Preoperative Stereotactic Radiosurgery Research Articles

Pre-operative Stereotactic Radiosurgery for Patients with One to Four Brain Metastases: A Single-Arm Phase 2 Trial Outcome Analysis (NCT03398694)

Abstract Background Stereotactic radiosurgery (SRS) following surgical resection is the standard of care for patients with symptomatic oligo brain metastasis (BM), however, it is associated with 10-15% local failure. Targeting a resection cavity is imprecise, thus pre-operative radiosurgery where the target is well defined may be superior, however, the efficacy of pre-operative SRS has not yet been tested in a clinical trial. Methods We conducted a phase II, single-arm trial of pre-operative SRS followed by surgical resection in patients with 1-4 symptomatic oligo BMs (NCT03398694) with the primary objective of measuring 6-month local control (LC). SRS was delivered to all patients utilizing gamma knife or linear accelerator as per RTOG-9005 dosing criteria24 based on tumor diameter with the exception that the largest lesion diameter treated was 5 cm with 15 Gy with all SRS treatment given in single fraction dosing. Results The trial screened 50 patients, 48 patients were treated under the protocol and 32 patients completed the entire follow-up period. Of all the patients who completed the follow-up period, primary endpoint of 6-month LC was 100% (95% CI: 0.891-1.000; p=0.005). Secondary endpoints, presented as medians, were overall-survival (17.6 months), progression-free survival (5.3 months), distant in-brain failure (40.8% at 1 year), leptomeningeal failure (4.8% at 1 year), and radiation necrosis (7.7% at 1 year). Conclusions Our data confirms superior local control in patients who received pre-operative SRS when compared to historical controls. Further study with a larger randomized cohort of patients is warranted to fully understand the benefits of pre-operative SRS.

Preoperative stereotactic radiosurgery for cerebral metastases: safe, effective, and decreases steroid dependency.

Preoperative stereotactic radiosurgery (SRS) is emerging as a viable alternative to standard postoperative SRS. Studies have suggested that preoperative SRS provides comparable tumor control and overall survival (OS) and may reduce the incidence of leptomeningeal disease (LMD) and adverse radiation effects (AREs). It is unknown, however, if preoperative SRS remains effective in cohorts including large brain metastases (> 14 cm3) or if preoperative SRS affects steroid taper/immunotherapy. Here, the authors report the results of a phase 2 single-arm trial assessing a prospectively acquired series of 26 patients who underwent preoperative SRS, without a volumetric cutoff, compared with a propensity score-matched concurrent cohort of 30 patients who underwent postoperative SRS to address these salient questions. Demographics, oncological history, surgical details, and outcomes were collected from the medical records. Coprimary endpoints were local tumor control (LTC) and a composite outcome of LTC, ARE, and LMD. Additional outcomes were OS, steroid taper details, and immunotherapy resumption. For survival analyses, cohorts were propensity score matched. Preoperative and postoperative SRS patients were comparable in terms of age, sex, Karnofsky Performance Status score, oncological history, and operative details. Gross tumor volume (GTV) was significantly higher in the preoperative group (median 12.2 vs 5.3 cm3, p < 0.001). One-year LTC (preoperative SRS: 77.2% vs postoperative SRS: 82.5%, p = 0.61) and composite outcome (68.3% vs 72.7%, p = 0.38) were not significantly different between the groups. In multivariable analysis, preoperative SRS did not have a significant effect on LTC (HR 1.57 [95% CI 0.38-6.49], p = 0.536) or the composite outcome (HR 1.18 [95% CI 0.38-3.72], p = 0.771), although the confidence intervals were large. The median OS (preoperative SRS: 17.0 vs postoperative SRS: 14.0 months, p = 0.61) was not significantly different. Rates of LMD were nonsignificantly lower in the preoperative SRS group (3.8% vs 16.7%, p = 0.200). Greater GTV volume was associated with prolonged (> 10 days) steroid taper (OR 1.24 [95% CI 1.04-1.55], p = 0.032). However, in multivariable analysis, preoperative SRS markedly reduced the steroid taper length (OR 0.13 [95% CI 0.02-0.61], p = 0.016). Time to immunotherapy was shorter in the preoperative SRS group (36 [IQR 26, 76] vs OR 228 [IQR 129, 436] days, p = 0.02). Compared with postoperative SRS, preoperative SRS is a safe and effective strategy in the management of cerebral metastases of all sizes and provides comparable tumor control without increased adverse effects. Notably, preoperative SRS enabled rapid steroid taper, even in larger tumors. Future studies should specifically examine the interaction of preoperative SRS with steroid usage and resumption of systemic therapies and the subsequent effects on systemic progression and OS.

Phase I trial of dose escalation for preoperative stereotactic radiosurgery for patients with large brain metastases.

Single session stereotactic radiosurgery (SRS) or surgical resection alone for brain metastases larger than 2cm results in unsatisfactory local control. We conducted a phase I trial for brain metastases(>2cm) to determine the safety of preoperative SRS at escalating doses. Radiosurgery dose was escalated at 3 Gy increments for 3 cohorts based on maximum tumor dimension starting at: 18 Gy for >2-3cm, 15 Gy for >3-4cm, and 12 Gy for >4-6cm. Dose limiting toxicity (DLT) was defined as grade III or greater acute toxicity. A total of 35 patients/36 lesions were enrolled. For tumor size >2-3cm, patients were enrolled up to the second dose level (21 Gy); for >3-4cm and >4-6cm cohorts the third dose level (21 Gy and 18 Gy, respectively) was reached. There were 2 DLTs in the >3-4cm arm at 21Gy. The maximum tolerated dose (MTD) of SRS for >2-3cm was not reached; and was 18 Gy for both >3-4cm arm and >4-6cm arm. With a median follow-up of 64.0 months, the 6- and 12-month local control rates were 85.9% and 76.6%, respectively. One patient developed grade 3 radiation necrosis at 5 months. The 2-year rate of leptomeningeal disease (LMD) was 0%. Preoperative SRS with dose escalation followed by surgical resection for brain metastases greater than 2cm in size demonstrates acceptable acute toxicity. The phase II portion of the trial will be conducted at the maximum tolerated SRS doses.

Analysis of DNA and RNA Genomic Profiles from Phase-II Clinical Trial NCT03398694 Showed Distinct Transcriptomic Profile for Patients With Local Failure

INTRODUCTION: Stereotactic radiosurgery (SRS) has become a standard of care for brain metastasis (BM). In the setting of lesions needing surgical intervention, it is typically delivered to the resection cavity after surgical resection to strike a balance between adverse effect from the dose of radiation and tumor recurrence. Pre-operative SRS is now being examined because of its ability to deliver radiation to all cells before surgical disruption and dispersion with added advantage of treating larger lesions with radiation. METHODS: We designed a phase II trial for patients with up to 4 BM and at least one resectable lesion. All lesions were treated with SRS and symptomatic lesions were resected. We examined both the clinical and biological outcomes. RESULTS: We performed whole genome DNA and RNA sequencing of the center and periphery of the resected lesion from the first 35 patients. We found that SRS causes significant and biologically observable damage to the tumor. Radiation induced DNA damage is qualitatively different between center and periphery of the tumor. Functionally distinct genetic profiles exist between both center and peripheral tumor locations as well as between different primary tumor types. Center of the tumor has higher functional mutation burden while peripheral samples initiate DNA repair pathways. Peripheral samples may interact more with surrounding environment when compared to central samples. Different radiation delivery modality has differential transcriptomic profile and patients who failed locally also had a distinct transcriptomic profile. CONCLUSIONS: In conclusion, radiation dosing fall-off has differential effect on the genomic landscape of the tumor and cells from the periphery are most likely gaining DNA repair abilities and that might explain tumor recurrence. Also, Gamma knife and LINAC as different genomic signature.

Where Do Surgical Resection and Radiosurgery Fall Short for Large Metastatic Brain Lesions?

INTRODUCTION: Stereotactic radiosurgery is established as the optimal treatment modality for metastatic disease of the brain, but there is ongoing debate about the optimal treatment for larger brain metastases. There have been few studies identifying and quantifying lesion characteristics where efficacy and local control of these lesions suffer. METHODS: We retrospectively identified patients who received surgical resection and/or hypofractionated Gamma Knife radiosurgery (HF-GKRS) between 2017 and 2022 for the treatment of metastatic brain tumors greater than 10cc. Clinical, treatment, and radiological data was collected. Local failure (LF) events were examined, and independent factors associated with subsequent local failure were identified. RESULTS: 105 lesions greater than 10cc (in 97 patients) were treated and the median patient follow-up was 10.1 months. The median gross tumor volume was 15.8cc (range 10.1-62.4). Prior surgical resection was performed on 49 lesions (54%). Tumor volume larger than 33.5cc (p = 0.029, 12-month LF rate 38%) and radioresistant histology (p=0.047, 12-month LF rate 54%) were associated with increased risk of LF (p=0.018) whereas surgical resection did not correlate with increased LC (p = 0.642, 12-month LF rate 19%). CONCLUSIONS: Patients with brain metastases that are greater than 4cm in diameter or are of radioresistant histology (primary origin of gastrointestinal adenocarcinoma, melanoma, or renal cell carcinoma) are especially prone to local failure despite aggressive surgical resection, stereotactic radiosurgery, and systemic chemotherapy. In these cases, the optimal management needs to be further elucidated and may involve preoperative stereotactic radiosurgery or intraoperative brachytherapy.

Pre-operative vs. post-operative stereotactic radiosurgery for operative metastatic brain tumors: study protocol for a phase III clinical trial

Background and ObjectivesAlmost one third of cancer patients in the United States will develop brain metastases on an annual basis. Surgical resection is indicated in the setting of brain metastases for reasons, such as maximizing local control in select patients, decompression of mass effect, and/or tissue diagnosis. The current standard of care following resection of a brain metastasis has shifted from whole brain radiation therapy to post-operative stereotactic radiosurgery (SRS). However, there is a significant rate of local recurrence within one year of postoperative SRS. Emerging retrospective and prospective data suggest pre-operative SRS is a safe and potentially effective treatment paradigm for surgical brain metastases. This trial intends to determine, for patients with an indication for resection of a brain metastasis, whether there is an increase in the time to a composite endpoint of adverse outcomes; including the first occurrence of either: local recurrence, leptomeningeal disease, or symptomatic radiation brain necrosis - in patients who receive pre-operative SRS as compared to patients who receive post-operative SRS.MethodsThis randomized phase III clinical trial compares pre-operative with post-operative SRS for brain metastases. A dynamic random allocation procedure will allocate an equal number of patients to each arm: pre-operative SRS followed by surgery or surgery followed by post-operative SRS.Expected outcomesIf pre-operative SRS improves outcomes relative to post-operative SRS, this will establish pre-operative SRS as superior. If post-operative SRS proves superior to pre-operative SRS, it will remain a standard of care and halt the increasing utilization of pre-operative SRS. If there is no difference in pre- versus post-operative SRS, then pre-operative SRS may still be preferred, given patient convenience and the potential for a condensed timeline.DiscussionEmerging retrospective and prospective data have demonstrated some benefits of pre-op SRS vs. post-op SRS. This study will show whether there is an increase in the time to the composite endpoint. Additionally, the study will compare overall survival; patient-reported outcomes; morbidity; completion of planned therapies; time to systemic therapy; time to regional progression; time to CNS progression; time to subsequent treatment; rate of radiation necrosis; rate of local recurrence; and rate of leptomeningeal disease.Trial registration numberNCT03750227 (Registration date: 21/11/2018).

CTNI-09. DOSE ESCALATION FOR NEOADJUVANT STEREOTACTIC RADIOSURGERY FOR LARGE BRAIN METASTASES: PHASE I RESULTS

Abstract BACKGROUND Surgical resection may be required for large and symptomatic brain metastases. Adjuvant radiotherapy or stereotactic radiosurgery (SRS) is needed to reduce local recurrence. Adjuvant radiosurgery has been associated with higher rates of leptomeningeal failure and radionecrosis. We conducted a phase I trial for brain metastases greater than 2 cm in size to determine the safety of preoperative SRS at escalating doses. METHODS Radiosurgery dose was escalated at 3 Gy increments starting with RTOG 90-05 dosing for 3 cohorts based on maximum tumor diameter: 18 Gy for &amp;gt;2-3 cm, 15 Gy for &amp;gt;3-4 cm, and 12 Gy &amp;gt;4-6 cm. Dose limiting toxicity (DLT) was defined as grade III or greater acute toxicity. Patients underwent surgical resection within 2 weeks and were followed with imaging and physical evaluations every 3 months. RESULTS For tumor size &amp;gt;2-3 cm, patients were enrolled up to the second dose level (21 Gy); for &amp;gt;3-4 cm and &amp;gt;4-6 cm cohorts the third dose level (21 Gy and 18 Gy, respectively) was reached. 35 patients were enrolled with 36 brain metastases treated with preoperative radiosurgery. There were 2 DLT (wound issues) in the &amp;gt;3-4 cm arm at the third dose level and 1 DLT (hemorrhage) in the &amp;gt;4-6 cm arm at the third dose level. The maximal tolerated SRS dose (MTD) for &amp;gt;-2-3 cm arm was not reached, for &amp;gt;3-4 cm arm was 18 Gy and for &amp;gt;4-6 cm arm was 18 Gy. With a median follow-up of 64 months, the 6- and 12-month local control rates were 88.8% and 79.1%, respectively. The 2-year rate of LMD was 0%. CONCLUSION This Phase I preoperative SRS dose escalation trial found a MTD for brain metastases greater than 3 and up to 6 cm in size. The phase II trial will be conducted at the maximum tolerated SRS doses.

Symptomatic radionecrosis after postoperative but not preoperative stereotactic radiosurgery in a single patient: illustrative case.

Standard of care for brain metastases involves stereotactic radiosurgery (SRS). For cases that also require surgery because of lesion size, edema, or neurological symptoms, whether to provide pre- or postoperative SRS has become a prevalent debate. Herein, the unique case of a patient with brain metastases of the same pathology and similar size in two different brain locations at two different times is described. The patient underwent surgery with preoperative SRS for the first lesion and surgery with postoperative SRS for the second lesion. Although both treatments resulted in successful local control, the location that received postoperative SRS developed symptomatic and rapidly progressive radiation necrosis (RN) requiring a third craniotomy. Large randomized controlled trials are ongoing to compare pre- versus postoperative SRS for the treatment of symptomatic brain metastases (e.g., study NRG-BN012). Recent interest in preoperative SRS has emerged from its theoretical potential to decrease rates of postoperative RN and leptomeningeal disease. This valuable case in which both therapies were applied in a single patient with a single pathology and similar lesions provides evidence supportive of preoperative SRS.

Preoperative stereotactic radiosurgery as neoadjuvant therapy for resectable brain tumors.

Stereotactic radiosurgery (SRS) is a method of delivering conformal radiation, which allows minimal radiation damage to surrounding healthy tissues. Adjuvant radiation therapy has been shown to improve local control in a variety of intracranial neoplasms, such as brain metastases, gliomas, and benign tumors (i.e., meningioma, vestibular schwannoma, etc.). For brain metastases, adjuvant SRS specifically has demonstrated positive oncologic outcomes as well as preserving cognitive function when compared to conventional whole brain radiation therapy. However, as compared with neoadjuvant SRS, larger post-operative volumes and greater target volume uncertainty may come with an increased risk of local failure and treatment-related complications, such as radiation necrosis. In addition to its role in brain metastases, neoadjuvant SRS for high grade gliomas may enable dose escalation and increase immunogenic effects and serve a purpose in benign tumors for which one cannot achieve a gross total resection (GTR). Finally, although neoadjuvant SRS has historically been delivered with photon therapy, there are high LET radiation modalities such as carbon-ion therapy which may allow radiation damage to tissue and should be further studied if done in the neoadjuvant setting. In this review we discuss the evolving role of neoadjuvant radiosurgery in the treatment for brain metastases, gliomas, and benign etiologies. We also offer perspective on the evolving role of high LET radiation such as carbon-ion therapy. PubMed was systemically reviewed using the search terms "neoadjuvant radiosurgery", "brain metastasis", and "glioma". ' Clinicaltrials.gov ' was also reviewed to include ongoing phase III trials. This comprehensive review describes the evolving role for neoadjuvant SRS in the treatment for brain metastases, gliomas, and benign etiologies. We also discuss the potential role for high LET radiation in this setting such as carbon-ion radiotherapy. Early clinical data is very promising for neoadjuvant SRS in the setting of brain metastases. There are three ongoing phase III trials that will be more definitive in evaluating the potential benefits. While there is less data available for neoadjuvant SRS for gliomas, there remains a potential role, particularly to enable dose escalation and increase immunogenic effects.

MD Anderson Phase III Randomized Preoperative Stereotactic Radiosurgery (SRS) vs. Postoperative SRS for Brain Metastases Trial

Postoperative stereotactic radiation therapy/radiosurgery (SRT/SRS) is being evaluated in comparison to Preoperative SRT for brain metastases (mets) in a limited number of prospective clinical trials. Our objective is to address the significant knowledge gap concerning the logistics of preoperative SRT in comparison to postoperative SRT in a randomized controlled study. Patients with brain mets with at least 1 surgically operable met were randomized (1:1) to Preop vs Postop SRT. In this abstract, we present non-primary endpoint data on the trial concept and logistics of treatment for this data safety monitoring board reviewed study. Patients enrolled had 1-2 lesions resected and <15 lesions treated at time of SRT to best reflect the standard population that receive SRT and surgery at our institution. From 12/2018 to 12/2022, 99 patients with 1-2 operable brain mets were enrolled and randomized to Preop (n = 49) or Postop (n = 50) SRT. Males represented 56% of the cohort compared to females, and <25% were age 18-49 years, while 27%, 29, and 19% respectively were 50-59, 60-69, and > = 70. The most frequent histologies enrolled were lung (29%), renal cell (15%), melanoma (14%), and breast (11%) cancers. The majority of patients (83%) had 1-4 brain mets on their baseline MRI and 91% subsequently had a single lesion resected. Seventy-nine patients completed both SRT and surgery, while 9% received no therapy due to drop out before study therapy initiation. Among patients receiving both therapies in the combined cohort, 68% received a non-invasive stereotactic radiosurgery instrument to the randomized cavity lesion compared to 32% receiving LINAC based SRT. Treatment of the lesion or cavity with single fraction SRT was 51% in the Preop arm vs 31% in the Postop arm. Multi-fraction (3-5 SRT) was 67% in the Postop cohort in contrast to 47% in the Preop cohort. Time from randomization to RT was 5.6 days and 33.7 days in the Preop and Postop cohorts respectively, and for surgery was 10.2 days vs 12.9 days in the Postop vs Preop cohorts. The average time from RT to surgery was 7.3 days in the Preop arm and 23.5 days in the Postop arm (to allow for incisional healing time). In one of the early initiated randomized prospective cohorts of Preop vs Postop SRT, we demonstrated logistical feasibility with an efficient clinical trial workflow for study treatment. Differences in Preop vs Postop logistics reflect clinical practice differences in time-to-treatment. Therapy with various modalities reflected real-world practice and possibly provider preferences in technique when addressing the nature of delineating cavities and changes in cavity volume with regard to fractionation. Independent of the primary outcomes, our data provides insights in the practical management of patients receiving these two modalities of therapy, and further data at the completion of trial will address relevant primary outcomes.

Results of a Phase I Trial of Dose Escalation for Preoperative Stereotactic Radiosurgery for Patients with Large Brain Metastases

Single session stereotactic radiosurgery (SRS) alone for brain metastases larger than 2 cm in diameter results in unsatisfactory local control. Surgical resection alone also produces unreliable local control and perioperative radiation is required. We conducted a prospective phase I trial (NCT01891318) for brain metastases greater than 2 cm to determine the safety of preoperative SRS at escalating doses followed by surgical resection. Radiosurgery dose started at RTOG 9005 dose levels for the 3 cohorts based on maximum tumor diameter of the index lesion: 18 Gy for >2-3 cm, 15 Gy for >3-4 cm, and 12 Gy >4-6 cm. Concurrent SRS alone to other smaller lesions was allowed using standard RTOG dose. Dose limiting toxicity (DLT) was defined as grade 3 or greater acute toxicity within 3 to 4 months after SRS. Patients underwent surgical resection within 2 weeks and were followed with imaging and neurological evaluations every 3 months. A total of 35 patients were enrolled into the trial (see Table 1 below). The median age was 63, and median interval between SRS and surgery was 2 days. The most common histology was non-small cell lung cancer (57.1%), followed by breast cancer (14.3%). For tumor size >2-3 cm, patients were enrolled up to the 2nd dose level (21 Gy); for >3-4 cm and >4-6 cm cohorts the 3rd dose level (21 Gy and 18 Gy, respectively) was reached. There was a total of 3 DLTs: 2 in the >3-4 cm cohort and 1 in the >4-6 cm cohort (Table 1). The maximum tolerable dose (MTD) was 18 Gy (2nd dose level) for >3-4 cm, and 18 Gy (3rd dose level) for >4-6 cm. With a median follow-up of 64 months, the 6- and 12-month local control rates were 88.8% and 79.1%, respectively. The 6- and 12-month distant brain control was 63.1% and 55.3%, respectively. Overall survival at 6 and 12 months was 82.9% and 59.0%. The rate of leptomeningeal disease (LMD) at 2 years was 0%. Preoperative SRS with dose escalation followed by surgical resection for brain metastases greater than 2 cm in size results in local control comparable to postoperative SRS or whole-brain radiation therapy and demonstrates acceptable acute toxicity. The Phase II portion of the trial will be conducted at the maximum tolerated SRS doses.

Single-Fraction Pre-Operative Stereotactic Radiosurgery for Early-Stage Breast Cancer: Pathological Findings

to assess pathological results after single-fraction pre-operative stereotactic radiosurgery of early-stage breast cancer. A phase 2 clinical trial to investigate the feasibility of pre-operative radiosurgery for early-stage breast cancer was conducted. Eligible patients are women older than 50 years, with histologically proven breast invasive ductal carcinoma, hormonal receptors positive/human epidermal grow factor receptor 2 negative, any grade, tumor size < 3cm, unifocal, with no nodal involvement, and suitable for breast conservative surgery. An expert radiologist injected ultrasound-guided a fiducial marker to precisely identify tumor positioning. The Planning Target Volume (PTV) is created by adding a 3mm margin to the Gross Tumor Volume (GTV). A single fraction of 30-33 Gy is delivered to 95% of PTV. Patients had a breast MRI scan 6-12 weeks after treatment to evaluate the rate of radiological response. Surgery was performed at 9 to 16 weeks after irradiation. From January 2022 to December 2022, 33 patients underwent single-fraction radiosurgery, of whom 29 had breast conserving surgery (BCS). BCS was performed at 9-10 weeks for the first 14 patients, at 14-16 weeks for 13 patients, and at 18-19 weeks for 2 patients. The pathological response was defined as complete response (pCR) if no residual tumor cells were found, partial response (pPR), or no response. The pPR were also subdivided into 3 subgroups according to the rate of residual disease: < 10%, 10-50%, and > 50%. Two patients (7%) achieved pCR, both treated with 33 Gy and operated at 14 weeks. Twenty-five patients (86%) had pPR, of which 7 patients (24%) had residual disease < 10%, 9 patients (31%) between 10-50% and 9 patients (31%) over 50%. Two patients (7%) had no pathological response. All patients had sentinel lymph node biopsy at the time of surgery. Positive micrometastatic nodal involvement was found in 3 patients (11%), of which 2 patients (7%) had macrometastases (pN1a) and received subsequent axillary lymph node dissection. All patients had negative surgical margins. Not any acute and sub-acute surgical complications were observed. Single-fraction pre-operative stereotactic radiosurgery for early-stage breast cancer leads to a high rate of complete or partial pathological response with surgery performed at 2-4 months following irradiation.

P11.74.A EXPERIENCE OF PREOPERATIVE GAMMA KNIFE RADIOSURGERY FOR RECURRENT BRAIN METASTASES

Abstract BACKGROUND Resection of brain metastases (BM) without additional radiation therapy yields a high local failure rate. Surgical resection of newly diagnosed BM combined with post-operative stereotactic radiosurgery (SRS) to reduce the risk of a local recurrence is an accepted and effective treatment option. Drawbacks of postoperative SRS include uncertainty in target delineation, potential delay in the administration of SRS and intraoperative risk of tumor spillage. Preoperative SRS might address these potential drawbacks. We present our experience with preoperative Gamma Knife radiosurgery (GKRS) for recurrent BM. MATERIAL AND METHODS Data of patients with recurrent BM treated with GKRS followed by surgical resection between June 2019 and June 2021 at the Elisabeth-TweeSteden Hospital Tilburg were retrospectively collected. Surgery was necessary according to the multidisciplinary team because of mass effect, a symptomatic lesion or a large tumor volume not eligible for salvage stereotactic radiosurgery. Pre-operative SRS was performed with GKRS followed by surgery within 24 hours. All patients had follow-up appointments with MRI scan as long as clinical meaningful. In case of new intracranial disease new treatment was offered if appropriate. Descriptive analyses were used to give an overview of the patient characteristics. Kaplan-Meier curves were used to analyze overall survival. RESULTS 25 patients (male 8, female 17; median age 64 years (range 20-79 years)) underwent preoperative GKRS for recurrent brain metastases. Most patients were previously treated with GKRS (76%) or SRS (24%). Most patients had non-small cell lung cancer (44%), followed by breast (12%), small cell lung cancer (12%), and melanoma (12%). The median overall survival was 18.5 months (95% CI, 4.9 to 32.1 months). Eight patients (32%) had (multiple) surgical complications, three of these patients died due to the postoperative complications. Twelve patients (48%) developed a local recurrence. The median time to local recurrence was 6.9 months (95% CI, 4.7 to 9.1months). Of the 16 patients with a subtotal resection, 10 patients developed a local recurrence, with 6 recurrences at the site of the macroscopic residual tumor. Two patients (8%) developed leptomeningeal disease at 2.8 months and 3.9 months. Two patients (8%) developed new brain metastases (distant failure) at 5.4 months and 23.8 months. CONCLUSION Pre-operative radiosurgery was well tolerated in a group of patients with recurrent BM who were eligible for surgery. Larger series are needed to perform multivariate analyses on predictors of local recurrence in order to evaluate for which patients this treatment option is best suited.

Single-Fraction Versus Fractionated Preoperative Radiosurgery for Resected Brain Metastases: A PROPS-BM International Multicenter Cohort Study

Preoperative stereotactic radiosurgery (SRS) is a feasible alternative to postoperative SRS for resected brain metastases (BM). Most reported studies of preoperative SRS used single-fraction SRS (SF-SRS). The goal of this study was to compare outcomes and toxicity of preoperative SF-SRS with multifraction (3-5 fractions) SRS (MF-SRS) in a large international multicenter cohort (Preoperative Radiosurgery for Brain Metastases-PROPS-BM). Patients with BM from solid cancers, of which at least 1 lesion was treated with preoperative SRS followed by planned resection, were included from 8 institutions. SRS to synchronous intact BM was allowed. Exclusion criteria included prior or planned whole brain radiation therapy. Intracranial outcomes were estimated using cumulative incidence with competing risk of death. Propensity score matched (PSM) analyses were performed. The study cohort included 404 patients with 416 resected index lesions, of which SF-SRS and MF-SRS were used for 317 (78.5%) and 87 patients (21.5%), respectively. Median dose was 15 Gy in 1 fraction for SF-SRS and 24 Gy in 3 fractions for MF-SRS. Univariable analysis demonstrated that SF-SRS was associated with higher cavity local recurrence (LR) compared with MF-SRS (2-year: 16.3% vs 2.9%; P=.004), which was also demonstrated in multivariable analysis. PSM yielded 81 matched pairs (n=162). PSM analysis also demonstrated significantly higher rate of cavity LR with SF-SRS (2-year: 19.8% vs 3.3%; P=.003). There was no difference in adverse radiation effect, meningeal disease, or overall survival between cohorts in either analysis. Preoperative MF-SRS was associated with significantly reduced risk of cavity LR in both the unmatched and PSM analyses. There was no difference in adverse radiation effect, meningeal disease, or overall survival based on fractionation. MF-SRS may be a preferred option for neoadjuvant radiation therapy of resected BMs. Additional confirmatory studies are needed. A phase 3 randomized trial of single-fraction preoperative versus postoperative SRS (NRG-BN012) is ongoing (NCT05438212).

BSBM-15 SYSTEMIC AND LOCAL IMMUNE RESPONSES FOLLOWING STEREOTACTIC RADIOSURGERY TO BRAIN METASTASES FROM HER2-AMPLIFIED BREAST CANCER

Abstract BACKGROUND Brain metastases (BMs) afflict 30-50% of HER2-amplified breast cancer (HER2-BC) patients. Stereotactic radiosurgery (SRS) is a highly effective focal treatment for BMs. Extracranial radiotherapy can promote anti-tumor immune responses that synergize with immunotherapy, but whether this applies to the brain microenvironment remains unclear. Here, we examined blood and BM samples from HER2-BC patients in the TROG 16.02 translational sub-study for immunological effects of SRS (ACTRN12616001265460). METHODS Blood samples from 10 patients taken pre- and 7-14 days post-SRS to intact HER2-BC BMs or post-resection BM cavities were analyzed by mass and flow cytometry for immune cell and cytokine modulation. One patient received pre-operative SRS for a BM that recurred 6 months after resection, followed by re-resection of the BM 7 days post-SRS. Tumors from pre- and post-SRS timepoints in this patient were analyzed by bulk RNAseq and immunohistochemistry. RESULTS Monocytes, CD8+ T effector memory and regulatory T cells were enriched in blood post-SRS, while conventional dendritic cells, CD4+ T early and CD4+ TEMRA cells were diminished. Stem cell factor (SCF) concentration, a growth factor important for monocyte production, was elevated in plasma post-SRS. In the tumor, SRS upregulated gene signatures for monocyte/macrophage processes (including SCF gene transcript levels), antigen presentation, and T cell activation. Cell type deconvolution from RNAseq suggested an SRS-induced loss of metastatic tumor cells and enrichment of macrophages and CD4+ T cells. Immunohistochemistry corroborated the influx of CD68+ macrophages and CD3+ T cells into tumor and brain regions post-SRS, with spatial co-localization evident between the cell types. Furthermore, the pre-SRS immune-excluded phenotype in tumor regions was no longer observed post-SRS. CONCLUSION Systemic and local immunological changes in this homogenous patient cohort receiving SRS to HER2-BC BMs suggest a radiation-induced adaptive immune response intracranially, involving the monocyte-macrophage lineage as antigen presenting cells, that should be further explored.

Comparison of preoperative versus postoperative treatment dosimetry plans of single-fraction stereotactic radiosurgery for surgically resected brain metastases.

Stereotactic radiosurgery (SRS) for operative brain metastasis (BrM) is usually administered 1 to 6 weeks after resection. Preoperative versus postoperative timing of SRS delivery related to surgery remains a critical question, as a pattern of failure is the development of leptomeningeal disease (LMD) in as many as 35% of patients who undergo postoperative SRS or the occurrence of radiation necrosis. As they await level I clinical data from ongoing trials, the authors aimed to bridge the gap by comparing postoperative with simulated preoperative single-fraction SRS dosimetry plans for patients with surgically resected BrM. The authors queried their institutional database to retrospectively identify patients who underwent postoperative Gamma Knife SRS (GKSRS) after resection of BrM between January 2014 and January 2021. Exclusion criteria were prior radiation delivered to the lesion, age < 18 years, and prior diagnosis of LMD. Once identified, a simulated preoperative SRS plan was designed to treat the unresected BrM and compared with the standard postoperative treatment delivered to the resection cavity per Radiation Therapy Oncology Group (RTOG) 90-05 guidelines. Numerous comparisons between preoperative and postoperative GKSRS treatment parameters were then made using paired statistical analyses. The authors' cohort included 45 patients with a median age of 59 years who were treated with GKSRS after resection of a BrM. Primary cancer origins included colorectal cancer (27%), non-small cell lung cancer (22%), breast cancer (11%), melanoma (11%), and others (29%). The mean tumor and cavity volumes were 15.06 cm3 and 12.61 cm3, respectively. In a paired comparison, there was no significant difference in the planned treatment volumes between the two groups. When the authors compared the volume of surrounding brain that received 12 Gy or more (V12Gy), an important predictor of radiation necrosis, 64% of patient plans in the postoperative SRS group (29/45, p = 0.008) recorded greater V12 volumes. Preoperative plans were more conformal (p < 0.001) and exhibited sharper dose drop-off at the lesion margins (p = 0.0018) when compared with postoperative plans. Comparison of simulated preoperative and delivered postoperative SRS plans administered to the BrM or resection cavity suggested that preoperative SRS allows for more highly conformal lesional coverage and sharper dose drop-off compared with postoperative plans. Furthermore, V12Gy was lower in the presurgical GKSRS plans, which may account for the decreased incidence of radiation necrosis seen in prior retrospective studies.

Risk Factors for Progression and Toxic Effects After Preoperative Stereotactic Radiosurgery for Patients With Resected Brain Metastases

Preoperative stereotactic radiosurgery (SRS) has been demonstrated as a feasible alternative to postoperative SRS for resectable brain metastases (BMs) with potential benefits in adverse radiation effects (AREs) and meningeal disease (MD). However, mature large-cohort multicenter data are lacking. To evaluate preoperative SRS outcomes and prognostic factors from a large international multicenter cohort (Preoperative Radiosurgery for Brain Metastases-PROPS-BM). This multicenter cohort study included patients with BMs from solid cancers, of which at least 1 lesion received preoperative SRS and a planned resection, from 8 institutions. Radiosurgery to synchronous intact BMs was allowed. Exclusion criteria included prior or planned whole-brain radiotherapy and no cranial imaging follow-up. Patients were treated between 2005 and 2021, with most treated between 2017 and 2021. Preoperative SRS to a median dose to 15 Gy in 1 fraction or 24 Gy in 3 fractions delivered at a median (IQR) of 2 (1-4) days before resection. The primary end points were cavity local recurrence (LR), MD, ARE, overall survival (OS), and multivariable analysis of prognostic factors associated with these outcomes. The study cohort included 404 patients (214 women [53%]; median [IQR] age, 60.6 [54.0-69.6] years) with 416 resected index lesions. The 2-year cavity LR rate was 13.7%. Systemic disease status, extent of resection, SRS fractionation, type of surgery (piecemeal vs en bloc), and primary tumor type were associated with cavity LR risk. The 2-year MD rate was 5.8%, with extent of resection, primary tumor type, and posterior fossa location being associated with MD risk. The 2-year any-grade ARE rate was 7.4%, with target margin expansion greater than 1 mm and melanoma primary being associated with ARE risk. Median OS was 17.2 months (95% CI, 14.1-21.3 months), with systemic disease status, extent of resection, and primary tumor type being the strongest prognostic factors associated with OS. In this cohort study, the rates of cavity LR, ARE, and MD after preoperative SRS were found to be notably low. Several tumor and treatment factors were identified that are associated with risk of cavity LR, ARE, MD, and OS after treatment with preoperative SRS. A phase 3 randomized clinical trial of preoperative vs postoperative SRS (NRG BN012) has began enrolling (NCT05438212).

The Emerging Paradigm of Preoperative Stereotactic Radiosurgery for Resectable Brain Metastases

The Emerging Paradigm of Preoperative Stereotactic Radiosurgery for Resectable Brain Metastases

OC-0441 Pre-operative stereotactic radiosurgery for brain metastases: a prospective observational study

OC-0441 Pre-operative stereotactic radiosurgery for brain metastases: a prospective observational study

A phase III, multicenter, randomized controlled trial of preoperative versus postoperative stereotactic radiosurgery for patients with surgically resectable brain metastases

BackgroundPostoperative stereotactic radiosurgery (SRS) is a standard management option for patients with resected brain metastases. Preoperative SRS may have certain advantages compared to postoperative SRS, including less uncertainty in delineation of the intact tumor compared to the postoperative resection cavity, reduced rate of leptomeningeal dissemination postoperatively, and a lower risk of radiation necrosis. The recently published ASCO-SNO-ASTRO consensus statement provides no recommendation for the preferred sequencing of radiotherapy and surgery for patients receiving both treatments for their brain metastases.MethodsThis multicenter, randomized controlled trial aims to recruit 88 patients with resectable brain metastases over an estimated three-year period. Patients with ten or fewer brain metastases with at least one resectable, fulfilling inclusion criteria will be randomized to postoperative SRS (standard arm) or preoperative SRS (investigational arm) in a 1:1 ratio. Randomization will be stratified by age (< 60 versus ≥60 years), histology (melanoma/renal cell carcinoma/sarcoma versus other), and number of metastases (one versus 2–10). In the standard arm, postoperative SRS will be delivered within 3 weeks of surgery, and all unresected metastases will receive primary SRS. In the investigational arm, enrolled patients will receive SRS of all brain metastases followed by surgery of resectable metastases within one week of SRS. In either arm, single fraction or hypofractionated SRS in three or five fractions is permitted. The primary endpoint is to assess local control at 12 months in both arms. Secondary endpoints include local control at other time points, regional/distant brain recurrence rates, leptomeningeal recurrence rates, overall survival, neurocognitive outcomes, and adverse radiation events including radiation necrosis rates in both arms.DiscussionThis trial addresses the unanswered question of the optimal sequencing of surgery and SRS in the management of patients with resectable brain metastases. No randomized data comparing preoperative and postoperative SRS for patients with brain metastases has been published to date.Trial registrationClinicaltrials.gov, NCT04474925; registered on July 17, 2020. Protocol version 1.0 (January 31, 2020). Sponsor: Alberta Health Services, Edmonton, Canada (Samir Patel, MD).