Predicting radiation-induced immune suppression in lung cancer patients treated with stereotactic body radiation therapy.

BACKGROUND: Stereotactic body radiation therapy (SBRT) is known to modulate the immune system and contribute to the generation of anti-tumor T cells and stimulate T cell infiltration into tumors. Radiation-induced immune suppression (RIIS) is a side effect of radiation therapy that can decrease immunological function by killing naive T cells as well as SBRT-induced newly created effector T cells, suppressing the immune response to tumors and increasing susceptibility to infections. PURPOSE: RIIS varies substantially among patients and it is currently unclear what drives this variability. Models that can accurately predict RIIS in near real time based on treatment plan characteristics would allow treatment planners to maintain current protocol specific dosimetric criteria while minimizing immune suppression. In this paper, we present an algorithm to predict RIIS based on a model of circulating blood using early stage lung cancer patients treated with SBRT. METHODS: This Python-based algorithm uses DICOM data for radiation therapy treatment plans, dose maps, patient CT data sets, and organ delineations to stochastically simulate blood flow and predict the doses absorbed by circulating lymphocytes. These absorbed doses are used to predict the fraction of lymphocytes killed by a given treatment plan. Finally, the time dependence of absolute lymphocyte count (ALC) following SBRT is modeled using longitudinal blood data up to a year after treatment. This model was developed and evaluated on a cohort of 64 patients with 10-fold cross validation. RESULTS: Our algorithm predicted post-treatment ALC with an average error of 0.24 ± 0.21 × 10 9 $0.24 \pm 0.21 \times {10}^9$ cells/L with 89% of the patients having a prediction error below 0.5 × 109 cells/L. The accuracy was consistent across a wide range of clinical and treatment variables. Our model is able to predict post-treatment ALC < 0.8 (grade 2 lymphopenia), with a sensitivity of 81% and a specificity of 98%. This model has a ∼38-s end-to-end prediction time of post treatment ALC. CONCLUSION: Our model performed well in predicting RIIS in patients treated using lung SBRT. With near-real time model prediction time, it has the capability to be interfaced with treatment planning systems to prospectively reduce immune cell toxicity while maintaining national SBRT conformity and plan quality criteria.

ZEB1 promotes non-homologous end joining double-strand break repair.

Repair of DSB induced by IR is primarily carried out by Non-Homologous End Joining (NHEJ), a pathway in which 53BP1 plays a key role. We have discovered that the EMT-inducing transcriptional repressor ZEB1 (i) interacts with 53BP1 and that this interaction occurs rapidly and is significantly amplified following exposure of cells to IR; (ii) is required for the localization of 53BP1 to a subset of double-stranded breaks, and for physiological DSB repair; (iii) co-localizes with 53BP1 at IR-induced foci (IRIF); (iv) promotes NHEJ and inhibits Homologous Recombination (HR); (v) depletion increases resection at DSBs and (vi) confers PARP inhibitor (PARPi) sensitivity on BRCA1-deficient cells. Lastly, ZEB1's effects on repair pathway choice, resection, and PARPi sensitivity all rely on its homeodomain. In contrast to the well-characterized therapeutic resistance of high ZEB1-expressing cancer cells, the novel ZEB1-53BP1-shieldin resection axis described here exposes a therapeutic vulnerability: ZEB1 levels in BRCA1-deficient tumors may serve as a predictive biomarker of response to PARPis.

Transcriptome-wide association study and eQTL colocalization identify potentially causal genes responsible for human bone mineral density GWAS associations.

Genome-wide association studies (GWASs) for bone mineral density (BMD) in humans have identified over 1100 associations to date. However, identifying causal genes implicated by such studies has been challenging. Recent advances in the development of transcriptome reference datasets and computational approaches such as transcriptome-wide association studies (TWASs) and expression quantitative trait loci (eQTL) colocalization have proven to be informative in identifying putatively causal genes underlying GWAS associations. Here, we used TWAS/eQTL colocalization in conjunction with transcriptomic data from the Genotype-Tissue Expression (GTEx) project to identify potentially causal genes for the largest BMD GWAS performed to date. Using this approach, we identified 512 genes as significant using both TWAS and eQTL colocalization. This set of genes was enriched for regulators of BMD and members of bone relevant biological processes. To investigate the significance of our findings, we selected PPP6R3, the gene with the strongest support from our analysis which was not previously implicated in the regulation of BMD, for further investigation. We observed that Ppp6r3 deletion in mice decreased BMD. In this work, we provide an updated resource of putatively causal BMD genes and demonstrate that PPP6R3 is a putatively causal BMD GWAS gene. These data increase our understanding of the genetics of BMD and provide further evidence for the utility of combined TWAS/colocalization approaches in untangling the genetics of complex traits.

Replicative Instability Drives Cancer Progression.

In the past decade, defective DNA repair has been increasingly linked with cancer progression. Human tumors with markers of defective DNA repair and increased replication stress exhibit genomic instability and poor survival rates across tumor types. Seminal studies have demonstrated that genomic instability develops following inactivation of BRCA1, BRCA2, or BRCA-related genes. However, it is recognized that many tumors exhibit genomic instability but lack BRCA inactivation. We sought to identify a pan-cancer mechanism that underpins genomic instability and cancer progression in BRCA-wildtype tumors. Methods: Using multi-omics data from two independent consortia, we analyzed data from dozens of tumor types to identify patient cohorts characterized by poor outcomes, genomic instability, and wildtype BRCA genes. We developed several novel metrics to identify the genetic underpinnings of genomic instability in tumors with wildtype BRCA. Associated clinical data was mined to analyze patient responses to standard of care therapies and potential differences in metastatic dissemination. Results: Systematic analysis of the DNA repair landscape revealed that defective single-strand break repair, translesion synthesis, and non-homologous end-joining effectors drive genomic instability in tumors with wildtype BRCA and BRCA-related genes. Importantly, we find that loss of these effectors promotes replication stress, therapy resistance, and increased primary carcinoma to brain metastasis. Conclusions: Our results have defined a new pan-cancer class of tumors characterized by replicative instability (RIN). RIN is defined by the accumulation of intra-chromosomal, gene-level gain and loss events at replication stress sensitive (RSS) genome sites. We find that RIN accelerates cancer progression by driving copy number alterations and transcriptional program rewiring that promote tumor evolution. Clinically, we find that RIN drives therapy resistance and distant metastases across multiple tumor types.

Racial and Treatment Center Differences on Time to Treatment Initiation for Nonsmall Cell Lung Cancer Patients Receiving Radiation Therapy As an Initial Treatment.

Objective: Because time to treatment has been shown to be associated with increase in the risk of death for Non Small Cell Lung Cancer (NSCLC) patients, we examined the prevalence and magnitude of racial disparities in mean time to radiation therapy (TTRT) for Stage I-III non-small cell lung cancer patients across a variety of treatment facilities. Methods: Utilizing the United States National Cancer Database (NCDB), we determined differences in TTRT between different races and different treatment facilities. Results: Concordant with past research, we found that non-White patients and patients treated at academic facilities, regardless of race, have longer mean TTRT, and that racial disparities in TTRT extend across all treatment facilities (all p<0.05). Conclusions: These findings shed light on the potential presence of and impact of structural racism on patients seeking cancer treatment, and the need for further investigation behind the reasonings behind longer TTI for non-White patients. To elucidate the real-world applicability of these results, further investigation into the societal determinants that perpetuate disparity in time to radiation therapy, and potential interventions in the clinical setting to improve cultural and racial sensitivity among healthcare professionals is recommended.

A Genome-Edited ERα-HiBiT Fusion Reporter Cell Line for the Identification of ERα Modulators Via High-Throughput Screening and CETSA.

The estrogen receptor α (ERα) is a target of intense pharmacological intervention and toxicological biomonitoring. Current methods to directly quantify cellular levels of ERα involve antibody-based assays, which are labor-intensive and of limited throughput. In this study, we generated a post-translational reporter cell line, referred to as MCF7-ERα-HiBiT, by fusing a small pro-luminescent nanoluciferase (NLuc) tag (HiBiT) to the C-terminus of endogenous ERα in MCF7 cells. The tag allows the luminescent detection and quantification of endogenous ERα protein by addition of the complementary NLuc enzyme fragment. This MCF7-ERα-HiBiT cell line was optimized for quantitative high-throughput screening (qHTS) to identify compounds that reduce ERα levels. In addition, the same cell line was optimized for a qHTS cellular thermal shift assay to identify compounds that bind and thermally stabilize ERα. Here, we interrogated the MCF7-ERα-HiBiT assay against the NCATS Pharmacological Collection (NPC) of 2,678 approved drugs and identified compounds that potently reduce and thermally stabilize ERα. Our novel post-translational reporter cell line provides a unique opportunity for profiling large pharmacological and toxicological compound libraries for their effect on ERα levels as well as for assessing direct compound binding to the receptor, thus facilitating mechanistic studies by which compounds exert their biological effects on ERα.

Recursive Partitioning Analysis for Local Control Achieved With Stereotactic Body Radiation Therapy for the Liver, Spine, or Lymph Nodes.

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.

Veliparib in combination with carboplatin/paclitaxel-based chemoradiotherapy in patients with stage III non-small cell lung cancer.

OBJECTIVES: Veliparib is a potent poly(ADP)-ribose polymerase (PARP) 1 and 2 inhibitor that impedes repair of DNA damage induced by cytotoxic and radiation therapies. This phase 1 study evaluated veliparib in combination with chemoradiotherapy in patients with unresectable stage III non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: Patients received veliparib orally twice daily (BID) in escalating doses (60-240 mg, Day -3 to 1 day after last dose of radiation) combined with weekly carboplatin (area under the curve [AUC] 2 mg/mL/min), paclitaxel (45 mg/m2), and daily radiation therapy (60 Gy in 30 fractions), followed by two cycles of veliparib (120-240 mg BID, Days -2 through 5 of each 21-day cycle), carboplatin (AUC 6 mg/mL/min, Day 1 of each cycle), and paclitaxel (200 mg/m2, Day 1 of each cycle) consolidation. Endpoints included veliparib maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), pharmacokinetics, safety, and efficacy. RESULTS: Forty-eight patients were enrolled. The MTD/RP2D of veliparib was 240 mg BID with chemoradiotherapy followed by 120 mg BID with consolidation. The most common any-grade adverse events (AEs) in this cohort for the whole treatment period were nausea (83%), esophagitis (75%), neutropenia (75%), and thrombocytopenia (75%). Dose-proportional pharmacokinetics of veliparib were observed. Median progression-free survival (mPFS) was 19.6 months (95% CI: 9.7-32.6). Median overall survival was estimated to be 32.6 months (95% CI: 15.0-not reached). In patients treated with the RP2D, mPFS was 19.6 months (95% CI: 3.0-not reached). CONCLUSIONS: When combined with standard concurrent chemoradiotherapy and consolidation chemotherapy in patients with stage III NSCLC, veliparib demonstrated an acceptable safety profile and antitumor activity with an mPFS of 19.6 months.

A single institutional experience with central lung stereotactic body radiation therapy demonstrating encouraging results with increased inter-fraction time.

BACKGROUND: Stereotactic body radiation therapy (SBRT) is an effective treatment modality for non-small cell lung cancer (NSCLC); however, there are concerns regarding potential toxicity for centrally located tumors. METHODS: This retrospective study considered patients with SBRT for central lung NSCLC (defined as a tumor within 2 cm of any mediastinal critical structure). The institutional protocol was that patients with central tumors received SBRT less frequently than daily-generally once or twice weekly. RESULTS: A total of 115 patients with 148 lesions were treated with SBRT to a median 45 [5-60] Gy in 4 [1-5] fractions over a median 5.3 [0-18] days. Many patients treated with this method presented with advanced disease: 58 treatments involved nodal targets, and 42 had stage 3 disease. 52% of patients had chronic obstructive pulmonary disease (COPD), and only 49% had a biopsy, often due to concerns regarding other medical comorbidities. Rates of prior chemotherapy, thoracic surgery, and thoracic radiotherapy were 32%, 21%, and 49%, respectively. Via the Kaplan-Meier method, 2-year overall survival was 65%, and 2-year local control was 77%. Two-year local-progression free survival was 53%, and 2-year progression-survival was 48%. Treatments for stage 3 disease had an impressive 82% 2-year local control that was comparable to early stage treatments. Patients with stage 3 disease had a 2-year overall survival of 59%, which trended towards decreased overall survival compared to early stage patients. There were 13 grade 1 (9%) and 14 grade 2 (9%) toxicities. There were no reported grade ≥3 acute or late toxicities and only 3 cases of pneumonitis. CONCLUSIONS: Our series demonstrates encouraging local control with low rates of toxicity for central lung SBRT, including many stage 3 patients. This may be the result of the relatively large inter-fraction interval. This interval may allow for greater tumor effects (such as reoxygenation) and improved tolerance from normal tissues.

Local control of 1-5 fraction radiotherapy regimens for spinal metastases: an analysis of the impacts of biologically effective dose and primary histology.

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.

Genesis of Quality Measurements to Improve the Care Delivered to Patients With Brain Metastases.

PURPOSE: High-value and high-quality health care requires outcome measurements to inform treatment decisions, but, to our knowledge, no standardized measurements exist to evaluate brain metastases (BMs) care. We propose a set of measurements and report on their implementation in the care of patients with BMs. METHODS: On the basis of a stakeholders' needs assessment and review of the literature, we identified outcome and process measurements to assess the care of patients with BMs according to treatment modality. Retrospectively, we applied these indicators of care to all patients diagnosed and treated at our institution over 2 years. RESULTS: We ascertained 5 outcome and 6 process measurements of relevance in the care of BMs. When applied to 209 patients (89.7%) who received cancer treatment, 77% were alive > 90 days after diagnosis. The proportion alive at 90 days after surgery, whole-brain radiation therapy (WBRT), and stereotactic radiosurgery (SRS) was 82%, 59%, and 81%, respectively. Other performance measurements included 30-day postoperative readmission rate (6%), SRS within 30 days of surgery (79%), use of memantine with WBRT (41%), advance directives within 6 months of diagnosis (53%), and palliative care consultation for patients with poor prognosis or receiving WBRT (45%). Measurements for the 24 patients (10.3%) receiving best supportive care were advance directives documentation (67%) and referral to palliative or hospice care (83%). CONCLUSION: We propose a set of measurements to apprise quality improvement efforts, inform treatment decision-making, and to use in evaluation of the performance of interdisciplinary BMs programs. Their refinement can potentially enhance the quality and value of care delivered to patients with BMs.

Clinical Outcomes and Predictors of Lung Toxicity After Multiple Courses of Lung Stereotactic Body Radiotherapy for Early-Stage Non-Small Cell Lung Cancer.

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 (V5 [proportion of lung structure receiving at least 5 Gy], V10, V20, V40, and mean lung dose) were correlated with the development of RP. When comprised of the first and second course of SBRT, a composite lung V5 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 V5 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 V5 and the timing of the second course of lung SBRT may be correlated to the development of RP.

A comparison of stereotactic body radiation therapy for metastases to the sacral spine and treatment of the thoracolumbar spine.

Background: This study compares the outcomes of stereotactic body radiation therapy (SBRT) for sacral and thoracolumbar spine metastases. Methods: This analysis considered each sacral spine SBRT treatment at a single institution and a cohort of consecutive thoracolumbar treatments. Results: 28 patients with 35 sacral treatments and 41 patients with 49 thoracolumbar treatments were included. Local control was 63% and 90%, respectively. The sacral cohort contained more lesions with ≥2 vertebrae and epidural and paraspinal involvement. Sacral patients had larger treatment volumes, increased rates of subsequent SBRT, decreased propensity for pain improvement, and decreased local control (p=0.02 on Kaplan-Meier analysis). Multivariate analysis demonstrated that PTV > 50 cc and epidural involvement were correlated with decreased local control. No cases had grade ≥3 toxicity. Conclusion: SBRT for sacral spine metastases is a distinct disease process than metastases to the thoracolumbar spine, resulting in lower rates of local control and pain improvement.

Stereotactic body radiation therapy for empirically treated hypermetabolic lung lesions: a single-institutional experience identifying the Charlson score as a key prognostic factor.

BACKGROUND: Though pathologic evidence for non-small cell lung cancer (NSCLC) is preferred, many patients do not receive a biopsy prior to treatment with stereotactic body radiation therapy (SBRT). This study seeks to analyze the overall survival (OS), local control, and toxicity rates for such patients. METHODS: This retrospective review included patients empirically treated with SBRT for presumed non-metastatic NSCLC at a single institution. Inclusion criteria included a hypermetabolic pulmonary lesion noted on positron emission tomography (PET) imaging but no pathological evidence of NSCLC. Patients with another known metastatic tumor were excluded. Statistical analysis was conducted with Cox proportional hazards analysis, univariate analysis, and the Kaplan-Meier method. RESULTS: Ninety-one treatments in 90 unique patients met inclusion criteria. Patients were a median 77.9 years at the start of treatment and had a median Charlson score of 7. Pre-treatment standardized uptake value (SUV) was a median 4.5 and 1.5 after treatment. At a median follow-up of 12.9 months, 36-month local control of 91.3% was achieved. Twenty-four-month OS and progression-free survival were 65.4% and 44.8%, respectively. On univariate analysis, biologically effective dose (BED) ≥120 Gy was predictive of improved OS (P=0.001), with 36-month OS of 50.5% for patients with BED ≥120 Gy and only 31.6% for patients with BED <120 Gy. On Kaplan-Meier analysis, Charlson score ≥9 was predictive of decreased OS (P=0.04), and BED ≥120 Gy trended towards improved OS (P=0.08). Thirty-two cases of grade <3 toxicity were reported, and only two cases of grade 3 morbidity (fatigue) were noted. CONCLUSIONS: Local control rates for empiric SBRT treatment for hypermetabolic, non-metastatic NSCLC are similar to those for biopsied NSCLC. OS is primarily dependent on a patient's overall health status, which can be accurately assessed with the Charlson score. BED ≥120 Gy may also contribute to improved OS.

A single-institutional experience with low dose stereotactic body radiation therapy for liver metastases.

AIM: This study reports a single-institutional experience treating liver metastases with stereotactic body radiation therapy (SBRT). MATERIALS AND METHODS: 107 patients with 169 lesions were assessed to determine factors predictive for local control, radiographic response, and overall survival (OS). Machine learning techniques, univariate analysis, and the Kaplan-Meier method were utilized. RESULTS: Patients were treated with a relatively low median dose of 30 Gy in 3 fractions. Fractions were generally delivered once weekly. Median biologically effective dose (BED) was 60 Gy, and the median gross tumor volume (GTV) was 12.16 cc. Median follow-up was 7.36 months. 1-year local control was 75% via the Kaplan-Meier method. On follow-up imaging, 43%, 40%, and 17% of lesions were decreased, stable, and increased in size, respectively. 1-year OS was 46% and varied by primary tumor, with median OS of 34.3, 25.1, 12.5, and 4.6 months for ovarian, breast, colorectal, and lung primary tumors, respectively. Breast and ovarian primary patients had better OS (p < 0.0001), and lung primary patients had worse OS (p = 0.032). Higher BED values, the number of hepatic lesions, and larger GTV were not predictive of local control, radiographic response, or OS. 21% of patients suffered from treatment toxicity, but no grade ≥3 toxicity was reported. CONCLUSION: Relatively low-dose SBRT for liver metastases demonstrated efficacy and minimal toxicity, even for patients with large tumors or multiple lesions. This approach may be useful for patients in whom higher-dose therapy is contraindicated or associated with high risk for toxicity. OS depends largely on the primary tumor.

Stereotactic body radiation therapy for spinal metastases: a novel local control stratification by spinal region.

OBJECTIVE: This study evaluated a large cohort of patients treated with stereotactic body radiation therapy for spinal metastases and investigated predictive factors for local control, local progression-free survival (LPFS), overall survival, and pain response between the different spinal regions. METHODS: The study was undertaken via retrospective review at a single institution. Patients with a tumor metastatic to the spine were included, while patients with benign tumors or primary spinal cord cancers were excluded. Statistical analysis involved univariate analysis, Cox proportional hazards analysis, the Kaplan-Meier method, and machine learning techniques (decision-tree analysis). RESULTS: A total of 165 patients with 190 distinct lesions met all inclusion criteria for the study. Lesions were distributed throughout the cervical (19%), thoracic (43%), lumbar (19%), and sacral (18%) spines. The most common treatment regimen was 24 Gy in 3 fractions (44%). Via the Kaplan-Meier method, the 24-month local control was 80%. Sacral spine lesions demonstrated decreased local control (p = 0.01) and LPFS (p < 0.005) compared with those of the thoracolumbar spine. The cervical spine cases had improved local control (p < 0.005) and LPFS (p < 0.005) compared with the sacral spine and trended toward improvement relative to the thoracolumbar spine. The 36-month local control rates for cervical, thoracolumbar, and sacral tumors were 86%, 73%, and 44%, respectively. Comparably, the 36-month LPFS rates for cervical, thoracolumbar, and sacral tumors were 85%, 67%, and 35%, respectively. A planning target volume (PTV) > 50 cm3 was also predictive of local failure (p = 0.04). Fewer cervical spine cases had disease with PTV > 50 cm3 than the thoracolumbar (p = 5.87 × 10-8) and sacral (p = 3.9 × 10-3) cases. Using decision-tree analysis, the highest-fidelity models for predicting pain-free status and local failure demonstrated the first splits as being cervical and sacral location, respectively. CONCLUSIONS: This study presents a novel risk stratification for local failure and LPFS by spinal region. Patients with metastases to the sacral spine may have decreased local control due to increased PTV, especially with a PTV of > 50 cm3. Multidisciplinary care should be emphasized in these patients, and both surgical intervention and radiotherapy should be strongly considered.

Intracranial disease control for EGFR-mutant and ALK-rearranged lung cancer with large volume or symptomatic brain metastases.

PURPOSE/OBJECTIVE(S): 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. MATERIALS/METHODS: 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). RESULTS: 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). CONCLUSION: 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.

Modeling the Impact of Cardiopulmonary Irradiation on Overall Survival in NRG Oncology Trial RTOG 0617.

PURPOSE: To quantitatively predict the impact of cardiopulmonary dose on overall survival (OS) after radiotherapy for locally advanced non-small cell lung cancer. EXPERIMENTAL DESIGN: We used the NRG Oncology/RTOG 0617 dataset. The model building procedure was preregistered on a public website. Patients were split between a training and a set-aside validation subset (N = 306/131). The 191 candidate variables covered disease, patient, treatment, and dose-volume characteristics from multiple cardiopulmonary substructures (atria, lung, pericardium, and ventricles), including the minimum dose to the hottest x% volume (Dx%[Gy]), mean dose of the hottest x% (MOHx%[Gy]), and minimum, mean (Mean[Gy]), and maximum dose. The model building was based on Cox regression and given 191 candidate variables; a Bonferroni-corrected P value threshold of 0.0003 was used to identify predictors. To reduce overreliance on the most highly correlated variables, stepwise multivariable analysis (MVA) was repeated on 1000 bootstrapped replicates. Multivariate sets selected in ≥10% of replicates were fit to the training subset and then averaged to generate a final model. In the validation subset, discrimination was assessed using Harrell c-index, and calibration was tested using risk group stratification. RESULTS: Four MVA models were identified on bootstrap. The averaged model included atria D45%[Gy], lung Mean[Gy], pericardium MOH55%[Gy], and ventricles MOH5%[Gy]. This model had excellent performance predicting OS in the validation subset (c = 0.89). CONCLUSIONS: The risk of death due to cardiopulmonary irradiation was accurately modeled, as demonstrated by predictions on the validation subset, and provides guidance on the delivery of safe thoracic radiotherapy.

Stereotactic radiosurgery for the treatment of bulky spine metastases.

INTRODUCTION: Stereotactic radiosurgery (SRS) has shown durable local control for the treatment of metastatic diseasespinal metastases. Multilevel disease or epidural or paraspinal involvement present challenges to achieving local control, and this study aims to analyze treatment outcomes for such lesions. METHODS: Patients treated at a single institution with SRS to the spine from 2010-2018 were retrospectively reviewed. Inclusion criteria required clinical follow-up with either a pain assessment or imaging study. Bulky spine metastasis was defined as consisting of multilevel disease or epidural or paraspinal tumor involvement. RESULTS: 54 patients treated for 62 lesions met inclusion criteria. 42 treatments included at least two vertebrae, and 21 and 31 had paraspinal and epidural involvement, respectively. Treatment regimens had a median 24 Gy in 3 fractions to a volume of 37.75 cm3. Median follow-up was 14.36 months, with 5 instances (8%) of local failure. Median overall survival was 13.32 months. Pain improvement was achieved in 47 treatments (76%), and pain improved with treatment (p < 0.0001). Severe pain (HR = 3.08, p = 0.05), additional bone metastases (HR = 4.82, p = 0.05), and paraspinal involvement (HR = 3.93, p < 0.005) were predictive for worse overall survival. Kaplan-Meier analysis demonstrated that prior chemotherapy (p = 0.03) and additional bone metastases (p = 0.02) were predictive of worse overall survival. Grade < 3 toxicity was observed in 19 cases; no grade ≥ 3 side effects were observed. CONCLUSIONS: SRS can effectively treat bulky metastases to the spine, resulting in improvement of pain with minimal toxicity. Severe pain independently predicts for worse overall survival, indicating that treatment prior to worsening of pain is strongly recommended.

Stereotactic Body Radiation Therapy for Salvage Treatment of Recurrent Non-Small Cell Lung Cancer.

PURPOSE: This study analyzes the outcomes and toxicity of stereotactic body radiation therapy (SBRT) as salvage treatment for recurrent non-small cell lung cancer (NSCLC). METHODS AND MATERIALS: This retrospective analysis considered patients treated with thoracic SBRT and a history of prior external beam radiation therapy (EBRT), SBRT, or surgical resection for NSCLC. Follow-up included positron emission tomography and computed tomography imaging at 2- to 3-month intervals. Key outcomes were presented with the Kaplan-Meier method. RESULTS: Forty patients with 52 treatments were included at a mean of 11.82 months after treatment with EBRT (n = 21), SBRT (n = 15), surgical resection (n = 9), and SBRT after EBRT (n = 7). Median imaging and clinical follow-up were 13.39 and 19.01 months, respectively. SBRT delivered a median dose of 40 Gy in 4 fractions. Median biologically effective dose (BED) was 79.60 Gy. Median gross tumor volume and planning target volume were 10.80 and 26.25 cm3, respectively. Local control was 65%, with a median time to local failure of 13.52 months. Local control was 87% after previous SBRT but only 33% after surgery. Median overall survival was 24.46 months, and median progression-free survival (PFS) was 14.11 months. Patients presenting after previous SBRT had improved local control (P = .021), and the same result was obtained including patients with SBRT after EBRT (P = .0037). Treatments after surgical resection trended toward worse local control (P = .061). Patients with BED ≥80 Gy had improved local PFS (P = .032), PFS (P = .021), time without any treatment failure (P = .033), and time to local failure (P = .041). Using the Kaplan-Meier method, BED ≥80 Gy was predictive of improved local PFS (P = .01) and PFS (P < .005). Toxicity consisted of 10 instances of grade <3 toxicity (16%) and no grade ≥3 toxicity. CONCLUSIONS: Salvage treatment for recurrent NSCLC with SBRT was effective and well tolerated, particularly after initial treatment with SBRT. When possible, salvage SBRT should aim to achieve a BED of ≥80 Gy.