study was conducted in patients (pts) with primary NSCLC or lung metastasis undergoing SBRT. Eligible pts had at least 1 cm of respiratory associated motion on free breathing 4DCT. Pts underwent planning CT with BH either in end inspiration or expiration per investigator choice. The GTV was contoured on the BH planning CT and a 5mm margin added for PTV expansion. During each SBRT treatment, pts performed BH and were aligned within tolerance based on the reference BH surface capture created from the BH planning CT. Pts underwent short-arc CBCT during BH for volumetric match of the target. Before shifts were made for target match, pts performed a BH within tolerance, then shifts were made prior to a new reference surface capture being immediately obtained during the same BH. Pts were then treated in BH based on the new reference surface with a tolerance of 3mm translations and 2 degree rotations. Treatment was stopped if pts fell outside of the predefined tolerances. Midway through treatment, pts underwent a second short arc CBCT during BH to verify the reliability of target position during BH treatment utilizing SGRT. Any subsequent shifts on target volumetric match after the second CBCT were recorded. Linear mixed models for repeated measures were used to analyze rotational and translational shift measurements. <h3>Results</h3> 13 pts and 39 SBRT fractions were treated utilizing SGRT alone for BH. All pts were treated with 54 Gy in 3 fractions. Median free breathing range of motion (4D ROM) was 1.3 cm. Mean displacements after mid-treatment CBCT were minimal in all directions as shown in Table 1. Only one observed fraction had a displacement that exceeded the 5mm PTV expansion (longitudinal shift of 0.59 cm with resulting vector shift of 0.68cm). Factors evaluated for association with shift magnitude included age, BMI, gender, tumor location, 4D ROM, and GTV and PTV size. Higher 4D ROM was associated with increased longitudinal and vector shifts (<i>P</i> = 0.019 and 0.046). <h3>Conclusion</h3> SGRT provides a reliable technique for BH SBRT treatments of the lung. Minimal target displacements on mid treatment BH CBCT were observed. Higher 4D ROM on free breathing scans correlated with larger displacements in tumor position utilizing this technique.