Purpose/Objective(s) To evaluate clinical characteristics and symptoms in patients with lung changes following intensity modulated proton therapy (IMPT) for breast cancer. Materials/Methods From a cohort of 107 patients treated with IMPT for breast cancer from 7/2019 – 12/2022, 45 patients were retrospectively identified with subsequent CT lung imaging changes during follow-up appointments. Ipsilateral lung constraint was typically V20Gy < 20%. Treatment details including type of surgery and utilization of chemotherapy, patient reported respiratory symptoms, development of rib fractures, and treatment planning details were abstracted. The areas of lung density changes on follow-up imaging were contoured to quantify volume of change. CTCAE V5 pneumonitis scoring was assigned at any point after completion of IMPT. Results Among the 45 patients, the average volume of post-radiation lung changes was 34 cc (range 0.7 cc – 144 cc). Most patients had been treated to 50 Gy in 25 fractions (42/45, 93%), with comprehensive nodal irradiation (41/45, 91%), and with a boost to cavity and/or nodal regions (25/45, 56%). Several patients (11/45, 24%) had received prior breast radiation. Most patients (33/45, 73%), were treated in the post-mastectomy setting with 11/45 (24%) patients having permanent implants, 6/45 (13%) having tissue expanders, 3/45 (7%) having a remote historical flap, and 13/45 (29%) having no reconstruction. Most patients had also received chemotherapy at some point in treatment (39/45, 87%). Using CTCAE V5 pneumonitis scoring, grade 1 (asymptomatic) was noted in 27/45 (60%) of patients, grade 2 (symptomatic, not limiting self-care or requiring oxygen) in 15/45 (33%), and grade 3 or higher (self-limiting or requiring oxygen) in 3/45 (7%). A proportion of patients (9/45, 20%) also developed rib fractures. The average time to develop rib fractures was 20 months (range 7- 41 months). Conclusion Post-mastectomy patients with radiologic lung changes are at risk for symptomatic pneumonitis and rib fracture following IMPT. Additional lung and chest wall objectives specific to proton therapy for breast cancer are warranted.

For the first time, we have shown that it is possible to reduce RIIS in a statistically significant manner, compared to standard of care, via optimized RT planning using a predictive model. This has implications in increasing the efficacy of immunotherapy by preserving the existing tumor reactive T cells in the immune system to enhance anti-tumor activity, and in reducing hospitalizations and improving survival.

Background Despite its common epigenetic suppression in multiple cancers, STING signaling has emerged as a major pathway for augmenting tumor cell antigenicity and initiation of T cell responses.1 2 Another aspect of intact activation of STING signaling in tumor cells is downstream induction of T cell-homing chemokines including CXCL10 and CCL5. These chemokines are also among our earlier reported 12-chemokine (12-CK) gene expression signature (GES) predicting the presence of tumor-localized tertiary lymphoid structures (TLSs), which are increasingly shown to correlate with improved survival in certain solid tumor types.3 4 Based on these findings, we hypothesized that epigenetic silencing of STING signaling genes through promoter hypermethylation would be inversely associated with the presence of TLSs. Methods We assessed the correlation between the expression of STING signaling genes and the chemokines present in the 12-CK GES across melanomas and urothelial bladder carcinomas using cBioPortal datasets. To extend these studies beyond these tumor types, we performed correlative and survival analyses using the TCGA PanCancer Atlas. Additionally, we determined the correlation between the promoter methylation levels of STING signaling genes and the 12-CK GES score. We also evaluated STING expression in TLS+ and TLS- melanoma samples in situ by immunohistochemistry (IHC). Results We identified a distinct correlation between STING-expressing tumors and each of the twelve chemokines among melanoma and urothelial bladder carcinoma samples. In particular, STING expression was positively correlated with secondary lymphoid organ-associated chemokines, CCL19 (p=0.0077), CCL21 (p=0.0046), and CXCL13 (p=0.0034) in urothelial bladder carcinomas. The presence of TLSs in STING-expressing melanomas was further confirmed by IHC. Using TCGA PanCancer datasets, we observed a strong correlation between the expression of cGAS (Pearson’s r=0.46) and STING (Pearson’s r=0.37) with the 12-CK GES score. In contrast, the methylation levels of cGAS and STING were inversely correlated with the 12-CK GES score (Pearson’s r=-0.37 and -0.41, respectively). Similarly, hypermethylation of STING was correlated with inferior disease-specific survival (DSS) (p<0.0001) in lung adenocarcinomas. Survival analysis on the TCGA skin cutaneous melanoma (SKCM) dataset also indicated significant DSS advantage in 12-CK GES scoreHigh cGASHighpatients (p<0.0001). Conclusions We provide evidence that epigenetic state of cGAS and STING cannot only shape tumor antigenicity but is also associated with the 12-CK GES and the presence of TLSs. Considering the well-established prognostic value of TLSs, these findings argue that targeting epigenetic suppression of STING signaling should be considered as a strategy to guide effective immunotherapy-based interventions. Acknowledgements This work was supported by the Moffitt Cancer Center Tissue Core and Analytic Microscopy Core Facilities, all comprehensive cancer center facilities designated by the National Cancer Institute (P30 CA076292). This work was funded by: NCI-NIH (1R01 CA148995, 1R01 CA184845, P30 CA076292, P50 CA168536), CJG Fund, Chris Sullivan Fund, V Foundation, Melanoma Research Foundation, and Dr. Miriam and Sheldon G. Adelson Medical Research Foundation. References Falahat R, Berglund A, Putney RM, Perez-Villarroel P, Aoyama S, Pilon- Thomas S, Barber GN, Mulé JJ. Epigenetic reprogramming of tumor cell-intrinsic STING function sculpts antigenicity and T cell recognition of melanoma. PNAS. 2021;118(15). Falahat R, Berglund A, Perez-Villarroel P, Putney RM, Hamaidi I, Kim S, Pilon-Thomas S, Barber GN, Mulé JJ. Epigenetic state determines the in vivo efficacy of STING agonist therapy. Nature Communications. 2023;14(1):1573. Messina JL, Fenstermacher DA, Eschrich S, Qu X, Berglund AE, Lloyd MC, Schell MJ, Sondak VK, Weber JS, Mulé JJ. 12-Chemokine gene signature identifies lymph node-like structures in melanoma: potential for patient selection for immunotherapy?. Scientific reports. 2012;2(1):765. Schumacher TN, Thommen DS. Tertiary lymphoid structures in cancer. Science. 2022;375(6576):eabf9419.

The purpose of this study was to quantify the rate of adherence to adjuvant endocrine therapy in early stage breast cancer patients based on what radiation modality they received. We found that patient's opting for a single fraction of radiation delivered at the time of lumpectomy, were less likely to complete the recommended 5 year duration of adjuvant endocrine therapy. Introduction: We compared the rates of long-term adjuvant endocrine therapy (AET) adherence after various radiation therapy (RT) modalities among patients with early stage breast cancer. Materials and Methods: Medical records from patients with stage 0, I, or IIA (tumors <= 3 cm), hormone receptor (HR) positive breast cancer that received adjuvant radiation therapy (RT) from 2013 to 2015 at a single institution were retrospectively reviewed. All patients received breast conser ving surger y (BCS) followed by adjuvant RT via one of the following modalities: whole breast radiotherapy (WBI), partial breast irradiation (PBI) with either external beam radiation therapy (EBRT) or fractionated intracavitary high-dose rate (HDR) brachytherapy, or single fraction HDR-brachytherapy intraoperative-radiation therapy (IORT). Results: One hundred fourteen patients were reviewed. Thirty patients received WBI, 41 PBI, and 43 IORT with a median follow up of 64.2, 72.0, and 58.6 months, respectively. For the entire cohort, AET adherence was approximately 64% at 2 years and 56% at 5 years. Among patients in the IORT clinical trial, adherence to AET was approximately 51% at 2 years and 40% at 5 years. After controlling for additional factors, DCIS histology (vs invasive disease) and IORT (compared to other radiation modalities) were associated with decreased endocrine therapy adherence ( P < 0.05). Conclusion: DCIS histology and receipt of IORT were associated with lower rates of adherence to AET at 5 years. Our findings suggest that examination of the efficacy of RT interventions such as PBI and IORT in patients who do not receive AET is warranted.

INTRODUCTION: Precision breast intraoperative radiation therapy (PB-IORT) is a novel ap-proach to adjuvant radiation therapy for early-stage breast cancer performed as part of a phase II clinical trial at two institutions. One institution performs the entire procedure in an integrated brachytherapy suite which contains a CT-on-rails imaging unit and full anesthesia capabilities. At the other, breast conserving surgery and radiation therapy take place in two separate locations. Here, we utilize time-driven activity-based costing (TDABC) to compare these two models for the delivery of PB-IORT.METHODS: Process maps were created to describe each step required to deliver PB-IORT at each institution, including personnel, equipment, and supplies. Time investment was estimated for each step. The capacity cost rate was determined for each resource, and total costs of care were then calculated by multiplying the capacity cost rates by the time estimate for the process step and adding any additional product costs.RESULTS: PB-IORT costs less to deliver at a distributed facility, as is more commonly available, than an integrated brachytherapy suite ($3,262.22 vs. $3,996.01). The largest source of costs in both settings ($2,400) was consumable supplies, including the brachytherapy balloon applicator. The difference in costs for the two facility types was driven by personnel costs ($1,263.41 vs. $764.89). In the integrated facility, increased time required by radiation oncology nursing and the anesthesia attending translated to the greatest increases in cost. Equipment costs were also slightly higher in the integrated suite setting ($332.60 vs. $97.33).CONCLUSIONS: The overall cost of care is higher when utilizing an integrated brachyther-apy suite to deliver PB-IORT. This was primarily driven by additional personnel costs from nursing and anesthesia, although the greatest cost of delivery in both settings was the disposable brachytherapy applicator. These differences in cost must be bal-anced against the potential impact on patient experience with these approaches.(c) 2021 The Authors. Published by Elsevier Inc. on behalf of American Brachytherapy Society. This is an open access article under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/ )

Introduction: Patients with brain metastases (BrMs) arising from EGFR and ALK driven non-small cell lung cancer (NSCLC) have favorable prognoses and evolving treatment options. We evaluated multicenter outcomes for stereotactic radiosurgery (SRS) to multiple (>= 4) BrMs, where randomized data remain limited. Methods: Data were collected retrospectively from 5 academic centers on EGFR and ALK NSCLC who received SRS to >= 4 BrMs with their first SRS treatment between 2008 and 2018. Analyzed endpoints included overall survival (OS), freedom from CNS progression (FFCNSP), and freedom from whole-brain radiotherapy (FFWBRT).Results: Eighty-nine patients (50 EGFR, 39 ALK) received a total of 159 SRS treatments to 1,080 BrMs, with a median follow up of 51.3 months. The median number of BrMs treated with SRS treatment-1 was 6 (range 4-26) and median for all treatments was 9 (range 4-47). Sixteen patients (18 %) had received WBRT prior to SRS treatment-1. The median OS was 24.2, 21.2, and 33.2 months for all patients, EGFR, and ALK subsets, respec-tively. After multivariable adjustment, only receipt of a next-generation tyrosine kinase inhibitor was associated with OS (HR 0.40, p = 0.005). No differences in OS were observed based on number of BrMs treated. The median FFCNSP was 9.4, 11.6, and 7.5 months, for all patients, EGFR, and ALK subsets, respectively. After multivariable adjustment, the number of BrMs (continuous) treated during treatment-1 was the only negative prognostic factor associated with FFCNSP (HR 1.071, p = 0.045). The 5-year FFWBRT was 73.6 %.Conclusions: This multicenter analysis over a >10-year period demonstrated favorable OS, FFCNSP, and FFWBRT, in patients with EGFR and ALK driven NSCLC receiving SRS to >= 4 BrMs. These data support SRS as an option in the upfront and salvage setting for higher burden CNS disease in this population.

Purpose: Proton beam therapy can significantly reduce cardiopulmonary radiation exposure compared with photon-based techniques in the postmastectomy setting for locally advanced breast cancer. For patients with metallic port tissue expanders, which are commonly placed in patients undergoing a staged breast reconstruction, dose uncertainties introduced by the high-density material pose challenges for proton therapy. In this report, we describe an intensity modulated proton therapy planning technique for port avoidance through a hybrid single-field optimization/multifield optimization approach. Methods and Materials: In this planning technique, 3 beams are utilized. For each beam, no proton spot is placed within or distal to the metal port plus a 5 mm margin. Therefore, precise modeling of the metal port is not required, and various tissue expander manufacturers/models are eligible. The blocked area of 1 beam is dosimetrically covered by 1 or 2 of the remaining beams. Multifield optimization is used in the chest wall target region with blockage of any beam, while single-field optimization is used for remainder of chest wall superior/inferior to the port. Results: Using this technique, clinical plans were created for 6 patients. Satisfactory plans were achieved in the 5 patients with port-to-posterior chest wall separations of 1.5 cm or greater, but not in the sixth patient with a 0.7 cm separation. Conclusions: We described a planning technique and the results suggest that the metallic port-to-chest wall distance may be a key parameter for optimal plan design.

PURPOSE:To reduce the likelihood of errors in organ delineations used for radiotherapy treatment planning, a knowledge-based quality control (KBQC) system, which discriminates between valid and anomalous delineations is developed. METHOD AND MATERIALS:The KBQC is comprised of a group-wise inference system and anomaly detection modules trained using historical priors from 296 locally advanced lung and prostate cancer patient computational tomographies (CTs). The inference system discriminates different organs based on shape, relational, and intensity features. For a given delineated image set, the inference system solves a combinatorial optimization problem that results in an organ group whose relational features follow those of the training set considering the posterior probabilities obtained from support vector machine (SVM), discriminant subspace ensemble (DSE), and artificial neural network (ANN) classifiers. These classifiers are trained on nonrelational features with a 10-fold cross-validation scheme. The anomaly detection module is a bank of ANN autoencoders, each corresponding with an organ, trained on nonrelational features. A heuristic rule detects anomalous organs that exceed predefined organ-specific tolerances for the feature reconstruction error and the classifier's posterior probabilities. Independent data sets with anomalous delineations were used to test the overall performance of the KBQC system. The anomalous delineations were manually manipulated, computer-generated, or propagated based on a transformation obtained by imperfect registrations. Both peer-review-based scoring system and shape similarity coefficient (DSC) were used to label regions of interest (ROIs) as normal or anomalous in two independent test cohorts. RESULTS:The accuracy of the classifiers was ≥ $\ge$ 99.8%, and the minimum per-class F1-scores were 0.99, 0.99, and 0.98 for SVM, DSE, and ANN, respectively. The group-wise inference system reduced the miss-classification likelihood for the test data set with anomalous delineations compared to each individual classifier and a fused classifier that used the average posterior probability of all classifiers. For 15 independent locally advanced lung patients, the system detected > $&gt;$ 79% of the anomalous ROIs. For 1320 auto-segmented abdominopelvic organs, the anomaly detection system identified anomalous delineations, which also had low Dice similarity coefficient values with respect to manually delineated organs in the training data set. CONCLUSION:The KBQC system detected anomalous delineations with superior accuracy compared to classification methods that judge only based on posterior probabilities.

BACKGROUND Chordoma is a rare primary bone tumour with a high propensity for local recurrence. Surgical resection is the mainstay of treatment, but complete resection is often morbid due to tumour location. Similarly, the dose of radiotherapy (RT) that surrounding healthy organs can tolerate is frequently below that required to provide effective tumour control. Therefore, clinicians have investigated different radiation delivery techniques, often in combination with surgery, aimed to improve the therapeutic ratio. OBJECTIVES To assess the effects and toxicity of proton and photon adjuvant radiotherapy (RT) in people with biopsy-confirmed chordoma. SEARCH METHODS We searched CENTRAL (2021, Issue 4); MEDLINE Ovid (1946 to April 2021); Embase Ovid (1980 to April 2021) and online registers of clinical trials, and abstracts of scientific meetings up until April 2021. SELECTION CRITERIA We included adults with pathologically confirmed primary chordoma, who were irradiated with curative intent, with protons or photons in the form of fractionated RT, SRS (stereotactic radiosurgery), SBRT (stereotactic body radiotherapy), or IMRT (intensity modulated radiation therapy). We limited analysis to studies that included outcomes of participants treated with both protons and photons. DATA COLLECTION AND ANALYSIS The primary outcomes were local control, mortality, recurrence, and treatment-related toxicity. We followed current standard Cochrane methodological procedures for data extraction, management, and analysis. We used the ROBINS-I tool to assess risk of bias, and GRADE to assess the certainty of the evidence. MAIN RESULTS We included six observational studies with 187 adult participants. We judged all studies to be at high risk of bias. Four studies were included in meta-analysis. We are uncertain if proton compared to photon therapy worsens or has no effect on local control (hazard ratio (HR) 5.34, 95% confidence interval (CI) 0.66 to 43.43; 2 observational studies, 39 participants; very low-certainty evidence). Median survival time ranged between 45.5 months and 66 months. We are uncertain if proton compared to photon therapy reduces or has no effect on mortality (HR 0.44, 95% CI 0.13 to 1.57; 4 observational studies, 65 participants; very low-certainty evidence). Median recurrence-free survival ranged between 3 and 10 years. We are uncertain whether proton compared to photon therapy reduces or has no effect on recurrence (HR 0.34, 95% CI 0.10 to 1.17; 4 observational studies, 94 participants; very low-certainty evidence). One study assessed treatment-related toxicity and reported that four participants on proton therapy developed radiation-induced necrosis in the temporal bone, radiation-induced damage to the brainstem, and chronic mastoiditis; one participant on photon therapy developed hearing loss, worsening of the seventh cranial nerve paresis, and ulcerative keratitis (risk ratio (RR) 1.28, 95% CI 0.17 to 9.86; 1 observational study, 33 participants; very low-certainty evidence). There is no evidence that protons led to reduced toxicity. There is very low-certainty evidence to show an advantage for proton therapy in comparison to photon therapy with respect to local control, mortality, recurrence, and treatment related toxicity. AUTHORS' CONCLUSIONS There is a lack of published evidence to confirm a clinical difference in effect with either proton or photon therapy for the treatment of chordoma. As radiation techniques evolve, multi-institutional data should be collected prospectively and published, to help identify persons that would most benefit from the available radiation treatment techniques.

Lung stereotactic body radiotherapy (SBRT) is a well-established modality for inoperable non-small-cell lung cancer (NSCLC). However, multicourse lung SBRT has not been validated in a prospective trial. In our single-institutional experience with multicourse lung SBRT, we found favorable outcomes and identified composite lung V-5 (proportion of lung structure receiving at least 5 Gy) and timing of the second course of SBRT to be potentially related to the development of radiation pneumonitis. Background: The clinical outcomes of multicourse lung stereotactic body radiotherapy (SBRT) have yet to be validated in a prospective study, and there are a lack of data on allowable composite dosimetry. Patients and Methods: Forty-four patients underwent multicourse lung SBRT for recurrent or metachronous NSCLC. The median biologically effective dose (BED10) for the first course and subsequent courses were 132 and 100 Gy, respectively. Patient and treatment characteristics were evaluated to determine the correlation with the development of radiation pneumonitis (RP). Results: The local control rate was 91%. A total of 13.6% developed a grade 2+ RP, and 4.5% developed a grade 3+ RP, including one grade 5. On univariable analysis, multiple composite dosimetric factors (V-5 [proportion of lung structure receiving at least 5 Gy], V-10, V-20, V-40, and mean lung dose) were correlated with the development of RP. When comprised of the first and second course of SBRT, a composite lung V-5 of < 30% and > 50% was associated with a 0 and 75% incidence of grade 2+ RP, respectively. We identified no significant correlation on multivariable analysis but observed a strong trend between composite lung V-5 and the development of grade 2+ RP (hazard ratio, 1.157; P = .058). Evaluation of multiple clinical factors also identified a significant correlation between the timing of repeat lung SBRT and the development of grade 2+ RP after the second course (P = .0028). Conclusion: Subsequent courses of lung SBRT, prescribed to a median BED10 of 100 Gy, can provide a high rate of local control with a 4.5% incidence of grade 3+ toxicity. Composite lung V-5 and the timing of the second course of lung SBRT may be correlated to the development of RP. (C) 2020 Elsevier Inc. All rights reserved.

Background: This analysis evaluates the impacts of biologically effective dose (BED) and histology on local control (LC) of spinal metastases treated with highly conformal radiotherapy to moderately-escalated doses. Materials and methods: Patients were treated at two institutions from 2010–2020. Treatments with less than 5 Gy per fraction or 8 Gy in 1 fraction were excluded. The dataset was divided into three RPA classes predictive of survival (1). The primary endpoint was LC. Results: 223 patients with 248 treatments met inclusion criteria. Patients had a median Karnofsky Performance Status (KPS) of 80, and common histologies included breast (29.4%), non-small cell lung cancer (15.7%), and prostate (13.3%). A median 24 Gy was delivered in 3 fractions (BED: 38.4 Gy) to a median planning target volume (PTV) of 37.3 cc. 2-year LC was 75.7%, and 2-year OS was 42.1%. Increased BED was predictive of improved LC for primary prostate cancer (HR = 0.85, 95% CI: 0.74–0.99). Patients with favorable survival (RPA class 1) had improved LC with BED ≥ 40 Gy (p = 0.05), unlike the intermediate and poor survival groups. No grade 3–5 toxicities were reported. Conclusions: Moderately-escalated treatments were efficacious and well-tolerated. BED ≥ 40 Gy may improve LC, particularly for prostate cancer and patients with favorable survival.

OBJECTIVES:To investigate the safety and outcomes of elective para-aortic (PA) nodal irradiation utilizing modern treatment techniques for patients with node positive cervical cancer.METHODS:Patients with pelvic lymph node positive cervical cancer who received radiation were included. All patients received radiation therapy (RT) to either a traditional pelvic field or an extended field to electively cover the PA nodes. Factors associated with survival were identified using a Cox proportional hazards model, and toxicities between groups were compared with a chi-square test.RESULTS:96 patients were identified with a mean follow up of 40 months. The incidence of acute grade ≥ 2 toxicity was 31% in the elective PA nodal RT group and 15% in the pelvic field group (Chi-square p = 0.067. There was no significant difference in rates of grade ≥ 3 acute or late toxicities between the two groups (p>0.05). The KM estimated 5-year OS was not statistically different for those receiving elective PA nodal irradiation compared to a pelvic only field, 54% vs. 73% respectively (log-rank p = 0.11).CONCLUSIONS:Elective PA nodal RT can safely be delivered utilizing modern planning techniques without a significant increase in severe (grade ≥ 3) acute or late toxicities, at the cost of a possible small increase in non-severe (grade 2) acute toxicities. In this series there was no survival benefit observed with the receipt of elective PA nodal RT, however, this benefit may have been obscured by the higher risk features of this population. While prospective randomized trials utilizing a risk adapted approach to elective PA nodal coverage are the only way to fully evaluate the benefit of elective PA nodal coverage, these trials are unlikely to be performed and instead we must rely on interpretation of results of risk adapted approaches like those used in ongoing clinical trials and retrospective data.

PURPOSE:For cervical brachytherapy planning, magnetic resonance imaging (MRI) is preferable to computed tomography (CT) for target delineation. However, due to logistical and financial restrictions, in-room MRI is sometimes not routinely available in brachytherapy centers. Our institution has created a workflow that integrates MRI-based target delineation with an in-room CT scanner, with the aim of improving target coverage and conformality. This study reports the initial dosimetric results with using this workflow. MATERIAL AND METHODS:A retrospective review was performed on 46 consecutive patients who received definitive chemoradiation with 5 fraction intracavitary high-dose-rate (HDR) brachytherapy for cervical cancer. Fraction 1 was planned from CT only. Outpatient MRI was obtained after Smit sleeve placement and first insertion to assess concurrent chemoradiotherapy tumor response. This MRI was registered to the CT for planning fractions 2-5. The median prescription dose for the cohort was 25 Gy (range, 25-29 Gy). RESULTS:The D90 to the high-risk clinical target volume (HR-CTV) and D2cc rectal dose were increased from fraction 1 to fraction 2-5 averaged (p < 0.05). Among the 18 patients with complete volumetric data, there was no significant difference in HR-CTV size, with an average decrease of 1.73 cc (p > 0.05) with MRI fusion. Eleven out of 18 patients had changes in high-risk target volume greater than 20%, with an absolute average change in volume of 31.5%. CONCLUSIONS:The use of asynchronous MRI for target delineation, with co-registration to CT for each fraction of brachytherapy was associated with higher D90 to the HR-CTV. We observed slightly higher D2cc rectal doses with MRI, but cumulative rectal doses were within accepted thresholds. High-risk target volumes were not consistently increased or decreased, but MRI fusion was associated with target volume changes greater than 20% in over half of the treated patients.

PURPOSE:This study aims to develop a local control risk stratification using recursive partitioning analysis (RPA) for patients receiving stereotactic body radiation therapy (SBRT) for metastatic cancer.METHODS AND MATERIALS:A single institutional database of 397 SBRT treatments to the liver, spine, and lymph nodes was constructed. All treatments required imaging follow-up to assess for local control. Cox proportional hazards analysis was implemented before the decision tree analysis. The data were split into training (70%), validation (10%), and testing (20%) sets for RPA to optimize the training set.RESULTS:In the study, 361 treatments were included in the local control analysis. Two-year local control was 71%. A decision tree analysis was used and the resulting model demonstrated 93.10% fidelity for the validation set and 87.67% for the test set. RPA class 3 was composed of patients with non-small cell lung cancer (NSCLC) primary tumors and treatment targets other than the cervical, thoracic, and lumbar spines. RPA class 2 included patients with primary cancers other than NSCLC or breast and treatments targets of the sacral spine or liver. RPA class 1 consisted of all other patients (including lymph node targets and patients with primary breast cancer). Classes 3, 2, and 1 demonstrated 3-year local controls rates of 29%, 50%, and 83%, respectively. On subgroup analysis using the Kaplan-Meier method, treatments for lymph nodes and primary ovarian disease demonstrated improved local control relative to other treatment targets (P < .005) and primary disease sites (P < .005), respectively.CONCLUSIONS:A local control risk stratification model for SBRT to sites of metastatic disease was developed. Treatment target and primary tumor were identified as critical factors determining local control. NSCLC primary lesions have increased local failure for targets other than the cervical, thoracic, or lumbar spines, and improved local control was identified for lymph node sites and breast or ovarian primary tumors.

Tyrosine kinase inhibitors (TKIs) are commonly employed for patients with brain metastases from lung cancer and specific driver mutations. We sought to identify the correlation between intracranial tumor burden and outcomes in patients with brain metastases treated with TKIs. We identified and retrospectively reviewed cases of EGFR-mutant or ALK-rearranged lung cancer with brain metastases at any time during their cancer course. Clinical characteristics and treatment information were abstracted from the medical records. Brain metastases were contoured to calculate total volume of disease at diagnosis and after initial therapy. High intracranial burden was defined as either > 10 brain metastases, volume of brain metastases > 15 cc, or largest lesion > 3 cm. Intracranial response was determined according to Response Assessment in Neuro-Oncology (RANO) criteria on the patient level. We determined the correlation between clinical and imaging characteristics and intracranial progression free survival (IC-PFS) and overall survival (OS). Fifty-seven patients with EGFR (n = 49) and ALK (n = 8) alterations were identified. Median follow-up from initial brain metastasis diagnosis was 17 months. Neurological symptoms were present in 54% at brain metastasis diagnosis. For those receiving TKIs alone or TKIs with radiation, at least a partial intracranial response (≥ 65% volume reduction) at 3 months from starting therapy was achieved in 94% and 58%. Progressive intracranial disease at 3 months occurred in 6.3% and 8.3%. Patients with high intracranial burden (n = 21) had a median 17 brain metastases, 6.5 cc volume, and 1.9 cm maximal tumor diameter. Median IC-PFS and OS for patients with high intracranial burden was 13.9 and 35.4 months. Patients with high intracranial burden and neurological symptoms at diagnosis had similar IC-PFS and OS compared to those with low burden and absence of neurological symptoms (p > 0.05 for each). Most patients receiving TKIs as part of their initial therapy achieve an early and durable volumetric intracranial response, irrespective of presenting disease burden or neurologic symptoms.

123 Background: Surgery has traditionally been the primary treatment for rectal cancer with consideration of neoadjuvant and adjuvant therapies based on stage. Recent studies have shown that Total Neoadjuvant Therapy (TNT) may provide excellent outcomes, with a possibility of non-operative management in patients with rectal cancer. This study is an initial report of our institution’s watchful waiting strategy. Methods: Patients with Stage II-III, low rectal adenocarcinomas treated from 2015-2018 with TNT were retrospectively reviewed. Patients were surgical candidates with no planned surgery. All patients received definitive radiation (median dose 54 Gy, range 50-56 Gy, at 1.8-2 Gy/fx) with concurrent Xeloda, with additional chemotherapy delivered either prior to or following chemoradiation. Kaplan-Meier (KM) method was utilized to estimate the 2 year permanent ostomy and surgery free survivals. Univariate and multivariate analysis using binary logistic regression were performed to assess the odds ratio (OR) of the need for surgery, with 95% confidence interval (CI). Results: 28 patients were treated with TNT with a median age of 59 years (range 32-79 yrs) and median follow up of 24 months (range 6-51 mon). Reasons for TNT included: clinical trial (50%, n = 14), patient desire to avoid surgery (43%, n = 12), and history of LDR prostate brachytherapy (7%, n = 2). The majority of patients had Stage III disease (68%, n = 19). Median tumor distance from the anal verge was 3 cm (range 0-7 cm). 75% (n = 21) of patients were initially managed without surgery, with 5 patients requiring LAR and 2 requiring APR for residual disease. 4 patients initially treated without surgery experienced local recurrence (LR) requiring APR, with a median time to LR of 20 months (range 12-27 mon). The KM estimated 2 year permanent ostomy and surgery free survivals were 69% and 56% respectively. Distant metastases occurred in two patients at 2 and 7 months post RT. An incomplete response on post-treatment MRI predicted eventual receipt of surgery (p = 0.012, OR = 19.8, 95% CI 1.9-202, compared to complete responders). Conclusions: These results support the growing evidence that TNT may provide a non-surgical option for select patients with low lying rectal cancer.

To evaluate the safety and efficacy of hypofractionated radiation therapy (RT) in the management of anaplastic thyroid cancer. Included subjects with biopsy-confirmed anaplastic thyroid cancer who received RT to the primary site regardless of AJCC 8th edition stage. Patient and treatment related characteristics and clinical outcomes were recorded. Kaplan-Meier (KM) method was used to estimate overall survival (OS) from completion of RT. Univariable and multivariable analyses using Cox regression were performed to assess for factors associated with OS. RT toxicities were graded using the Common Terminology Criteria for Adverse Events version 5.0. 14 consecutive subjects from 2010-2019 with anaplastic thyroid cancer who received RT to the thyroid or thyroid surgical bed were identified. Median survival was 3.6 months (range <1-76 months), and median follow up for those currently alive was 7 months (range 3-76 months). KM estimated 3 month and 6-month OS were 71% and 32% respectively. 64% (n = 9) of subjects had Stage IVB disease at diagnosis due to T4 (n = 7) and/or N1 (n = 8) disease, and 36% (n = 5) had Stage IVC disease at diagnosis. 64% (n = 9) received upfront surgery prior to their course of RT. Four subjects received conventionally fractionated RT with a median dose was 66 Gy (range 66-68 Gy at 2 Gy/fraction, BED10 79-82 Gy). Hypofractionated regimens were utilized in 10 cases and consisted of an expansion on the gross tumor volume (GTV) treated to a lower total dose with dose escalation within the GTV to avoid excessive dose to the larynx. 13 of 14 cases utilized an IMRT technique. The median dose within the GTV was 40 Gy (range 30-45 Gy at 4-9 Gy/fraction, BED10 48-86 Gy) in 5-10 fractions. Median BED10 to the GTV was 72 Gy (range 48-86 Gy) for hypofractionated regimens. On univariable analysis, M0 and increased BED were predictive of OS (p<0.05), while age, primary tumor size, T category, N category, use of systemic therapy, and surgical resection were not (p>0.1). On multivariable analysis, subjects with Stage IVC had worse OS (p = 0.026, HR = 16, 95% CI 1-265), while subjects treated to a higher BED had improved OS (p = 0.048, HR = 0.84, 95% CI 0.712-9.79). 43% (n = 6) of subjects were placed on steroids during RT. Grade 3 toxicities occurred in 4 cases, all receiving conventionally fractionated RT, and included: dermatitis (n = 3), mucositis (n = 2), and tracheitis (n = 1). There were no reported grade 4 or 5 toxicities. In this series, hypofractionated regimens with dose painting to limit risk of laryngeal edema allows for short treatment duration in 5-10 fractions while safely delivering substantial BED. While the hypofractionated regimens had no grade 3 or higher toxicities, evaluation of acute and chronic toxicities may be limited by the short OS of this cohort.