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Purpose: Newer-generation tyrosine kinase inhibitors (TKIs) for non-small cell lung cancer (NSCLC) with epidermal growth factor receptor ( EGFR ) mutations and anaplastic lymphoma kinase ( ALK ) rearrangements have demonstrated high CNS activity. The optimal use of up-front stereotactic radiosurgery (SRS) for brain metastases (BM) in patients eligible for CNS-penetrant TKIs is controversial, and data to guide patient management are limited., Materials and Methods: Data on TKI-naïve patients with EGFR- and ALK-driven NSCLC with BM treated with CNS-penetrant TKIs with and without up-front SRS were retrospectively collected from seven academic centers in the United States. Time-to-CNS progression and overall survival (OS) were analyzed, with multivariable adjustment in Fine & Gray and Cox proportional hazards models for clinically relevant factors., Results: From 2013 to 2022, 317 patients were identified (200 TKI-only and 117 TKI + SRS). Two hundred fifty (79%) and 61 (19%) patients received osimertinib and alectinib, respectively. Patients receiving TKI + SRS were more likely to have BM ≥1 cm ( P < .001) and neurologic symptoms ( P < .001) at presentation. Median OS was similar between the TKI and TKI + SRS groups (median 41 v 40 months, respectively; P = .5). On multivariable analysis, TKI + SRS was associated with a significant improvement in time-to-CNS progression (hazard ratio [HR], 0.63 [95% CI, 0.42 to 0.96]; P = .033). Local CNS control was significantly improved with TKI + SRS (HR, 0.30 [95% CI, 0.16 to 0.55]; P < .001), whereas no significant differences were observed in distant CNS control. Subgroup analyses demonstrated a greater benefit from TKI + SRS in patients with BM ≥1 cm in diameter for time-to-CNS progression and CNS progression-free survival., Conclusion: The addition of up-front SRS to CNS-penetrant TKI improved time-to-CNS progression and local CNS control, but not OS, in patients with BM from EGFR - and ALK-driven NSCLC. Patients with larger BM (≥1 cm) may benefit the most from up-front SRS.

A single-institution prospective pilot clinical trial was performed to demonstrate the feasibility of combining [ 177 Lu]Lu-PSMA-617 radiopharmaceutical therapy (RPT) with stereotactic body radiotherapy (SBRT) for the treatment of oligometastatic castration-sensitive prostate cancer. Methods: Six patients with 9 prostate-specific membrane antigen (PSMA)-positive oligometastases received 2 cycles of [ 177 Lu]Lu-PSMA-617 RPT followed by SBRT. After the first intravenous infusion of [ 177 Lu]Lu-PSMA-617 (7.46 ± 0.15 GBq), patients underwent SPECT/CT at 3.2 ± 0.5, 23.9 ± 0.4, and 87.4 ± 12.0 h. Voxel-based dosimetry was performed with calibration factors (11.7 counts per second/MBq) and recovery coefficients derived from in-house phantom experiments. Lesions were segmented on baseline PSMA PET/CT (50% SUV max ). After a second cycle of [ 177 Lu]Lu-PSMA-617 (44 ± 3 d; 7.50 ± 0.10 GBq) and an interim PSMA PET/CT scan, SBRT (27 Gy in 3 fractions) was delivered to all PSMA-avid oligometastatic sites, followed by post-PSMA PET/CT. RPT and SBRT voxelwise dose maps were scaled (α/β = 3 Gy; repair half-time, 1.5 h) to calculate the biologically effective dose (BED). Results: All patients completed the combination therapy without complications. No grade 3+ toxicities were noted. The median of the lesion SUV max as measured on PSMA PET was 16.8 (interquartile range [IQR], 11.6) (baseline), 6.2 (IQR, 2.7) (interim), and 2.9 (IQR, 1.4) (post). PET-derived lesion volumes were 0.4-1.7 cm 3 The median lesion-absorbed dose (AD) from the first cycle of [ 177 Lu]Lu-PSMA-617 RPT (AD RPT ) was 27.7 Gy (range, 8.3-58.2 Gy; corresponding to 3.7 Gy/GBq, range, 1.1-7.7 Gy/GBq), whereas the median lesion AD from SBRT was 28.1 Gy (range, 26.7-28.8 Gy). Spearman rank correlation, ρ, was 0.90 between the baseline lesion PET SUV max and SPECT SUV max ( P = 0.005), 0.74 ( P = 0.046) between the baseline PET SUV max and the lesion AD RPT , and -0.81 ( P = 0.022) between the lesion AD RPT and the percent change in PET SUV max (baseline to interim). The median for the lesion BED from RPT and SBRT was 159 Gy (range, 124-219 Gy). ρ between the BED from RPT and SBRT and the percent change in PET SUV max (baseline to post) was -0.88 ( P = 0.007). Two cycles of [ 177 Lu]Lu-PSMA-617 RPT contributed approximately 40% to the maximum BED from RPT and SBRT. Conclusion: Lesional dosimetry in patients with oligometastatic castration-sensitive prostate cancer undergoing [ 177 Lu]Lu-PSMA-617 RPT followed by SBRT is feasible. Combined RPT and SBRT may provide an efficient method to maximize the delivery of meaningful doses to oligometastatic disease while addressing potential microscopic disease reservoirs and limiting the dose exposure to normal tissues., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)

Importance: Adjuvant stereotactic radiosurgery (SRS) enhances the local control of resected brain metastases (BrM). However, the risks of local failure (LF) and potential for posttreatment adverse radiation effects (PTRE) after early postoperative adjuvant SRS have not yet been established., Objective: To evaluate whether adjuvant SRS delivered within a median of 14 days after surgery is associated with improved LF without a concomitant increase in PTRE., Design, Setting, and Participants: This prospective cohort study examines a clinical workflow (RapidRT) that was implemented from 2019 to 2022 to deliver SRS to surgical patients within a median of 14 days, ensuring all patients were treated within 30 days postoperatively. This prospective cohort was compared with a historical cohort (StanRT) of patients with BrM resected between 2013 and 2019 to assess the association of the RapidRT workflow with LF and PTRE. The 2 cohorts were combined to identify optimal SRS timing, with a median follow-up of 3.3 years for survivors., Exposure: Timing of adjuvant SRS (14, 21, and 30 days postoperatively)., Main Outcomes and Measures: LF and PTRE, according to modified Response Assessment in Neuro-Oncology Brain Metastases criteria., Results: There were 438 patients (265 [60.5%] female patients; 23 [5.3%] Asian, 27 [6.2%] Black, and 364 [83.1%] White patients) with a mean (SD) age of 62 (13) years; 377 were in the StanRT cohort and 61 in the RapidRT cohort. LF and PTRE rates at 1 year were not significantly different between RapidRT and StanRT cohorts. Timing of SRS was associated with radiographic PTRE. Patients receiving radiation within 14 days had the highest 1-year PTRE rate (18.08%; 95% CI, 8.31%-30.86%), and patients receiving radiation between 22 and 30 days had the lowest 1-year PTRE rate (4.10%; 95% CI, 1.52%-8.73%; P = .03). LF rates were highest for patients receiving radiation more than 30 days from surgery (10.65%; 95% CI, 6.90%-15.32%) but comparable for patients receiving radiation within 14 days, between 15 and 21 days, and between 22 and 30 days (≤14 days: 5.12%; 95% CI, 0.86%-15.60%; 15 to ≤21 days: 3.21%; 95% CI, 0.59%-9.99%; 22 to ≤30 days: 6.58%; 95% CI, 3.06%-11.94%; P = .20)., Conclusions and Relevance: In this cohort study of adjuvant SRS timing following surgical resection of BrM, the optimal timing for adjuvant SRS appears to be within 22 to 30 days following surgery. The findings of this study suggest that this timing allows for a balanced approach that minimizes the risks associated with LF and PTRE.

Purpose: Timely surgical cavity stereotactic radiosurgery (SRS) is an important adjuvant to brain metastasis resection, with earlier treatment associated with less frequent recurrence. The logistical complexity of treatment organization, however, has resulted in suboptimal start times postsurgically. We implemented a process improvement approach to reduce the time from surgery to adjuvant irradiation of resected brain metastases., Methods: A multidisciplinary working group used process mapping to identify opportunities to reduce visits and shorten treatment times. The care delivery process was modified to streamline perioperative SRS preparation with (1) early patient identification, (2) preoperative intrateam communication, and (3) consolidation of required steps. Plan-Do-Study-Act cycles were used for process improvement. The surgery-to-SRS initiation time interval was the primary outcome. Secondary outcomes included the number of associated patient encounters., Results: After implementation, the median (interquartile range) interval from surgery to SRS was reduced 48% from 27 (21-34) to 14 days (13-17; P < .001). The rate of surgical cavity SRS within 30 days increased from 64% (n = 63 of 98) to 97% (n = 60 of 62; P < .001). The median (interquartile range) number of CNS-associated encounters between resection and SRS decreased from 5 (4-6) to 4 (3-5; P < .001). The proportion of patients who had > 1 magnetic resonance imaging/computed tomography between surgery and SRS decreased from 45% (44 of 98) to 13% (8 of 62; P < .001). The time from surgery to systemic therapy resumption/initiation among patients treated within 90 days postoperatively decreased from 35 (24-48) to 32 days (23-40; P = .074). There were no wound complications in either group., Conclusion: Adjuvant SRS latency and treatment-associated encounters were significantly reduced after care-coordination implementation. This approach reduces patient and health care system burden and can be applied to other scenarios where early postoperative SRS administration is critical., Competing Interests: Nelson S. MossConsulting or Advisory Role: AstraZenecaResearch Funding: GT Medical Technologies (Inst) Samantha BrownResearch Funding: AACR (Inst) Justin ChenStock and Other Ownership Interests: MindMed, Moderna Therapeutics, Tonix Pharmaceuticals, Ocugen, Ocuphire Pharma, Innerscope Hearing Technologies, Heat Biologics Brandon S. ImberHonoraria: GT Medical Technologies Luke PikeStock and Other Ownership Interests: Clovis Oncology, Schrodinger, NovavaxConsulting or Advisory Role: Blackstone, Deerfield Management, Third Rock Ventures, Aviko, Monograph Capital, Roivant, Galera Therapeutics, Dynamo Therapeutics, Myst Therapeutics, Turnstone Bio, Best Doctors Inc Katherine S. PanageasStock and Other Ownership Interests: AstraZeneca, Pfizer, Sunesis Pharmaceuticals Cameron BrennanStock and Other Ownership Interests: AVEOPatents, Royalties, Other Intellectual Property: Co-inventor on patents licensed through Memorial Sloan Kettering to Elucida Oncology Viviane TabarStock and Other Ownership Interests: BlueRock Therapeutics (I)Honoraria: BlueRock Therapeutics (I)Consulting or Advisory Role: BlueRock Therapeutics (I)Research Funding: BlueRock Therapeutics (I)Patents, Royalties, Other Intellectual Property: BlueRock Therapeutics (I)Travel, Accommodations, Expenses: BlueRock Therapeutics (I) Kathryn BealStock and Other Ownership Interests: MMT (I)No other potential conflicts of interest were reported.

Background: Salvage of recurrent previously irradiated brain metastases (rBrM) is a significant challenge. Resection without adjuvant re-irradiation is associated with a high local failure rate, while reirradiation only partially reduces failure but is associated with greater radiation necrosis risk. Salvage resection plus Cs131 brachytherapy may offer dosimetric and biologic advantages including improved local control versus observation, with reduced normal brain dose versus re-irradiation, however data are limited., Methods: A prospective registry of consecutive patients with post-stereotactic radiosurgery (SRS) rBrM undergoing resection plus implantation of collagen-matrix embedded Cs131 seeds (GammaTile, GT Medical Technologies) prescribed to 60 Gy at 5 mm from the cavity was analyzed., Results: Twenty patients underwent 24 operations with Cs131 implantation in 25 tumor cavities. Median maximum preoperative diameter was 3.0 cm (range 1.1-6.3). Gross- or near-total resection was achieved in 80% of lesions. A median of 16 Cs131 seeds (range 6-30), with a median air-kerma strength of 3.5 U/seed were implanted. There was one postoperative wound dehiscence. With median follow-up of 1.6 years for survivors, two tumors recurred (one in-field, one marginal) resulting in 8.4% 1-year progression incidence (95%CI = 0.0-19.9). Radiographic seed settling was identified in 7/25 cavities (28%) 1.9-11.7 months post-implantation, with 1 case of distant migration (4%), without clinical sequelae. There were 8 cases of radiation necrosis, of which 4 were symptomatic., Conclusions: With > 1.5 years of follow-up, intraoperative brachytherapy with commercially available Cs131 implants was associated with favorable local control and toxicity profiles. Weak correlation between preoperative tumor geometry and implanted tiles highlights a need to optimize planning criteria., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose of Review: Radiation therapy (RT) is a mainstay of treatment for brain metastases from solid tumors. Treatment of these patients is complex and should focus on minimizing symptoms, preserving functional status, and prolonging survival., Recent Findings: Whole-brain radiotherapy (WBRT) can lead to toxicity, and while it does reduce recurrence in the CNS, this has not been shown to provide a survival benefit. Recent advances focus on reducing the toxicity of WBRT or using more targeted radiation therapy. New paradigms including the use of proton RT for leptomeningeal metastases (LM) and stereotactic radiosurgery (SRS) before craniotomy hold promise in improving treatment efficacy and reducing toxicity. Omission or replacement of WBRT is often safe and the use of SRS is expanding to include patients with more lesions and preoperative RT. Proton RT holds promise for LM. Progress is being made in improving patient-centered outcomes and reducing toxicity for patients with brain metastases., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: Stereotactic biopsy is increasingly performed on brain metastases (BrMs) as improving cancer outcomes drive aggressive multimodality treatment, including laser interstitial thermal therapy (LITT). However, the tract recurrence (TR) risk is poorly defined in an era defined by focused-irradiation paradigms. As such, the authors aimed to define indications and adjuvant therapies for this procedure and evaluate the BrM-biopsy TR rate., Methods: In a single-center retrospective review, the authors identified stereotactic BrM biopsies performed from 2002 to 2020. Surgical indications, radiographic characteristics, stereotactic planning, dosimetry, pre- and postoperative CNS-directed and systemic treatments, and clinical courses were collected. Recurrence was evaluated using RANO-BM (Response Assessment in Neuro-Oncology Brain Metastases) criteria., Results: In total, 499 patients underwent stereotactic intracranial biopsy for any diagnosis, of whom 25 patients (5.0%) underwent biopsy for pathologically confirmed viable BrM, a proportion that increased over the time period studied. Twelve of the 25 BrM patients had ≥ 3 months of radiographic follow-up, of whom 6 patients (50%) developed new metastatic growth along the tract at a median of 5.0 months post-biopsy (range 2.3-17.1 months). All of the TR cases had undergone pre- or early post-biopsy stereotactic radiosurgery (SRS), and 3 had also undergone LITT at the time of initial biopsy. TRs were treated with resection, reirradiation, or observation/systemic therapy., Conclusions: In this study the authors identified a nontrivial, higher than previously described rate of BrM-biopsy tract recurrence, which often required additional surgery or radiation and justified close radiographic surveillance. As BrMs are commonly treated with SRS limited to enhancing tumor margins, consideration should be made, in cases lacking CNS-active systemic treatments, to include biopsy tracts in adjuvant radiation plans where feasible.

Background: The role of stereotactic radiosurgery (SRS) for recurrent glioblastoma and the radionecrosis risk in this setting remain unclear., Objective: To perform a large retrospective study to help inform proper indications, efficacy, and anticipated complications of SRS for recurrent glioblastoma., Methods: We retrospectively analyzed patients who underwent Gamma Knife SRS between 1991 and 2013. We used the partitioning deletion/substitution/addition algorithm to identify potential predictor covariate cut points and Kaplan-Meier and proportional hazards modeling to identify factors associated with post-SRS and postdiagnosis survival., Results: One hundred seventy-four glioblastoma patients (median age, 54.1 years) underwent SRS a median of 8.7 months after initial diagnosis. Seventy-five percent had 1 treatment target (range, 1-6), and median target volume and prescriptions were 7.0 cm 3 (range, 0.3-39.0 cm 3 ) and 16.0 Gy (range, 10-22 Gy), respectively. Median overall survival was 10.6 months after SRS and 19.1 months after diagnosis. Kaplan-Meier and multivariable modeling revealed that younger age at SRS, higher prescription dose, and longer interval between original surgery and SRS are significantly associated with improved post-SRS survival. Forty-six patients (26%) underwent salvage craniotomy after SRS, with 63% showing radionecrosis or mixed tumor/necrosis vs 35% showing purely recurrent tumor. The necrosis/mixed group had lower mean isodose prescription compared with the tumor group (16.2 vs 17.8 Gy; P = .003) and larger mean treatment volume (10.0 vs 5.4 cm 3 ; P = .009)., Conclusion: Gamma Knife may benefit a subset of focally recurrent patients, particularly those who are younger with smaller recurrences. Higher prescriptions are associated with improved post-SRS survival and do not seem to have greater risk of symptomatic treatment effect., (Copyright © 2016 by the Congress of Neurological Surgeons)