Clinical outcomes of melanoma brain metastases treated with nivolumab and ipilimumab alone versus nivolumab and ipilimumab with stereotactic radiosurgery.

PURPOSE: Upfront dual checkpoint blockade with immune checkpoint inhibitors (ICI) has demonstrated efficacy for treating melanoma brain metastases (MBM) in asymptomatic patients. Whether the combination of stereotactic radiosurgery (SRS) with dual checkpoint blockade improves outcomes over dual-checkpoint blockade alone is unknown. We evaluated clinical outcomes of patients with MBM receiving ICI with nivolumab and ipilimumab, with and without SRS. METHODS: 49 patients with 158 MBM receiving nivolumab and ipilimumab for untreated MBM between 2015 and 2022 were identified at our institution. Patient and tumor characteristics including age, Karnofsky Performance Status (KPS), presence of symptoms, cancer history, MBM burden, and therapy course were recorded. Outcomes measured from initiation of MBM-directed therapy included overall survival (OS), local control (LC), and distant intracranial control (DIC). Time-to-event analysis was conducted with the Kaplan-Meier method. RESULTS: 25 patients with 74 MBM received ICI alone, and 24 patients with 84 MBM received concurrent SRS. Median follow-up was 24 months. No differences in age (p = 0.96), KPS (p = 0.85), presence of symptoms (p = 0.79), prior MBM (p = 0.68), prior MBM-directed surgery (p = 0.96) or SRS (p = 0.68), MBM size (p = 0.67), or MBM number (p = 0.94) were seen. There was a higher rate of nivolumab and ipilimumab course completion in the SRS group (54% vs. 24%; p = 0.029). The SRS group received prior immunotherapy more often than the ICI alone group (54% vs. 8.0%; p < 0.001). There was no significant difference in 1-year OS (72% vs. 71%, p = 0.20) and DIC (63% v 51%, p = 0.26) between groups. The SRS group had higher 1-year LC (92% vs. 64%; p = 0.002). On multivariate analysis, LC was improved with combination therapy (AHR 0.38, p = 0.01). CONCLUSION: In our analysis, patients who received SRS with nivolumab and ipilimumab had superior LC without increased risk of toxicity or compromised immunotherapy treatment completion despite the SRS cohort having higher rates of prior immunotherapy. Further prospective study of combination nivolumab and ipilimumab with SRS is warranted.

Technical feasibility of novel immunostimulatory low-dose radiation for polymetastatic disease with CBCT-based online adaptive and conventional approaches.

PURPOSE: A workflow/planning strategy delivering low-dose radiation therapy (LDRT) (1 Gy) to all polymetastatic diseases using conventional planning/delivery (Raystation/Halcyon = "conventional") and the AI-based Ethos online adaptive RT (oART) platform is developed/evaluated. METHODS: Using retrospective data for ten polymetastatic non-small cell lung cancer patients (5-52 lesions each) with PET/CTs, gross tumor volumes (GTVs) were delineated using PET standardized-uptake-value (SUV) thresholding. A 1 cm uniform expansion of GTVs to account for setup/contour uncertainty and organ motion-generated planning target volumes (PTVs). Dose optimization/calculation used the diagnostic CT from PET/CT. Dosimetric objectives were: Dmin,0.03cc ≥ 95% (acceptable variation (Δ) ≥ 90%), V100% ≥ 95% (Δ ≥ 90%), and D0.03cc ≤ 120% (Δ ≤ 125%). Additionally, online adaptation was simulated. When available, subsequent diagnostic CT was used to represent on-treatment CBCT. Otherwise, the CT from PET/CT used for initial planning was deformed to simulate clinically representative changes. RESULTS: All initial plans generated, both for Raystation and Ethos, achieved clinical goals within acceptable variation. For all patients, Dmin,0.03cc ≥ 95%, V100% ≥ 95%, and D0.03cc ≤ 120% goals were achieved for 84.8%/99.5%, 97.7%/98.7%, 97.4%/92.3%, in conventional/Ethos plans, respectively. The ratio of 50% isodose volume to PTV volume (R50%), maximum dose at 2 cm from PTV (D2cm), and the ratio of the 100% isodose volume to PTV volume (conformity index) in Raystation/Ethos plans were 7.9/5.9; 102.3%/88.44%; and 0.99/1.01, respectively. In Ethos, online adapted plans maintained PTV coverage whereas scheduled plans often resulted in geographic misses due to changes in tumor size, patient position, and body habitus. The average total duration of the oART workflow was 26:15 (min:sec) ranging from 6:43 to 57:30. The duration of each oART workflow step as a function of a number of targets showed a low correlation coefficient for influencer generation and editing (R2 = 0.04 and 0.02, respectively) and high correlation coefficient for target generation, target editing and plan generation (R2 = 0.68, 0.63 and 0.69, respectively). CONCLUSIONS: This study demonstrates feasibility of conventional planning/treatment with Raystation/Halcyon and highlights efficiency gains when utilizing semi-automated planning/online-adaptive treatment with Ethos for immunostimulatory LDRT conformally delivered to all sites of polymetastatic disease.

Tucatinib and stereotactic radiosurgery in the management of HER2 positive breast cancer brain metastases.

PURPOSE: HER2-positive breast cancer has a high risk of brain metastasis. Stereotactic radiosurgery (SRS) is standard of care for limited brain metastases. Tucatinib, a HER2-targeted tyrosine kinase inhibitor, has demonstrated intracranial efficacy in the HER2-CLIMB Trial. However, it is unknown whether tucatinib with SRS is safe or effective. METHODS: A retrospective analysis of HER2-positive breast cancer treated with SRS and tucatinib for brain metastases management was performed. All patients received tucatinib and SRS for the management of active brain metastases. The primary endpoint was local and distant brain tumor control. Secondary endpoints were intracranial progression free survival (CNS-PFS), systemic PFS, overall survival (OS), and neurotoxicity. RESULTS: A total of 135 lesions treated with SRS over 39 treatment sessions in 22 patients were identified. Median follow-up from tucatinib initiation was 20.8 months. Local brain control was 94% at 12-months and 81% at 24-months. Distant brain control was 39% at 12-months and 26% at 24-months. Median survival was 21.2 months, with 12- and 24-month OS rates of 84% and 50%, respectively. Median CNS-PFS was 11.3 months, with 12- and 24-month CNS-PFS rates of 44.9% at both time points. Median systemic PFS was not reached, with 12- and 24-month systemic PFS rates of 86% and 57%, respectively. Symptomatic radiation necrosis occurred in 6 (4%) lesions. No additional unexpected toxicities were noted. CONCLUSIONS: SRS in combination with tucatinib, capecitabine, and trastuzumab appears to be a safe and feasible treatment for HER2 + brain metastases. Further prospective evaluation of potential synergistic effects is warranted.

The presentation of brain metastases in melanoma, non-small cell lung cancer, and breast cancer and potential implications for screening brain MRIs.

PURPOSE: This study assessed the presentation and institutional outcomes treating brain metastases (BM) of breast cancer (BC), non-small cell lung cancer (NSCLC), and melanoma origin. METHODS: Patients with brain metastases treated between 2014 and 2019 with primary melanoma, NSCLC, and BC were identified. Overall survival (OS) was calculated from dates of initial BM diagnosis using the Kaplan-Meier method. RESULTS: A total of 959 patients were identified including melanoma (31%), NSCLC (51%), and BC (18%). Patients with BC were younger at BM diagnosis (median age: 57) than NSCLC (65) and melanoma patients (62, p < 0.0001). Breast cancer patients were more likely to present with at least 5 BM (27%) than NSCLC (14%) and melanoma (13%), leptomeningeal disease (23%, 6%, and 6%, p = 0.0004) and receive whole brain radiation therapy (WBRT) (58%, 37%, and 22%, p < 0.0001). There were no differences in surgical resection (24%, 24%, and 29%, p = 0.166). Median OS was shorter for BC patients (9.9, 10.3, and 13.7 months, p = 0.0006). CONCLUSION: Breast cancer patients were more likely to be younger, present with advanced disease, require WBRT, and have poorer OS than NSCLC and melanoma patients. Further investigation is needed to determine which BC patients are at sufficient risk for brain MRI screening.

Dosimetric feasibility of hippocampal avoidance whole brain radiotherapy with an MRI-guided linear accelerator.

PURPOSE/OBJECTIVE(S): Whole brain radiotherapy with hippocampal avoidance (HA-WBRT) is a technique utilized to treat metastatic brain disease while preserving memory and neurocognitive function. We hypothesized that the treatment planning and delivery of HA-WBRT plans is feasible with an MRI-guided linear accelerator (linac) and compared plan results with clinical non-MRI-guided C-Arm linac plans. MATERIALS/METHODS: Twelve HA-WBRT patients treated on a non-MRI-guided C-Arm linac were selected for retrospective analysis. Treatment plans were developed using a 0.35T MRI-guided linac system for comparison to clinical plans. Treatment planning goals were defined as provided in the Phase II Trial NRG CC001. MRI-guided radiotherapy (MRgRT) treatment plans were developed by a dosimetrist and compared with clinical plans. quality assurance (QA) plans were generated and delivered on the MRI-guided linac to a cylindrical diode detector array. Planning target volume (PTV) coverage was normalized to ∼95% to provide a control point for comparison of dose to the organs at risk. RESULTS: MRgRT plans were deliverable and met all clinical goals. Mean values demonstrated that the clinical plans were less heterogeneous than MRgRT plans with mean PTV V37.5 Gy of 0.00% and 0.03% (p = 0.013), respectively. Average hippocampi maximum doses were 14.19 ± 1.29 Gy and 15.00 ± 1.51 Gy, respectively. The gamma analysis comparing planned and measured doses resulted in a mean of 99.9% ± 0.12% of passing points (3%/2mm criteria). MRgRT plans had an average of 38.33 beams with average total delivery time and beam-on time of 13.7 (11.2-17.5) min and 4.1 (3.2-5.4) min, respectively. Clinical plan delivery times ranged from 3 to 7 min depending on the number of noncoplanar arcs. Planning time between the clinical and MRgRT plans was comparable. CONCLUSION: This study demonstrates that HA-WBRT can be treated using an MRI-guided linear accelerator with comparable treatment plan quality and delivery accuracy.

Pan-cancer prediction of radiotherapy benefit using genomic-adjusted radiation dose (GARD): a cohort-based pooled analysis.

BACKGROUND: Despite advances in cancer genomics, radiotherapy is still prescribed on the basis of an empirical one-size-fits-all paradigm. Previously, we proposed a novel algorithm using the genomic-adjusted radiation dose (GARD) model to personalise prescription of radiation dose on the basis of the biological effect of a given physical dose of radiation, calculated using individual tumour genomics. We hypothesise that GARD will reveal interpatient heterogeneity associated with opportunities to improve outcomes compared with physical dose of radiotherapy alone. We aimed to test this hypothesis and investigate the GARD-based radiotherapy dosing paradigm. METHODS: We did a pooled, pan-cancer analysis of 11 previously published clinical cohorts of unique patients with seven different types of cancer, which are all available cohorts with the data required to calculate GARD, together with clinical outcome. The included cancers were breast cancer, head and neck cancer, non-small-cell lung cancer, pancreatic cancer, endometrial cancer, melanoma, and glioma. Our dataset comprised 1615 unique patients, of whom 1298 (982 with radiotherapy, 316 without radiotherapy) were assessed for time to first recurrence and 677 patients (424 with radiotherapy and 253 without radiotherapy) were assessed for overall survival. We analysed two clinical outcomes of interest: time to first recurrence and overall survival. We used Cox regression, stratified by cohort, to test the association between GARD and outcome with separate models using dose of radiation and sham-GARD (ie, patients treated without radiotherapy, but modelled as having a standard-of-care dose of radiotherapy) for comparison. We did interaction tests between GARD and treatment (with or without radiotherapy) using the Wald statistic. FINDINGS: Pooled analysis of all available data showed that GARD as a continuous variable is associated with time to first recurrence (hazard ratio [HR] 0·98 [95% CI 0·97-0·99]; p=0·0017) and overall survival (0·97 [0·95-0·99]; p=0·0007). The interaction test showed the effect of GARD on overall survival depends on whether or not that patient received radiotherapy (Wald statistic p=0·011). The interaction test for GARD and radiotherapy was not significant for time to first recurrence (Wald statistic p=0·22). The HR for physical dose of radiation was 0·99 (95% CI 0·97-1·01; p=0·53) for time to first recurrence and 1·00 (0·96-1·04; p=0·95) for overall survival. The HR for sham-GARD was 1·00 (0·97-1·03; p=1·00) for time to first recurrence and 1·00 (0·98-1·02; p=0·87) for overall survival. INTERPRETATION: The biological effect of radiotherapy, as quantified by GARD, is significantly associated with time to first recurrence and overall survival for patients with cancer treated with radiation. It is predictive of radiotherapy benefit, and physical dose of radiation is not. We propose integration of genomics into radiation dosing decisions, using a GARD-based framework, as the new paradigm for personalising radiotherapy prescription dose. FUNDING: None. VIDEO ABSTRACT.

Capecitabine and stereotactic radiation in the management of breast cancer brain metastases.

BACKGROUND: Little is known about the safety and efficacy of concurrent capecitabine and stereotactic radiotherapy in the setting of breast cancer brain metastases (BCBM). METHODS: Twenty-three patients with BCBM underwent 31 stereotactic sessions to 90 lesions from 2005 to 2019 with receipt of capecitabine. The Kaplan-Meier method was used to calculate overall survival (OS), local control (LC), and distant intracranial control (DIC) from the date of stereotactic radiation. Imaging was independently reviewed by a neuro-radiologist. RESULTS: Median follow-up from stereotactic radiation was 9.2 months. Receptor types of patients treated included triple negative (n = 7), hormone receptor (HR)+/HER2- (n = 7), HR+/HER2+ (n = 6), and HR-/HER2+ (n = 3). Fourteen patients had stage IV disease prior to BCBM diagnosis. The median number of brain metastases treated per patient was 3 (1 to 12). The median dose of stereotactic radiosurgery (SRS) was 21 Gy (range: 15-24 Gy) treated in a single fraction and for lesions treated with fractionated stereotactic radiation therapy (FSRT) 25 Gy (24-30 Gy) in a median of 5 fractions (range: 3-5). Of the 31 stereotactic sessions, 71% occurred within 1 month of capecitabine. No increased toxicity was noted in our series with no cases of radionecrosis. The 1-year OS, LC, and DIC were 46, 88, and 30%, respectively. CONCLUSIONS: In our single institution experience, we demonstrate stereotactic radiation and capecitabine to be a safe treatment for patients with BCBM with adequate LC. Further study is needed to determine the potential synergy between stereotactic radiation and capecitabine in the management of BCBM.

Breast cancer subtype predicts clinical outcomes after stereotactic radiation for brain metastases.

PURPOSE: We investigated the prognostic ability of tumor subtype for patients with breast cancer brain metastases (BCBM) treated with stereotactic radiation (SRT). METHODS: This is a retrospective review of 181 patients who underwent SRT to 664 BCBM from 2004 to 2019. Patients were stratified by subtype: hormone receptor (HR)-positive, HER2-negative (HR+/HER2-), HR-positive, HER2-positive (HR+/HER2+), HR-negative, HER2-positive (HR-/HER2+), and triple negative (TN). The Kaplan-Meier method was used to calculate overall survival (OS), local control (LC), and distant intracranial control (DIC) from the date of SRT. Multivariate analysis (MVA) was conducted using the Cox proportional hazards model. RESULTS: Median follow up from SRT was 11.4 months. Of the 181 patients, 47 (26%) were HR+/HER2+, 30 (17%) were HR-/HER2+, 60 (33%) were HR+/HER2-, and 44 (24%) were TN. Of the 664 BCBMs, 534 (80%) received single fraction stereotactic radiosurgery (SRS) with a median dose of 21 Gy (range 12-24 Gy), and 130 (20%) received fractionated stereotactic radiation therapy (FSRT), with a median dose of 25 Gy (range 12.5-35 Gy) delivered in 3 to 5 fractions. One-year LC was 90%. Two-year DIC was 35%, 23%, 27%, and 16% (log rank, p = 0.0003) and 2-year OS was 54%, 47%, 24%, and 12% (log rank, p < 0.0001) for HR+/HER2+, HR-/HER2+, HR+/HER2-, and TN subtypes, respectively. On MVA, the TN subtype predicted for inferior DIC (HR 1.62, 95% CI 1.00-2.60, p = 0.049). The modified breast-Graded Prognostic Assessment (GPA) significantly predicted DIC and OS (both p < 0.001). CONCLUSIONS: Subtype is prognostic for OS and DIC for patients with BCBM treated with SRT.

The role of dose escalation and proton therapy in perioperative or definitive treatment of chondrosarcoma and chordoma: An analysis of the National Cancer Data Base.

BACKGROUND: Chordomas and chondrosarcomas are a rare but challenging subset of tumors to treat; however, previous studies have shown benefits from proton therapy, which are thought to be primarily driven by prescription conformality permitting homogeneous tumor dosing and the allowance of higher doses. No retrospective studies to date have directly compared the outcomes of conventional and particle therapy or examined the role of high doses (specifically ≥70 Gy) in definitive radiotherapy (DRT) or perioperative radiotherapy (PRT) for both types of malignancies. METHODS: A total of 863 patients with chondrosarcoma and 715 patients with chordoma treated with nonpalliative proton or conventional radiation therapy with a dose range of 20 to 80 Gy and at least 15 months of follow-up were identified from the National Cancer Data Base for the years 2003-2014. The primary endpoint of overall survival (OS) was evaluated, and clinical features, including age, sex, grade, clinical stage, and Charlson-Deyo comorbidity index, were compared. RESULTS: Patients receiving DRT were older and had more advanced disease. In DRT for chondrosarcoma, a high dose (40.6% vs 16.9%; P = .006) and proton therapy (75.0% vs 19.1%; P = .046) were associated with improved OS at 5 years in a multivariate analysis. In DRT for chordoma, proton therapy was associated with improved OS at 5 years in a multivariate analysis (100% vs 34.1%; P = .031), and a high dose for chordoma was significant for improved OS in a univariate analysis with both DRT (79.0% vs 54.1%; P = .027) and PRT (83.3% vs 77.4%; P = .007). CONCLUSIONS: In the largest retrospective series to date, dose escalation and proton radiotherapy were associated with improved OS in patients with chondrosarcoma and chordoma despite limited follow-up and access to particle therapy.

Management of Sentinel Lymph Node Metastasis in Merkel Cell Carcinoma: Completion Lymphadenectomy, Radiation, or Both?

BACKGROUND: Approximately 30% of patients with clinically localized Merkel cell carcinoma (MCC) show nodal involvement on sentinel lymph node biopsy (SLNB). Optimal management of SLNB-positive disease has not been defined. This study compared outcomes after completion lymphadenectomy (CLND), radiation, and combined CLND plus radiation after a positive SLNB. METHODS: All patients treated at a single institution for SLNB-positive MCC (1998-2015) were retrospectively evaluated, with examination of patient demographics, clinicopathologic characteristics, outcomes, and regional toxicity. RESULTS: The study identified 71 evaluable patients with SLNB-positive disease. The median age of these patients was 76 years, and 76.1% were men. Of the 71 patients, 11 (15.5%) underwent CLND, 40 (56.3%) received radiation, and 20 (28.2%) underwent CLND plus postoperative radiation. Lymphovascular invasion was significantly more common in the radiation-alone cohort (p = 0.04). For the three cohorts, the median percentages of nodal involvement were respectively 2, 10, and 30% (p = 0.06). After a median follow-up period of 22.3 months, four patients had recurrence in their regional nodal basin (3 radiation-alone patients and 1 CLND + radiation patient). The three cohorts did not differ significantly in the development of distant metastases (p = 0.68) or overall survival (p = 0.72). Six patients experienced surgical-site infections (2 CLND and 4 CLND + radiation patients), and three patients experienced symptomatic lymphedema (1 CLND patient and 2 CLND + radiation patients). CONCLUSIONS: Regional failure was infrequent (≤ 10%) regardless of treatment, and morbidity appeared to be low with all approaches. Given that multiple treatment approaches can be successful in treating micrometastatic MCC, future efforts should be directed at refining criteria for allocating patients to a specific method, or possibly no further nodal basin treatment, in an effort to maximize regional control at the lowest cost and morbidity.

CDK 4/6 inhibitors and stereotactic radiation in the management of hormone receptor positive breast cancer brain metastases.

PURPOSE: Cyclin-dependent kinase (CDK) 4/6 inhibitors are becoming increasingly utilized in the setting of advanced, hormone receptor (HR+) positive breast cancer. Pre-clinical data suggests a potential synergy between radiation therapy (RT) and CDK4/6 inhibitors. We assessed clinical outcomes of patients treated at our institution with the use of CDK4/6 inhibitors and stereotactic radiation in the management of HR+ breast brain metastases. METHODS: A retrospective analysis of patients who received stereotactic radiotherapy for HR+ brain metastases within 6 months of CDK4/6 inhibitor administration was performed. The primary endpoint was neurotoxicity during or after stereotactic radiation. Secondary endpoints were local brain control, distant brain control, and overall survival (OS). RESULTS: A total of 42 lesions treated with stereotactic radiation in 15 patients were identified. Patients received either palbociclib (n = 10; 67%) or abemaciclib (n = 5; 33%). RT was delivered concurrently, before, or after CDK4/6 inhibitors in 18 (43%), 9 (21%), and 15 (36%) lesions, respectively. Median follow-up following stereotactic radiation was 9 months. Two lesions (5%) developed radionecrosis, both of which received four prior RT courses to the affected lesion prior to onset of radionecrosis and subsequently managed with steroids and bevacizumab. Six- and 12-month local control of treated lesions was 88% and 88%, while 6- and 12-month distant brain control was 61% and 39%, respectively. Median OS was 36.7 months from the date of brain metastases diagnosis. CONCLUSIONS: Stereotactic radiation to breast brain metastases was well tolerated alongside CDK4/6 inhibitors. Compared to historical data, brain metastases control rates are similar whereas survival appears prolonged.

Resection Margins in Merkel Cell Carcinoma: Is a 1-cm Margin Wide Enough?

BACKGROUND: Guidelines regarding specific resection margins for primary Merkel cell carcinoma (MCC) are not well established. The current National Comprehensive Cancer Network (NCCN) guidelines recommend 1- to 2-cm resection margins. This study aimed to determine the impact of margin width on local recurrence (LR), disease-specific survival (DSS), overall survival (OS), and type of wound closure. METHODS: All patients who underwent resection of primary MCC at a single institution from 2000 to 2015 were reviewed. Patient demographics, clinicopathologic characteristics, treatments, and outcomes were reviewed. RESULTS: A total of 240 patients underwent resection of primary MCC with resection margin width identified in the operative report. The median age was 76 years, and 65.8% of the patients were men. Of the 240 patients, 85 (35.4%) had head and neck primaries, 140 (58.3%) had extremity primaries, and 15 (6.3%) had trunk primaries. In terms of margins, 69 patients (28.8%) had a margin of 1 cm, 36 patients (15%) had a margin of 1.1-1.9 cm, and 135 patients (56.2%) had a margin of 2 cm or more. The median follow-up period was 21 months. The LR rate was 2.9% for a margin of 1 cm, 2.8% for a margin of 1.1-1.9 cm, and 5.2% for a margin of 2 cm or more (p = 0.80). The 5-year OS was 63.6% for a margin of 1 cm, 59.7% for a margin of 1.1-1.9, and 70.7% for a margin of 2 cm or more (p = 0.66). The 5-year DSS was 80.3% for a margin of 1 cm, 66.2% for a margin of 1.1-1.9 cm, and 91.8% for a margin of 2 cm or more (p = 0.28). For wound closure, 43.5, 50, and 65.9% of the patients respectively required a flap or graft with a margin of 1, 1.1-1.9, and 2 cm or more (p = 0.006). CONCLUSIONS: A 1-cm resection margins did not increase the risk of LR. Margin width did not make a significant difference in DSS or OS. Larger resection margins increase the need for a graft or flap closure.

Regional Radiation Therapy Impacts Outcome for Node-Positive Cutaneous Melanoma.

Background: Regional radiation therapy (RT) has been shown to reduce the risk of regional recurrence with node-positive cutaneous melanoma. However, risk factors for regional recurrence, especially in the era of sentinel lymph node biopsy (SLNB), are less clear. Our goals were to identify risk factors associated with regional recurrence and to determine whether a radiosensitivity index (RSI) gene expression signature (GES) could identify patients who experience a survival benefit with regional RT. Methods: A single-institution, Institutional Review Board-approved study was performed including 410 patients treated with either SLNB with or without completion lymph node dissection (LND; n=270) or therapeutic LND (n=91). Postoperative regional RT was delivered to the involved nodal basin in 83 cases (20.2%), to a median dose of 54 Gy (range, 30-60 Gy) in 27 fractions (range, 5-30). Primary outcomes were regional control and overall survival by RSI GES status. Results: Median follow-up was 69 months (range, 13-180). Postoperative regional RT was associated with a reduced risk of regional recurrence among all patients on univariate (5-year estimate: 95.0% vs 83.3%; P=.036) and multivariate analysis (hazard ratio[HR], 0.15; 95% CI, 0.05-0.43; P<.001). Among higher-risk subgroups, regional RT was associated with a lower risk of regional recurrence among patients with clinically detected lymph nodes (n=175; 5-year regional control: 94.1% vs 69.5%; P=.003) and extracapsular extension (ECE) present (n=138; 5-year regional control: 96.7% vs 62.2%; P<.001). Among a subset of radiated patients with gene expression data available, a low RSI GES (radiosensitive) tumor status was associated with improved survival compared with a high RSI GES (5-year: 75% vs 0%; HR, 10.68; 95% CI, 1.24-92.14). Conclusions: Regional RT was associated with a reduced risk of regional recurrence among patients with ECE and clinically detected nodal disease. Gene expression data show promise for better predicting radiocurable patients in the future. In the era of increasingly effective systemic therapies, the value of improved regional control potentially takes on greater significance.

Intracranial control and radiographic changes with adjuvant radiation therapy for resected brain metastases: whole brain radiotherapy versus stereotactic radiosurgery alone.

The aim of this study was to compare outcomes of postoperative whole brain radiation therapy (WBRT) to stereotactic radiosurgery (SRS) alone in patients with resected brain metastases (BM). We reviewed records of patients who underwent surgical resection of BM followed by WBRT or SRS alone between 2003 and 2013. Local control (LC) of the treated resected cavity, distant brain control (DBC), leptomeningeal disease (LMD), overall survival (OS), and radiographic leukoencephalopathy rates were estimated by the Kaplan-Meier method. One-hundred thirty-two patients underwent surgical resection for 141 intracranial metastases: 36 (27 %) patients received adjuvant WBRT and 96 (73 %) received SRS alone to the resection cavity. One-year OS (56 vs. 55 %, p = 0.64) and LC (83 vs. 74 %, p = 0.31) were similar between patients receiving WBRT and SRS. After controlling for number of BM, WBRT was associated with higher 1-year DBC compared with SRS (70 vs. 48 %, p = 0.03); single metastasis and WBRT were the only significant predictors for reduced distant brain recurrence in multi-variate analysis. Freedom from LMD was higher with WBRT at 18 months (87 vs. 69 %, p = 0.045), while incidence of radiographic leukoencephalopathy was higher with WBRT at 12 months (47 vs. 7 %, p = 0.001). One-year freedom from WBRT in the SRS alone group was 86 %. Compared with WBRT for patients with resected BM, SRS alone demonstrated similar LC, higher rates of LMD and inferior DBC, after controlling for the number of BM. However, OS was similar between groups. The results of ongoing clinical trials are needed to confirm these findings.

Clinical Outcomes of Patients with Non-Small Cell Lung Cancer Leptomeningeal Disease Following Receipt of EGFR-Targeted Therapy, Immune-Checkpoint Blockade, Intrathecal Chemotherapy, or Radiation Therapy Alone.

BACKGROUND: EGFR-targeted therapy (ETT) and immune-checkpoint blockade (ICB) have shown promising results in treating NSCLC brain metastases (BM). However, little is known of their effect in treating leptomeningeal disease (LMD). PATIENTS AND METHODS: This is a retrospective review of 80 patients diagnosed with NSCLC LMD from January 2014 to March 2021. Patients were grouped based on initial LMD treatment: radiotherapy (RT) alone, ETT, ICB, and intrathecal chemotherapy (ITC). RESULTS: EGFR mutation was present in 22 patients (28%). Twenty patients had positive cytology in cerebrospinal fluid, while 60 patients were diagnosed based on MRI with clinical correlation. The RT alone group consisted primarily of whole brain radiation (n = 20; 77%), stereotactic radiation (n = 3; 12%), and palliative spine radiation (n = 2; 7%). There were no significant differences amongst the treatment groups in age, performance status, or neurologic symptoms. Overall, the 6-month overall survival (OS) and craniospinal progression free survival (CS-PFS) were 35% and 24%, respectively. The 6-month OS for the ETT, ICB, ITC, and RT alone groups was 64%, 33%, 57%, and 29% respectively (log-rank P = .026). The 6-month CS-PFS for the ETT, ICB, ITC, and RT alone groups was 43%, 33%, 29%, and 19% respectively (log-rank P = .049). Upon univariate analysis, receipt of ETT compared to RT alone reached significance for OS (HR 0.35, P = .006) and CS-PFS (HR 0.39, P = .013). CONCLUSIONS: The prognosis for patients with NSCLC LMD remains poor overall. However, the receipt of ETT for patients with EGFR-positive disease was associated with improved outcomes.

Treatment of Central Nervous System Tumors on Combination MR-Linear Accelerators: Review of Current Practice and Future Directions.

Magnetic resonance imaging (MRI) provides excellent visualization of central nervous system (CNS) tumors due to its superior soft tissue contrast. Magnetic resonance-guided radiotherapy (MRgRT) has historically been limited to use in the initial treatment planning stage due to cost and feasibility. MRI-guided linear accelerators (MRLs) allow clinicians to visualize tumors and organs at risk (OARs) directly before and during treatment, a process known as online MRgRT. This novel system permits adaptive treatment planning based on anatomical changes to ensure accurate dose delivery to the tumor while minimizing unnecessary toxicity to healthy tissue. These advancements are critical to treatment adaptation in the brain and spinal cord, where both preliminary MRI and daily CT guidance have typically had limited benefit. In this narrative review, we investigate the application of online MRgRT in the treatment of various CNS malignancies and any relevant ongoing clinical trials. Imaging of glioblastoma patients has shown significant changes in the gross tumor volume over a standard course of chemoradiotherapy. The use of adaptive online MRgRT in these patients demonstrated reduced target volumes with cavity shrinkage and a resulting reduction in radiation dose to uninvolved tissue. Dosimetric feasibility studies have shown MRL-guided stereotactic radiotherapy (SRT) for intracranial and spine tumors to have potential dosimetric advantages and reduced morbidity compared with conventional linear accelerators. Similarly, dosimetric feasibility studies have shown promise in hippocampal avoidance whole brain radiotherapy (HA-WBRT). Next, we explore the potential of MRL-based multiparametric MRI (mpMRI) and genomically informed radiotherapy to treat CNS disease with cutting-edge precision. Lastly, we explore the challenges of treating CNS malignancies and special limitations MRL systems face.

Stereotactic radiosurgery and anti-PD-1 + CTLA-4 therapy, anti-PD-1 therapy, anti-CTLA-4 therapy, BRAF/MEK inhibitors, BRAF inhibitors, or conventional chemotherapy for the management of melanoma brain metastases.

BACKGROUND: Immunotherapy and targeted BRAF/MEK inhibitors (i) have revolutionised the systemic management of advanced melanoma. Given the role of stereotactic radiosurgery (SRS) in the local management of brain metastases, we sought to evaluate clinical outcomes in patients with melanoma brain metastases (MBM) treated with SRS and various systemic therapies. METHODS: Patients were included if MBM were diagnosed and treated with SRS within 3 months of receiving anti-PD-1+CTLA-4 therapy, anti-PD-1 therapy, anti-CTLA-4 therapy, BRAF/MEK-i, BRAF-i, or conventional chemotherapy. Comparisons between groups were made for overall survival (OS), distant MBM control, local MBM, systemic progression-free survival (sPFS), and neurotoxicity. RESULTS: In total, 257 patients with 1048 MBM treated over 368 SRS sessions between 2011 and 2020 were identified. On MVA, treatment with anti-PD1+anti-CTLA-4, anti-PD-1, and BRAF/MEK-i improved distant intracranial control over conventional chemotherapy. No significant differences were noted in local control (LC) between groups (p = 0.78). Kaplan-Meier OS at 12 months for anti-PD-1 + CTLA-4 therapy, anti-PD-1 therapy, anti-CTLA-4 therapy, BRAF/MEK-i, BRAF-i, and conventional chemotherapy was 68%, 59%, 45%, 62%, 21%, and 15%, respectively (p = <0.0001). The sPFS rates at 12 months were 57%, 53%, 42%, 45%, 14%, and 6% (p = <0.0001). No significant differences were noted in rates of radiation necrosis (p = 0.93). CONCLUSIONS: This is among the largest series evaluating MBM treated with SRS and various systemic therapy regimens. Our analysis noted significant differences in OS, distant MBM control, and sPFS by systemic therapy. No differences in LC or radiation necrosis risk were noted.

Early-Stage Primary Lung Neuroendocrine Tumors Treated With Stereotactic Body Radiation Therapy: A Multi-Institution Experience.

PURPOSE: Current guidelines recommend surgery as standard of care for primary lung neuroendocrine tumor (LNET). Given that LNET is a rare clinical entity, there is a lack of literature regarding treatment of LNET with stereotactic body radiation therapy (SBRT). We hypothesized that SBRT could lead to effective locoregional tumor control and long-term outcomes. METHODS AND MATERIALS: We retrospectively reviewed 48 tumors in 46 patients from 11 institutions with a histologically confirmed diagnosis of LNET, treated with primary radiation therapy. Data were collected for patients treated nonoperatively with primary radiation therapy between 2006 and 2020. Patient records were reviewed for lesion characteristics and clinical risk factors. Kaplan-Meier analysis, log-rank tests, and Cox multivariate models were used to compare outcomes. RESULTS: Median age at treatment was 71 years and mean tumor size was 2 cm. Thirty-two lesions were typical carcinoid histology, 7 were atypical, and 9 were indeterminate. The most common SBRT fractionation schedule was 50 to 60 Gy in 5 daily fractions. Overall survival at 3, 6, and 9 years was 64%, 43%, and 26%, respectively. Progression-free survival at 3, 6, and 9 years was 88%, 78%, and 78%, respectively. Local control at 3, 6, and 9 years was 97%, 91%, and 91%, respectively. There was 1 regional recurrence in a paraesophageal lymph node. No grade 3 or higher toxicity was identified. CONCLUSIONS: This is the largest series evaluating outcomes in patients with LNET treated with SBRT. This treatment is well tolerated, provides excellent locoregional control, and should be offered as an alternative to surgical resection for patients with early-stage LNET, particularly those who may not be ideal surgical candidates.

Improving Brain Metastases Outcomes Through Therapeutic Synergy Between Stereotactic Radiosurgery and Targeted Cancer Therapies.

Brain metastases are the most common form of brain cancer. Increasing knowledge of primary tumor biology, actionable molecular targets and continued improvements in systemic and radiotherapy regimens have helped improve survival but necessitate multidisciplinary collaboration between neurosurgical, medical and radiation oncologists. In this review, we will discuss the advances of targeted therapies to date and discuss findings of studies investigating the synergy between these therapies and stereotactic radiosurgery for non-small cell lung cancer, breast cancer, melanoma, and renal cell carcinoma brain metastases.

Clinical outcomes of non-small cell lung cancer brain metastases treated with stereotactic radiosurgery and immune checkpoint inhibitors, EGFR tyrosine kinase inhibitors, chemotherapy and immune checkpoint inhibitors, or chemotherapy alone.

OBJECTIVE: Immune checkpoint inhibitors (ICIs) and epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are commonly used in the systemic management of non-small cell lung cancer (NSCLC) brain metastases (BMs). However, optimizing control of NSCLC BM with stereotactic radiosurgery (SRS) and various systemic therapies remains an area of investigation. METHODS: Between 2016 and 2019, the authors identified 171 NSCLC BM patients with 646 BMs treated with single-fraction SRS within 3 months of receiving treatment with ICIs (n = 56; 33%), EGFR-TKI (n = 30; 18%), chemotherapy and ICIs (n = 23; 14%), or standard chemotherapy alone (n = 62; 36%). Time-to-event analysis was conducted, and outcomes included distant intracranial control (DIC), local control (LC), and overall survival from SRS. RESULTS: The median follow-up from BM diagnosis was 8.9 months (range 0.3-127 months). The 12-month Kaplan-Meier DIC rates were 37%, 53%, 41%, and 21% (p = 0.047) for the ICI, EGFR-TKI, ICI and chemotherapy, and chemotherapy-alone groups, respectively. On multivariate analysis, DIC was improved with EGFR-TKI (HR 0.4, 95% CI 0.3-0.8, p = 0.005) compared with conventional chemotherapy and treatment with SRS before systemic therapy (HR 0.5, 95% CI 0.3-0.9, p = 0.03) compared with after; and LC was improved with SRS before (HR 0.4, 95% CI 0.2-0.9, p = 0.03) or concurrently (HR 0.3, 95% CI 0.1-0.6, p = 0.003) compared with after. No differences in radionecrosis were noted by timing or type of systemic therapy. CONCLUSIONS: The authors' analysis showed significant differences in DIC based on receipt of systemic therapy and treatment with SRS before systemic therapy improved DIC. Prospective evaluation of the potential synergism between systemic therapy and SRS in NSCLC BM management is warranted.