Therapy, Safety, and Logistics of Preoperative vs Postoperative Stereotactic Radiation Therapy: A Preliminary Analysis of a Randomized Clinical Trial

Debra Nana Yeboa; Jing Li; Ruitao Lin; Sujit S Prabhu; Thomas H Beckham; Kristina Woodhouse; Todd Allen Swanson; Jeffrey S Weinberg; Xuemei Wang; Xiaohan Chi; Chinenye Lynette Ejezie; Dima Suki; Chenyang Wang; Chibawanye Ene; Ian E McCutcheon; Susan McGovern; Mary Frances McAleer; Martin Tom; Amol Ghia; Subha Perni; Wen Jiang; Brian De; Caroline Chung; Betty Y S Kim; Barbara J O’Brien; Jason T Huse; Jeffrey S Wefel; Laurence Court; Hussein Tawbi; Filip Janku; Nandita Guha-Thakurta; J Matthew Debnam; Jason Johnson; Ceylan Altintas Taslicay; Christopher Alvarez-Breckenridge; Shaan M Raza; Amy B Heimberger; Franco DeMonte; Robert North; Tina M Briere; John F de Groot; Raymond Sawaya; David Grosshans; Frederick F Lang; Ganesh Rao; Sherise D Ferguson

doi:10.1001/jamaoncol.2025.1770

. 2025 Jun 18;11(8):890–899. doi: 10.1001/jamaoncol.2025.1770

Therapy, Safety, and Logistics of Preoperative vs Postoperative Stereotactic Radiation Therapy

A Preliminary Analysis of a Randomized Clinical Trial

Debra Nana Yeboa ^1,^✉, Jing Li ¹, Ruitao Lin ¹, Sujit S Prabhu ¹, Thomas H Beckham ¹, Kristina Woodhouse ², Todd Allen Swanson ¹, Jeffrey S Weinberg ¹, Xuemei Wang ¹, Xiaohan Chi ¹, Chinenye Lynette Ejezie ³, Dima Suki ¹, Chenyang Wang ¹, Chibawanye Ene ¹, Ian E McCutcheon ¹, Susan McGovern ¹, Mary Frances McAleer ¹, Martin Tom ¹, Amol Ghia ¹, Subha Perni ¹, Wen Jiang ¹, Brian De ¹, Caroline Chung ¹, Betty Y S Kim ¹, Barbara J O’Brien ¹, Jason T Huse ¹, Jeffrey S Wefel ¹, Laurence Court ¹, Hussein Tawbi ¹, Filip Janku ⁴, Nandita Guha-Thakurta ¹, J Matthew Debnam ¹, Jason Johnson ⁵, Ceylan Altintas Taslicay ¹, Christopher Alvarez-Breckenridge ¹, Shaan M Raza ¹, Amy B Heimberger ⁶, Franco DeMonte ¹, Robert North ¹, Tina M Briere ¹, John F de Groot ⁷, Raymond Sawaya ⁸, David Grosshans ¹, Frederick F Lang ¹, Ganesh Rao ⁹, Sherise D Ferguson ¹

¹University of Texas MD Anderson Cancer Center, Houston

²Merck & Co, Upper Gywnedd, Pennsylvania

³Towson University, Towson, Maryland

⁴Monte Rosa Therapeutics, Boston, Massachusetts

⁵Yale School of Medicine, New Haven, Connecticut

⁶Northwestern University, Evanston, Illinois

⁷University of California, San Francisco

⁸American University of Beirut, Beirut, Lebanon

⁹Baylor College of Medicine, Houston, Texas

Accepted for Publication: April 21, 2025.

Published Online: June 18, 2025. doi:10.1001/jamaoncol.2025.1770

^✉

Corresponding Author: Debra Nana Yeboa, MD, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 97, Houston, TX 77030 (dnyeboa@mdanderson.org).

Author Contributions: Dr Yeboa had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Yeboa, Li, Lin, Swanson, C. Wang, Ghia, O'Brien, Wefel, Court, Tawbi, Janku, Johnson, Heimberger, Grosshans, Lang, Rao, Ferguson.

Acquisition, analysis, or interpretation of data: Yeboa, Li, Lin, Prabhu, Beckham, Woodhouse, Swanson, Weinberg, X. Wang, Chi, Ejezie, Suki, Ene, McCutcheon, McGovern, McAleer, Tom, Perni, Jiang, De, Chung, Kim, O'Brien, Huse, Wefel, Guha-Thakurta, Debnam, Johnson, Altintas Taslicay, Alvarez-Breckenridge, Raza, Heimberger, DeMonte, North, Briere, de Groot, Sawaya, Rao, Ferguson.

Drafting of the manuscript: Yeboa, Lin, Kim, Tawbi, Johnson, Altintas Taslicay, Grosshans, Ferguson.

Critical review of the manuscript for important intellectual content: Yeboa, Li, Lin, Prabhu, Beckham, Woodhouse, Swanson, Weinberg, X. Wang, Chi, Ejezie, Suki, C. Wang, Ene, McCutcheon, McGovern, McAleer, Tom, Ghia, Perni, Jiang, De, Chung, Kim, O'Brien, Huse, Wefel, Court, Janku, Guha-Thakurta, Debnam, Johnson, Alvarez-Breckenridge, Raza, Heimberger, DeMonte, North, Briere, de Groot, Sawaya, Grosshans, Lang, Rao, Ferguson.

Statistical analysis: Yeboa, Lin, X. Wang, Chi, Ejezie, Tawbi, Ferguson.

Obtained funding: Yeboa, Wefel, Grosshans, Lang, Rao.

Administrative, technical, or material support: Li, Swanson, Weinberg, Ejezie, Suki, Ene, McCutcheon, McGovern, Kim, Huse, Wefel, Court, Janku, Guha-Thakurta, Debnam, Johnson, Alvarez-Breckenridge, Raza, Heimberger, North, Grosshans, Lang.

Supervision: Yeboa, Li, Lin, Woodhouse, Ghia, Kim, Huse, Wefel, Guha-Thakurta, Johnson, Raza, de Groot, Grosshans, Lang, Rao, Ferguson.

Conflict of Interest Disclosures: Dr Yeboa reported institutional grants from Robert Wood Johnson Foundation, Brockman Foundation, and MD Anderson Cancer Center during the conduct of the study as well as institutional grants from MD Anderson Cancer Center and Novartis outside the submitted work. Dr Lin reported personal fees from Eli Lilly and Merck Sharp & Dohme outside the submitted work. Dr Suki reported grants from Brockman Foundation during the conduct of the study. Dr C. Wang reported grants from Elekta outside the submitted work. Dr McGovern reported serving on the advisory board for Chimerix outside the submitted work. Dr O’Brien reported serving on the data safety monitoring board for Plus Therapeutics outside the submitted work. Dr Wefel reported grants from MD Anderson Cancer Center and Brockman Foundation during the conduct of the study; grants from GT Medical Technologies and Novocure; and personal fees from Astellas, Bayer, and Intra-Cellular Therapies outside the submitted work. Dr Court reported grants from Varian Medical Systems outside the submitted work. Dr Tawbi reported grants from Dragonfly Therapeutics, Eisai, Genentech, GlaxoSmithKline, Merck, Novartis, Regeneron, and Syntrix as well as personal fees from Bristol Myers Squibb, Corcept Therapeutics, Eisai, IO Biotech, Immunocore, Iovance, Krystal Biotech, Medicenna, Merck, Novartis, Pfizer, Regeneron, Strand Therapeutics, and T-Knife Therapeutics outside the submitted work. Dr Janku reported owning stock or stock options in Monte Rosa Therapeutics outside the submitted work. Dr Debnam reported royalties from Springer Nature outside the submitted work. Dr North reported research support from Stryker Corporation outside the submitted work. Dr Lang reported grants from Brockman Foundation during the conduct of the study. No other disclosures were reported.

Funding/Support: Supported in part by an institutional research grant by the University of Texas MD Anderson Cancer Center, Brockman Foundation, and a Robert Wood Johnson Foundation Harold Amos Grant.

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Data Sharing Statement: See Supplement 3.

Additional Contributions: We acknowledge the following individuals for current or prior contributions: Juanita Hicks, RN (research nurse at MD Anderson Cancer Center, Houston, Texas); Laura Valencia, BS (research data coordinator at MD Anderson Cancer Center); Swapnil Khose, MD (graduate student assisting with prior data collection at UTHealth Houston, Houston, Texas); and Kayode Ahmed, MD (program manager assisting with figure formatting at MD Anderson Cancer Center). None of the contributors were compensated for their work outside normal salary.

^✉

Corresponding author.

PMCID: PMC12177721 PMID: 40531511

Key Points

Question

What is the comparative clinical feasibility and safety of preoperative stereotactic radiation therapy (SRT) in a cohort of patients with surgically resectable brain metastases?

Finding

In this randomized clinical trial reporting on the initial 103 patients with resectable brain metastases, preoperative SRT was not associated with increased neurological complications, and the time between surgery and radiation therapy was shorter in patients randomized to preoperative SRT, highlighting its safety and feasibility.

Meaning

Preoperative SRT was safe and logistically feasible with the potential benefit of expediting treatment.

This randomized clinical trial evaluates preoperative stereotactic radiation therapy logistics and safety profile compared with postoperative stereotactic radiation therapy in patients with brain metastases.

Abstract

Importance

Preoperative stereotactic radiation therapy (SRT) vs postoperative SRT logistics and toxic effects provides clinically significant data on management outcomes.

Objective

To determine preoperative SRT logistics and safety profile compared with postoperative in patients with brain metastases.

Design, Setting, and Participants

This single-institution phase 3 randomized clinical trial included patients 18 years and older and undergoing a planned surgical resection. Patients were required to have an Eastern Cooperative Oncology Group Performance Status score of 2 or greater and be candidates for SRT within 30 days of surgical resection. Patients with radiosensitive histologies (eg, small cell lung cancer and lymphoma), brain metastasis of unknown primary, and/or radiographic evidence of leptomeningeal disease were excluded. Data were collected from December 2018 to August 2023, and data were analyzed from September 2023 to December 2024.

Interventions

Patients were randomized 1:1. Patients randomized to the preoperative SRT cohort underwent SRT (in 1 to 5 fractions) followed by surgical resection within 1 month of radiation therapy. Patients randomized to the postoperative SRT cohort underwent resection followed by postoperative SRT within 1 month of surgery.

Main Outcomes and Measures

Outcomes reported focus on nonprimary end point analysis of the trial, including comparative toxic effect outcomes of preoperative vs postoperative SRT postprocedural events, feasibility of preoperative SRT, and radiation therapy management.

Results

Of 103 patients, 56 (54.4%) were male, and the median (range) age was 59 (26-83) years. Of 103 patients, 83 (80.6%) completed both radiation and surgery for brain metastases while in the study. Of these, 70 patients (84%) had 1 to 4 brain metastases at enrollment, 11 (13%) had 5 to 10 lesions, and 2 (2%) had more than 10 lesions. In the preoperative stereotactic radiosurgery (SRS)/SRT cohort, 45 (88%) completed both treatments compared with 38 (73%) in the postoperative SRS/SRT arm. There were no statistically significant differences between treatment groups in 30-day postoperative morbidity or postprocedural events. The median (range) time between surgery and SRT was significantly shorter in the preoperative arm (6 [0-24] days) compared with the postoperative arm (22 [12-42] days; P < .001). The median (range) time from randomization to receiving both brain-directed therapies was 10 (4-31) days in the preoperative arm compared with 32.5 (19-55) days for the postoperative arm (P < .001).

Conclusions and Relevance

In this randomized clinical trial, preoperative SRT had comparable safety to postoperative SRT and resulted in shorter time to treatment completion, potentially facilitating expedited care.

Trial Registration

ClinicalTrials.gov Identifier: NCT03741673

Introduction

The oncologic benefit of postoperative stereotactic radiosurgery (SRS)/stereotactic radiation therapy (SRS/SRT) following surgical resection of brain metastasis is well established. Overall, these trials demonstrated that postoperative SRS is associated with high rates of local control with minimum adverse effects, while avoiding the cognitive adverse effects of traditional whole-brain radiation therapy.^1,2,3,4,5 Even with the success of postoperative SRS, patients with brain metastases are still susceptible to distant recurrence outside the surgical cavity, including leptomeningeal disease (LMD), a devastating subset of metastatic central nervous system disease with a dismal prognosis.⁶ Previous experience from phase 3 clinical trials of postoperative SRS reported a notable incidence of LMD. Specifically, Mahajan et al⁵ reported 12-month LMD incidence of 28% in patients receiving standard postoperative SRS. Additionally, a large retrospective review of 500 postoperative surgical cavities treated with SRS reported a 12-month LMD rate of 15.8%.³ This result has been reproduced in multiple follow-up studies, and overall, the reported rate of LMD in patients receiving postoperative SRS is approximately 12% to 35%.^3,5,7,8,9,10

Preoperative SRS/SRT has been a proposed treatment strategy for resectable brain metastasis to address the challenge of leptomeningeal recurrence. Furthermore, preoperative SRS/SRT potentially offers additional radiation treatment planning and logistical benefits.^11,12,13 There are currently several retrospective and prospective studies of preoperative SRT^8,14,15; however, to our knowledge, there are no published randomized clinical studies evaluating the outcomes of preoperative vs postoperative SRT. Reporting the logistical operative outcomes and therapeutic management differences are important factors that are independent of the primary outcomes of local or distant intracranial recurrence. We are conducting a phase 3 clinical trial to evaluate the primary end point of the rate of LMD-free survival between patients who were randomized to receive preoperative vs postoperative SRT for surgical brain metastasis. Primary end point oncological outcomes cannot be reported in the data safety monitoring board–monitored ongoing trial at this juncture. However, in this report, we present our initial experience regarding the differences in therapy logistics of preoperative vs postoperative SRS/SRT and early safety outcomes for each treatment strategy, which significantly inform the current practice of these approaches in a clinical setting.

Methods

Study Design and Participants

This study was designed as a single-center phase 3 randomized clinical trial comparing preoperative and postoperative SRS/SRT for patients with brain metastases dispositioned for surgical resection. The primary objective was to investigate the 1-year LMD-free rate among patients with surgically resectable metastatic brain lesions randomized to postoperative SRT (standard care) vs preoperative SRT followed by surgery (experimental arm). The secondary objectives were to investigate the local control, distant brain metastasis rate, and overall survival. Exploratory objectives included neurocognitive function, symptom burden, health outcomes toxic effects, local control of nontarget/noncavity lesions from time of initial treatment, radiographic radiation treatment effects, biomarker tissue analysis, and cerebral spinal fluid analysis. This study protocol was approved by the MD Anderson Cancer Center Institutional Review Board and can be found in Supplement 1. All patients provided written informed consent. This study followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline for enrolled patients with brain metastases.

As this is an ongoing data safety monitoring board–controlled study with less than 100% accrual complete, we are unable to report on primary outcomes in this report. We are reporting on initial preoperative and postoperative surgical outcomes, radiation treatment management, and logistical clinical considerations, which are highly informative to the clinical management of preoperative SRT vs postoperative SRT in the first more than 100 patients with brain metastases enrolled in the trial. For this study, we included patients 18 years and older diagnosed with brain metastases undergoing a planned surgical resection. Race and ethnicity were self-reported and documented from the electronic health record. Patients were required to have a Karnofsky performance status of at least 70 or Eastern Cooperative Oncology Group Performance Status score of 2 or more for enrollment and had to be considered candidates for SRS/SRT within 30 days of surgical resection. Patients with radiosensitive pathologies (ie, small cell lung cancer, lymphoma, multiple myeloma) or brain metastasis of unknown primary (ie, unidentifiable primary malignancy) were not eligible for enrollment. Additionally, patients with radiographic evidence of LMD (on contrast-enhanced brain or spine magnetic resonance imaging [MRI]) were also excluded.

Procedures and Interventions

Patients randomized to the preoperative SRT cohort underwent SRT in 1 to 5 fractions followed by surgical resection within 30 days of radiation therapy. Patients randomized to postoperative SRT cohort underwent surgical resection followed by postoperative SRT within 30 days of surgery. The technique of SRS/SRT was at the discretion of the treating physician (ie, framed vs frameless, radiation modality). Target lesions were defined as the planned resected lesion that was randomized to either preoperative or postoperative SRS/SRT. Nonrandomized/nontarget lesions were unresected lesions being treated with radiation in the same therapeutic course of management. Data are presented by per-patient characteristics and by per-lesion characteristics. Time to therapy data presented per lesion reflect the time from randomization to the earliest treatment initiation of the target lesion(s) in each arm. Radiation dosing followed recommended institutional standard departmental treatment guidelines.

Statistical Analysis

Randomization was 1:1 using the Pocock-Simon method to balance the stratification factors of target size (3 cm or smaller vs larger than 3 cm), anatomical location (supratentorial or infratentorial), and histology (ie, histologies with higher risk of LMD based on data from the prior postoperative phase 3 trial,⁵ such as breast cancer, non–small cell lung cancer, and melanoma vs others). We based our sample size justification on a log-rank test comparing freedom from LMD between groups with assumed 1-year rates of 90% vs 70% with a 2-sided 5% alpha and 80% power, accrual rate based on the prior postoperative SRS trial (2 per month), and 12-month postaccrual follow-up (ie, follow-up on all patients after last patient is accrued), requiring 110 evaluable patients. The final analysis will be performed after 22 LMD events have been observed. Taking into consideration updated dropout rates from the COVID-19 pandemic period, we plan a total accrual of up to 180 patients. This report presents preliminary analysis of the initial 103 enrolled patients with pathologically confirmed brain metastases, reporting descriptive statistics on patient characteristics, including demographic characteristics, histology, number of lesion, cavities treated, and radiation therapy. Frequency and percentages between the 2 arms on the presenting presurgical symptoms of the population enrolled and the postsurgery morbidity are reported and are compared using the χ² test or Fisher exact test, as appropriate. Time to treatment, calculated from randomization, is compared between arms using the Mann-Whitney U test. A P value of less than .05 from a 2-sided test is considered statistically significant. Data analyses were performed using R version 4.3.2 (The R Foundation). Data were collected from December 2018 to August 2023, and data were analyzed from September 2023 to December 2024.

Results

Patient Characteristics

From December 2018 to January 2023, a total of 103 patients with pathologically confirmed brain metastases were enrolled at a single institution (Figure). The median (range) age was 59 (26-83) years, and 56 (54.4%) were male. The most common cancer diagnoses included non–small cell lung cancer (30 [29.1%]), renal cell carcinoma (15 [14.6%]), melanoma (14 [13.6%]), and breast cancer (12 [11.7%]). At baseline enrollment MRI, 86 patients had 1 to 4 brain metastases, 15 patients had 5 to 10 metastases, and 2 had more than 10 brain metastases (Table 1). Most patients (90 [87.4%]) had a single randomized target/resected lesion, and 13 (12.6%) had multiple lesions randomized. If 2 proximal/adjoining lesions were resected together and created a single cavity, they were categorized as a single cavity or target because, from a radiation dosing approach, they would be clinically treated as a single large lesion. If any 1 site had residual disease, the case was categorized as residual disease. A total of 52 patients (50.5%) had a resection for a lesion that was 3 cm or smaller. Most patients (87 [84.5%]) had supratentorial lesion(s) and 57 (55.3%) had histologies presumed to be higher risk for LMD. There were no statistical differences in the enrollment between the preoperative (n = 51) vs postoperative (n = 52) cohorts based on the above strata. Ten specific preoperative/procedural symptoms were evaluated between the treatment groups among patients who completed all protocol therapy (eTable 1 in Supplement 2). Only preoperative memory issues and unsteady gait differed between treatment cohorts. Specifically, preoperative memory deficits were observed in 1 patient (2%) in the preoperative SRT group vs 8 (21%) in the postoperative SRT group (P = .01). Preoperative unsteady gait was more frequent in the postoperative SRT cohort (14 [37%]) compared with the preoperative SRT cohort (6 [13%]) (P = .02). Data regarding the battery of neurocognitive functional baseline testing on trial and changes over time will be reported separately as a distinct end point of the study.

Figure. — LMD indicates leptomeningeal disease; MRI, magnetic resonance imaging; SRT, stereotactic radiation therapy; WBRT, whole-brain radiation therapy.

Table 1. Descriptive Statistics of Patients Enrolled in the Preoperative and Postoperative Arms.

Characteristic	Patients, No. (%)
Characteristic	Total (N = 103)	Preoperative arm (n = 51)	Postoperative arm (n = 52)
Sex
Female	47 (45.6)	25 (49.0)	22 (42.3)
Male	56 (54.4)	26 (51.0)	30 (57.7)
Age, median (range), y	59 (26-83)	61 (26-79)	59 (34-83)
Race and ethnicity^a
Hispanic	17 (16.5)	9 (17.6)	8 (15.4)
Non-Hispanic Black	5 (4.9)	2 (3.9)	3 (5.8)
Non-Hispanic White	75 (72.8)	36 (70.6)	39 (75.0)
Non-Hispanic other race	6 (5.8)	4 (7.8)	2 (3.8)
Treatment^b
No treatment	9 (8.7)	4 (7.8)	5 (9.6)
Received SRS/SRT	85 (82.5)	47 (92.1)	38 (73.1)
Received surgery	92 (89.3)	45 (88.2)	47 (90.4)
Received SRS/SRT and surgery	83 (80.6)	45 (88.2)	38 (73.1)
Primary histology
Breast	12 (11.7)	6 (11.8)	6 (11.5)
Melanoma	14 (13.6)	8 (15.7)	6 (11.5)
NSCLC	30 (29.1)	13 (25.5)	17 (32.7)
Renal cell carcinoma	15 (14.6)	8 (15.7)	7 (13.5)
Other	32 (31.0)	16 (31.3)	16 (30.8)
Resected lesions
1/1^c	90 (87.4)	46 (90.2)	44 (84.6)
>1	13 (12.6)	5 (9.8)	8 (15.4)
Brain lesions at baseline
1-4	86 (83.5)	43 (84.3)	43 (82.7)
5-10	15 (14.6)	7 (13.7)	8 (15.4)
>10	2 (1.9)	1 (2.0)	1 (1.9)
Stratification factors
Maximum size of brain lesion
≤3 cm	52 (50.5)	24 (47.1)	28 (53.8)
>3 cm	51 (49.5)	27 (52.9)	24 (46.2)
Location
Supratentorial	87 (84.5)	43 (84.3)	44 (84.6)
Infratentorial	16 (15.5)	8 (15.7)	8 (15.4)
Histology
Histology with presumed higher risk of LMD (ie, breast, NSCLC, melanoma)	57 (55.3)	28 (54.9)	29 (55.8)
Other histology	46 (44.7)	23 (45.1)	23 (44.2)

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Abbreviations: LMD, leptomeningeal disease; NSCLC, non–small cell lung cancer; SRS, stereotactic radiosurgery; SRT, stereotactic radiation therapy.

^{^a}

Race and ethnicity were self-reported and documented from the electronic health record. The other race category included Asian race and those self-identifying as other race.

^{^b}

Categories are not mutually exclusive, and column percentages exceed 100%.

^{^c}

Two proximal/adjoining lesions resected together creating a single cavity.

Treatment of Enrolled Patients

Patient Characteristics

Of 103 enrolled patients (Figure), 83 (80.6%) completed both radiation and surgery for brain metastases (Table 2). Approximately 10% did not receive therapy after enrollment. The distribution by histology was similar between the 2 randomized groups. Patients’ baseline MRI were evaluated at time of enrollment. Of those completing protocol therapy, 70 (84%) had 1 to 4 brain metastases at enrollment, 11 (13%) had 5 to 10 lesions, and 2 (2%) had more than 10 lesions. Overall, there were slight shifts in the number of total lesions requiring radiation at the time of treatment compared with baseline, with more patients having 5 to 10 lesions by time of therapy, with a median (range) brain metastasis increase of 2 (1-8). eTable 2 in Supplement 2 includes resection characteristics.

Table 2. Descriptive Statistics of Patients Enrolled in the Preoperative vs Postoperative Trial Who Completed Both Therapies.

Characteristic	Patients, No. (%)
Characteristic	Total (n = 83)	Preoperative arm (n = 45)	Postoperative arm (n = 38)
Sex
Female	39 (47.0)	21 (46.7)	18 (47.4)
Male	44 (53.0)	24 (53.3)	20 (52.6)
Age, median (range), y	59 (26-83)	61 (26-79)	59 (37-83)
Race and ethnicity^a
Hispanic	14 (16.9)	8 (17.8)	6 (15.8)
Non-Hispanic Black	4 (4.8)	2 (4.4)	2 (5.2)
Non-Hispanic White	59 (71.1)	31 (68.9)	28 (73.7)
Non-Hispanic other race	6 (7.2)	4 (8.9)	2 (5.2)
Primary histology
Breast	8 (9.6)	4 (8.9)	4 (10.5)
Melanoma	10 (12.0)	6 (13.3)	4 (10.5)
NSCLC	27 (32.5)	13 (28.9)	14 (36.8)
Renal cell carcinoma	15 (18.1)	8 (17.8)	7 (18.4)
Other	23 (27.7)	14 (31.1)	9 (23.7)
Resected lesions
1/1^b	73 (88.0)	41 (91.1)	32 (84.2)
>1	10 (12.0)	4 (8.9)	6 (15.8)
Brain lesions at baseline
1-4	70 (84.3)	38 (84.4)	32 (84.2)
5-10	11 (13.3)	6 (13.3)	5 (13.2)
>10	2 (2.4)	1 (2.2)	1 (2.6)
Total treated lesions at time of radiation
1-4	67 (80.7)	39 (86.7)	28 (73.7)
5-10	14 (16.9)	5 (11.1)	9 (23.7)
>10	2 (2.4)	1 (2.2)	1 (2.6)
Total treated nonresected lesions
0	33 (39.8)	16 (35.6)	17 (44.7)
1-4	40 (48.2)	25 (55.6)	15 (39.5)
5-10	8 (9.6)	3 (6.7)	5 (13.2)
>10	2 (2.4)	1 (2.2)	1 (2.6)
Treatment of resected lesion
GK only	57 (68.7)	38 (84.4)	19 (50.0)
Linear accelerator only	26 (31.3)	7 (15.6)	19 (50.0)
Fractionation of planned resected/target lesion
1 Fraction only	34 (41.0)	23 (51.1)	11 (28.9)
3-5 Fractions only	47 (56.6)	21 (46.7)	26 (64.8)
Both 1 and 3-5 fractions	2 (2.4)	1 (2.2)	1 (2.6)
Treatment of nonresected/nontarget lesion
GK only	48 (57.8)	27 (60.0)	21 (55.3)
Linear accelerator only	1 (1.2)	1 (2.2)	0
Both GK and linear accelerator	1 (1.2)	1 (2.2)	0
Fractionation of nonresected/nontarget lesion
1 Fraction only	45 (54.2)	27 (60.0)	18 (47.4)
3-5 Fractions only	1 (1.2)	1 (2.2)	0
Both 1 and 3-5 fractions	4 (4.8)	1 (2.2)	3 (7.9)

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Abbreviations: GK, Gamma Knife; NSCLC, non–small cell lung cancer.

^{^a}

Race and ethnicity were self-reported and documented from the electronic health record. The other race category included Asian race and those self-identifying as other race.

^{^b}

Two proximal/adjoining lesions resected together creating a single cavity.

Radiation Therapy

For preoperative or postoperative SRT, the choice of machine modality was at the discretion of the treating physician reflecting the real-world setting of different machinery techniques available nationally for standard treatment. Typically, only 1 modality was used for all targets (lesion or cavity). At our institution, 57 patients (69%) were treated with Gamma Knife and 26 (31%) were treated with linear accelerator. Most patients randomized to the preoperative cohort (38 [84%]) received Gamma Knife compared with 19 patients in the postoperative group (50%) (P = .002). Patients treated with 1 fraction represented 51% of the preoperative group (n = 23) and 29% of the postoperative group (n = 11) (Table 2). Overall, the most common radiation dose range for single-fraction SRS was 17 to 19 Gy (27 [29%]; most received 18 Gy). The target lesion volume necessitated this dose range in 19 in the preoperative group (38%) and 8 in the postoperative group (19%). For multifraction SRT, the most common prescription dose range was 24 to 27 Gy in 3 fractions (48 [52%]; most received 27 Gy). This dose was more common in the postoperative arm group (28 [65%]) compared with the preoperative SRT group (20 [40%]). A total of 148 nonresected lesions were treated. The most common single-fraction prescription dose was 20 to 22 Gy (137 [92.6%]) followed by 17 to 18 Gy (6 [4.1%]). The most common multifraction SRT dose for nontarget/randomized cavity lesions was 24 to 27 Gy in 3 fractions in both treatment groups (Table 3). There were no statistical differences in the RT dose ranges between the 2 randomized groups.

Table 3. Per-Lesion Tumor Characteristics and Time to Therapy.

Characteristic	Lesions, No. (%)			P value
Characteristic	Total	Preoperative arm	Postoperative arm	P value
Cavities treated per protocol, No.	94	50	44	NA
Anatomic lobe
Frontal	40 (42.6)	18 (36.0)	22 (50.0)	.04
Parietal	23 (24.5)	9 (18.0)	14 (31.8)
Temporal	11 (11.7)	7 (14.0)	4 (9.1)
Occipital	9 (9.6)	8 (16.0)	1 (2.3)
Cerebellar	11 (11.7)	8 (16.0)	3 (6.8)
Planned treatment dose resected lesion
Single-fraction targets	38 (40.9)	26 (52.0)	12 (27.9)
15-16 Gy	5 (5.4)	4 (8.0)	1 (2.3)	.55
17-19 Gy	27 (29.0)	19 (38.0)	8 (18.6)
20-22 Gy	6 (6.5)	3 (6.0)	3 (7.0)
Multifraction targets	54 (58.1)	23 (46.0)	31 (72.1)
21-23 Gy in 3 fractions	2 (2.2)	0	2 (4.7)	.27
24-27 Gy in 3 fractions	48 (51.6)	20 (40.0)	28 (65.1)
25-30 Gy in 5 fractions	4 (4.3)	3 (6.0)	1 (2.3)
Nontarget lesions treated per protocol, No.	148	72	76	NA
Planned treatment dose nontarget lesion
Single-fraction lesions	143 (96.6)	70 (97.2)	73 (96.1)
15-16 Gy	0	0	0	>.99
17-19 Gy	6 (4.1)	3 (4.2)	3 (3.9)
20-22 Gy	137 (92.6)	67 (93.1)	70 (92.1)
Multifraction lesions	5 (3.4)	2 (2.8)	3 (3.9)
24-27 Gy in 3 fractions	5 (3.4)	2 (2.8)	3 (3.9)	>.99
25-30 Gy in 5 fractions	0	0	0	>.99
Time to therapy, median (range), d
Time from randomization to start of RT	13.0 (0-55)	6.0 (0-14)	32.5 (19-55)	<.001
Time from randomization to surgery	9.0 (1-31)	10.0 (4-31)	8.5 (1-29)	.06
Time between start of RT and surgery	14.0 (0-42)	6.0 (0-24)	22.0 (12-42)	<.001
Time from randomization to receipt of both RT and surgery	21.0 (4-55)	10.0 (4-31)	32.5 (19-55)	<.001

Open in a new tab

Abbreviations: NA, not applicable; RT, radiation therapy.

Timing of Therapy

Among the patients enrolled in the preoperative SRT cohort, 45 (88%) completed both treatments compared with 38 (73%) in the postoperative SRT arm (P = .09). The time between treatment interventions (surgery and SRT) was shorter in the preoperative arm. Specifically, in the preoperative arm, the median (range) time between SRT (first intervention) and surgery (second intervention) was 6 (0-24) days. Conversely, in the postoperative arm, the timing between surgery (first intervention) and SRT (second intervention) was 22 (12-42) days (P < .001). The median (range) time from randomization to RT was 6 (0-14) days in the preoperative arm vs 32.5 (19-55) days in the postoperative arm (P < .001). The median (range) time from randomization to surgery was 10 (4-31) days in the preoperative arm compared with 8.5 (1-29) days in the postoperative arm (P = .06), indicating no significant delay in planned surgery. The median (range) time from randomization to receiving both RT and surgery was significantly shorter in the preoperative arm (10 [4-31] days) compared with the postoperative arm (32.5 [19-55] days; P < .001).

Postprocedural Events in Enrolled Patients

Thirty-day postoperative morbidity (or events) between the 2 randomized groups were not statistically significant (Table 4). Specifically, 22 postoperative events were reported in the preoperative SRT group vs 17 events in the postoperative SRT group (P = .87). Event types included neurological, respiratory, infectious, vascular, cardiac, gastrointestinal, or genitourinary events and minor events. The 30-day surgical postoperative event reporting is separate from the final total adverse event analysis, which must be reserved to the conclusion of this study.

Table 4. Descriptive Statistics of Postsurgical Procedure 30-Day Events by Randomized Group.

Event	Patients, No. (%)			P value
Event	Total (n = 83)	Preoperative arm (n = 45)	Postoperative arm (n = 38)	P value
Any 30-d postoperative event	39 (47.0)	22 (48.9)	17 (44.7)	.87
Event by organ system
Neurological event
Any neurological	30 (36.1)	16 (35.5)	14 (36.8)	.70
Focal motor deficit	12 (14.5)	7 (15.6)	5 (13.2)	>.99
Focal sensory deficit	4 (4.8)	2 (4.4)	2 (5.3)	>.99
Speech impairment	0	0	0	>.99
Visual impairment	3 (3.6)	0	3 (7.9)	.07
Cranial nerve deficit	0	0	0	>.99
Hydrocephalus	0	0	0	>.99
Radiation necrosis	0	0	0	>.99
Progressive edema	0	0	0	>.99
Cerebral abscess	0	0	0	>.99
Seizures	2 (2.4)	2 (4.4)	0	.49
CSF leakage	0	0	0	>.99
Pneumocephalus	1 (1.2)	1 (2.2)	0	>.99
Hemorrhage	0	0	0	>.99
Intracranial	0	0	0	>.99
Subdural	0	0	0	>.99
Epidural	0	0	0	>.99
Intraparenchymal	0	0	0	>.99
Other neurological^a	23 (27.7)	13 (28.9)	10 (26.3)	>.99
Respiratory event
Any respiratory	8 (9.6)	4 (8.9)	4 (10.5)	.70
Respiratory failure	1 (1.2)	0	1 (2.6)	.43
Atelectasis	0	0	0	>.99
Pneumothorax	0	0	0	>.99
Pulmonary embolus	4 (4.8)	3 (6.7)	1 (2.6)	.61
Other respiratory	5 (6.0)	1 (2.2)	4 (10.5)	.14
Infectious disease event
Any infectious disease	5 (6.0)	2 (4.4)	3 (7.9)	.63
Wound	1 (1.2)	0	1 (2.6)	.43
Meningitis	0	0	0	>.99
Encephalitis	0	0	0	>.99
Pneumonia	2 (5.1)	1 (2.2)	1 (2.6)	>.99
Bacteremia	0	0	0	>.99
UTI	2 (2.4)	1 (2.2)	1 (2.6)	>.99
Other infectious disease	1 (1.2)	0	1 (2.6)	.43
Peripheral/vascular event
Any peripheral/vascular	0	0	0	>.99
DVT	0	0	0	>.99
Other peripheral/vascular	0	0	0	>.99
GI tract event				>.99
Any GI tract	3 (3.6)	2 (4.4)	1 (2.6)	>.99
Bleed	0	0	0	>.99
Perforation	0	0	0	>.99
GI tract obstruction	0	0	0	>.99
Other GI tract	3 (3.6)	2 (4.4)	1 (2.6)	>.99
Genitourinary event
Any genitourinary	4 (4.8)	2 (4.4)	2 (5.3)	>.99
Retention	1 (1.2)	1 (2.2)	0	>.99
Incontinence	1 (1.2)	1 (2.2)	0	>.99
Other genitourinary	3 (3.6)	1 (2.2)	2 (5.3)	.57
Cardiac event
Any cardiac	8 (9.6)	3 (6.7)	5 (13.2)	.26
Myocardial infarction	0	0	0	>.99
Transischemia	0	0	0	>.99
Arrythmia	1 (1.2)	0	1 (2.6)	.43
Other cardiac	6 (7.2)	3 (6.7)	3 (7.9)	>.99
Angiogram	1 (1.2)	0	1 (2.6)	.43

Open in a new tab

Abbreviations: CSF, cerebrospinal fluid; DVT, deep vein thrombosis; GI, gastrointestinal; UTI, urinary tract infection.

^{^a}

May include nonspecific tremors, insomnia, agitation or behavioral changes, or difficulty concentrating.

Discussion

To address the potential benefit of preoperative SRT, we are conducting a phase 3 single-institution trial randomizing patients with surgically resectable brain metastasis to receive either preoperative or postoperative SRT. In this report, we evaluated the initial subset population of patients with surgical brain metastases treated preoperatively or postoperatively with radiation therapy in this study and report the logistics and safety. Although we cannot yet report the primary end point oncologic outcomes of the treatment cohorts, our presented data are highly relevant to clinicians using neoadjuvant SRT regarding expected feasibility, logistics, and appropriate target populations.

A powerful advantage of preoperative SRT delivery is the logistical aspects, specifically the higher likelihood of patient completion of both surgery and radiation therapy and decreased treatment delay. Unexpected events and/or complications can extend postoperative treatment delay. The metastatic cancer population is often older and may have additional medical comorbidities complicating their postoperative course and recovery and ultimately delay adjuvant therapy. The cumulative impact of these logistical issues is highlighted in a phase 2 clinical trial by Brennan at al,¹⁶ focused on postoperative SRS. In this trial, they found that 20% of postoperative patients did not undergo their scheduled adjuvant SRS.¹⁶ These may also have implications for the delay of SRT impacting oncology outcomes. In our initial observation, we found that a higher proportion of patients in the preoperative SRS group completed their treatment course (surgery plus SRT) compared with the postoperative SRT cohort (45 [88%] vs 38 [73%]).

In addition to adherence, there is also the issue of timing. For postoperative SRT, the patient is typically required to wait 10 to 14 days to allow for incision healing. This also allows time for resolution of immediate radiographic postoperative changes and surgical cavity size stabilization. This wait time is not necessary with preoperative treatment, and there is an opportunity to increase treatment efficiency. Preoperative SRT and surgery can be completed within the same week and, if carefully planned, potentially the same hospitalization. Expedited radiation therapy may reflect an interest in not delaying surgery for lesions that are infratentorial or with radiographic compressive findings. Furthermore, time between surgical resection and adjuvant SRS has been associated with rates of local recurrence, with a median time to postoperative SRS of 37 days associated with a rate of 16%.¹⁷ Thus far in our trial, the time to completion of all therapies (surgery and SRT) was approximately 3-fold longer in the postoperative SRT group compared with the preoperative SRT group. In addition to improved patient satisfaction, completing cranial treatment quickly facilitates expedited initiation of systemic therapy, which is critical in this population with advanced metastatic disease.

One of the concerns regarding preoperative SRT is upfront radiation to lesions that are often large and/or symptomatic. Importantly, we did not observe a significant difference between treatment cohorts with regard to 30-day postprocedure complications. Our observation is consistent with the current literature reporting the safety of preoperative SRT,^14,18 although those reports were not phase 3 randomized clinical trials. Another concern from patients and clinicians has been that awaiting preoperative SRT may significantly delay a patient’s surgery because the logistics for RT may require additional planning time upfront. Our analysis found that the time to completion of surgery was not statistically different between the 2 groups (median [range] time, 10 [4-31] days in the preoperative arm compared with 8.5 [1-29] days in the postoperative arm).

Lastly, the treatment algorithm of preoperative SRT has potential advantages in treatment planning and addressing the concern of intraoperative tumor spillage. It has been suggested that surgical resection itself may disrupt anatomical borders, theoretically contributing to cerebral spinal fluid contamination with malignant cells and increased risk of LMD.¹⁹ One potential benefit of neoadjuvant treatment is to treat the tumor and cavity prior to surgical manipulation. Thus, tumor cells fated to spill into the resection cavity have already been treated with SRT and thus are less likely to recur locally or proliferate distantly and establish LMD.⁸ In addition, the treatment planning benefits of preoperative SRT are also discussed in the literature due to improved target delineation.^11,12,13,20 Our data highlight how radiation treatment planning has been comparable in both groups despite the target tumor size.

Limitations

Our initial findings on surgical outcomes and treatment logistics have limitations as a subset cohort analysis of an ongoing trial. Our preliminary analysis represents 30-day surgical outcomes, and long-term follow-up is of value. While final reporting of trial analysis and adverse events could theoretically reveal additional insights, our current large sample size of more than 100 patients may mitigate that likelihood. Next, the study is potentially limited by therapy reflecting a high-volume academic institution with the capacity to deliver SRT to acute inpatients, which may not be feasible at all institutions. This may result in greater trial enrollment of patients with larger volume brain metastases compared with community practice of SRT. Trial participation is at the discretion of the clinical team, and thereby patients that are emergent or have lesions deemed neurosurgically high risk, such as patients requiring intensive care unit therapy or lesions that are 5.5 cm or larger, were often not enrolled. Lastly, we did not enroll patients with unknown primary diagnosis, and our data would not apply to this population.

Conclusions

In conclusion, our current findings of this randomized clinical trial are significant to the real-world community offering preoperative or postoperative SRS/SRT and highlight minimal differences in postoperative 30-day morbidity. It also provides unique insights from other currently enrolling clinical trials that may differ in approach and methodology. For instance, our study provides analysis of both single-fraction SRS and multifractionation SRT, which is applicable to more real-world radiation oncology practices. We report in one of the earliest phase 3 randomized clinical trials that preoperative SRT is logistically feasible and potentially favorable compared with postoperative SRT, with more patients completing the planned treatment course (radiation and surgery) and with shorter time to completion of brain-directed therapy.

Supplement 1.

Trial Protocol

jamaoncol-e251770-s001.pdf^{(547.3KB, pdf)}

Supplement 2.

eTable 1. Presurgical Procedure Signs or Symptoms by Randomized Group of Preoperative Radiation vs Postoperative Radiation

eTable 2. Description of SRT, Radiographic, and Surgical Characteristics of Patients With Brain Metastases Enrolled in the Preoperative vs Postoperative Trial that Completed Both Therapies

jamaoncol-e251770-s002.pdf^{(223.2KB, pdf)}

Supplement 3.

Data Sharing Statement

jamaoncol-e251770-s003.pdf^{(14.1KB, pdf)}

References

1.Brown PD, Ballman KV, Cerhan JH, et al. Postoperative stereotactic radiosurgery compared with whole brain radiotherapy for resected metastatic brain disease (NCCTG N107C/CEC·3): a multicentre, randomised, controlled, phase 3 trial. Lancet Oncol. 2017;18(8):1049-1060. doi: 10.1016/S1470-2045(17)30441-2 [DOI] [PMC free article] [PubMed] [Google Scholar]
2.Prabhu RS, Miller KR, Asher AL, et al. Preoperative stereotactic radiosurgery before planned resection of brain metastases: updated analysis of efficacy and toxicity of a novel treatment paradigm. J Neurosurg. 2018;131(5):1387-1394. doi: 10.3171/2018.7.JNS181293 [DOI] [PubMed] [Google Scholar]
3.Shi S, Sandhu N, Jin MC, et al. Stereotactic radiosurgery for resected brain metastases: single-institutional experience of over 500 cavities. Int J Radiat Oncol Biol Phys. 2020;106(4):764-771. doi: 10.1016/j.ijrobp.2019.11.022 [DOI] [PubMed] [Google Scholar]
4.Chang EL, Wefel JS, Hess KR, et al. Neurocognition in patients with brain metastases treated with radiosurgery or radiosurgery plus whole-brain irradiation: a randomised controlled trial. Lancet Oncol. 2009;10(11):1037-1044. doi: 10.1016/S1470-2045(09)70263-3 [DOI] [PubMed] [Google Scholar]
5.Mahajan A, Ahmed S, McAleer MF, et al. Post-operative stereotactic radiosurgery versus observation for completely resected brain metastases: a single-centre, randomised, controlled, phase 3 trial. Lancet Oncol. 2017;18(8):1040-1048. doi: 10.1016/S1470-2045(17)30414-X [DOI] [PMC free article] [PubMed] [Google Scholar]
6.Ferguson SD, Bindal S, Bassett RL Jr, et al. Predictors of survival in metastatic melanoma patients with leptomeningeal disease (LMD). J Neurooncol. 2019;142(3):499-509. doi: 10.1007/s11060-019-03121-2 [DOI] [PubMed] [Google Scholar]
7.Johnson MD, Avkshtol V, Baschnagel AM, et al. Surgical resection of brain metastases and the risk of leptomeningeal recurrence in patients treated with stereotactic radiosurgery. Int J Radiat Oncol Biol Phys. 2016;94(3):537-543. doi: 10.1016/j.ijrobp.2015.11.022 [DOI] [PubMed] [Google Scholar]
8.Patel KR, Burri SH, Asher AL, et al. Comparing preoperative with postoperative stereotactic radiosurgery for resectable brain metastases: a multi-institutional analysis. Neurosurgery. 2016;79(2):279-285. doi: 10.1227/NEU.0000000000001096 [DOI] [PubMed] [Google Scholar]
9.Press RH, Zhang C, Chowdhary M, et al. Hemorrhagic and cystic brain metastases are associated with an increased risk of leptomeningeal dissemination after surgical resection and adjuvant stereotactic radiosurgery. Neurosurgery. 2019;85(5):632-641. doi: 10.1093/neuros/nyy436 [DOI] [PubMed] [Google Scholar]
10.Atalar B, Modlin LA, Choi CY, et al. Risk of leptomeningeal disease in patients treated with stereotactic radiosurgery targeting the postoperative resection cavity for brain metastases. Int J Radiat Oncol Biol Phys. 2013;87(4):713-718. doi: 10.1016/j.ijrobp.2013.07.034 [DOI] [PubMed] [Google Scholar]
11.El Shafie RA, Tonndorf-Martini E, Schmitt D, et al. Pre-operative versus post-operative radiosurgery of brain metastases-volumetric and dosimetric impact of treatment sequence and margin concept. Cancers (Basel). 2019;11(3):294. doi: 10.3390/cancers11030294 [DOI] [PMC free article] [PubMed] [Google Scholar]
12.Vellayappan BA, Doody J, Vandervoort E, et al. Pre-operative versus post-operative radiosurgery for brain metastasis: effects on treatment volume and inter-observer variability. J Radiosurg SBRT. 2018;5(2):89-97. [PMC free article] [PubMed] [Google Scholar]
13.Redmond KJ, De Salles AAF, Fariselli L, et al. Stereotactic radiosurgery for postoperative metastatic surgical cavities: a critical review and International Stereotactic Radiosurgery Society (ISRS) practice guidelines. Int J Radiat Oncol Biol Phys. 2021;111(1):68-80. doi: 10.1016/j.ijrobp.2021.04.016 [DOI] [PubMed] [Google Scholar]
14.Prabhu RS, Dhakal R, Vaslow ZK, et al. Preoperative radiosurgery for resected brain metastases: the PROPS-BM multicenter cohort study. Int J Radiat Oncol Biol Phys. 2021;111(3):764-772. doi: 10.1016/j.ijrobp.2021.05.124 [DOI] [PubMed] [Google Scholar]
15.Asher AL, Burri SH, Wiggins WF, et al. A new treatment paradigm: neoadjuvant radiosurgery before surgical resection of brain metastases with analysis of local tumor recurrence. Int J Radiat Oncol Biol Phys. 2014;88(4):899-906. doi: 10.1016/j.ijrobp.2013.12.013 [DOI] [PubMed] [Google Scholar]
16.Brennan C, Yang TJ, Hilden P, et al. A phase 2 trial of stereotactic radiosurgery boost after surgical resection for brain metastases. Int J Radiat Oncol Biol Phys. 2014;88(1):130-136. doi: 10.1016/j.ijrobp.2013.09.051 [DOI] [PMC free article] [PubMed] [Google Scholar]
17.Roth O’Brien DA, Poppas P, Kaye SM, et al. Timing of adjuvant fractionated stereotactic radiosurgery affects local control of resected brain metastases. Pract Radiat Oncol. 2021;11(3):e267-e275. doi: 10.1016/j.prro.2021.01.011 [DOI] [PubMed] [Google Scholar]
18.Prabhu RS, Patel KR, Press RH, et al. Preoperative vs postoperative radiosurgery for resected brain metastases: a review. Neurosurgery. 2019;84(1):19-29. doi: 10.1093/neuros/nyy146 [DOI] [PubMed] [Google Scholar]
19.Lowe SR, Wang CP, Brisco A, et al. Surgical and anatomic factors predict development of leptomeningeal disease in patients with melanoma brain metastases. Neuro Oncol. 2022;24(8):1307-1317. doi: 10.1093/neuonc/noac023 [DOI] [PMC free article] [PubMed] [Google Scholar]
20.Cheok SK, Yu C, Feng JJ, et al. Comparison of preoperative versus postoperative treatment dosimetry plans of single-fraction stereotactic radiosurgery for surgically resected brain metastases. Neurosurg Focus. 2023;55(2):E9. doi: 10.3171/2023.5.FOCUS23209 [DOI] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplement 1.

Trial Protocol

jamaoncol-e251770-s001.pdf^{(547.3KB, pdf)}

Supplement 2.

eTable 1. Presurgical Procedure Signs or Symptoms by Randomized Group of Preoperative Radiation vs Postoperative Radiation

eTable 2. Description of SRT, Radiographic, and Surgical Characteristics of Patients With Brain Metastases Enrolled in the Preoperative vs Postoperative Trial that Completed Both Therapies

jamaoncol-e251770-s002.pdf^{(223.2KB, pdf)}

Supplement 3.

Data Sharing Statement

jamaoncol-e251770-s003.pdf^{(14.1KB, pdf)}

[coi250028r1] 1.Brown PD, Ballman KV, Cerhan JH, et al. Postoperative stereotactic radiosurgery compared with whole brain radiotherapy for resected metastatic brain disease (NCCTG N107C/CEC·3): a multicentre, randomised, controlled, phase 3 trial. Lancet Oncol. 2017;18(8):1049-1060. doi: 10.1016/S1470-2045(17)30441-2 [DOI] [PMC free article] [PubMed] [Google Scholar]

[coi250028r2] 2.Prabhu RS, Miller KR, Asher AL, et al. Preoperative stereotactic radiosurgery before planned resection of brain metastases: updated analysis of efficacy and toxicity of a novel treatment paradigm. J Neurosurg. 2018;131(5):1387-1394. doi: 10.3171/2018.7.JNS181293 [DOI] [PubMed] [Google Scholar]

[coi250028r3] 3.Shi S, Sandhu N, Jin MC, et al. Stereotactic radiosurgery for resected brain metastases: single-institutional experience of over 500 cavities. Int J Radiat Oncol Biol Phys. 2020;106(4):764-771. doi: 10.1016/j.ijrobp.2019.11.022 [DOI] [PubMed] [Google Scholar]

[coi250028r4] 4.Chang EL, Wefel JS, Hess KR, et al. Neurocognition in patients with brain metastases treated with radiosurgery or radiosurgery plus whole-brain irradiation: a randomised controlled trial. Lancet Oncol. 2009;10(11):1037-1044. doi: 10.1016/S1470-2045(09)70263-3 [DOI] [PubMed] [Google Scholar]

[coi250028r5] 5.Mahajan A, Ahmed S, McAleer MF, et al. Post-operative stereotactic radiosurgery versus observation for completely resected brain metastases: a single-centre, randomised, controlled, phase 3 trial. Lancet Oncol. 2017;18(8):1040-1048. doi: 10.1016/S1470-2045(17)30414-X [DOI] [PMC free article] [PubMed] [Google Scholar]

[coi250028r6] 6.Ferguson SD, Bindal S, Bassett RL Jr, et al. Predictors of survival in metastatic melanoma patients with leptomeningeal disease (LMD). J Neurooncol. 2019;142(3):499-509. doi: 10.1007/s11060-019-03121-2 [DOI] [PubMed] [Google Scholar]

[coi250028r7] 7.Johnson MD, Avkshtol V, Baschnagel AM, et al. Surgical resection of brain metastases and the risk of leptomeningeal recurrence in patients treated with stereotactic radiosurgery. Int J Radiat Oncol Biol Phys. 2016;94(3):537-543. doi: 10.1016/j.ijrobp.2015.11.022 [DOI] [PubMed] [Google Scholar]

[coi250028r8] 8.Patel KR, Burri SH, Asher AL, et al. Comparing preoperative with postoperative stereotactic radiosurgery for resectable brain metastases: a multi-institutional analysis. Neurosurgery. 2016;79(2):279-285. doi: 10.1227/NEU.0000000000001096 [DOI] [PubMed] [Google Scholar]

[coi250028r9] 9.Press RH, Zhang C, Chowdhary M, et al. Hemorrhagic and cystic brain metastases are associated with an increased risk of leptomeningeal dissemination after surgical resection and adjuvant stereotactic radiosurgery. Neurosurgery. 2019;85(5):632-641. doi: 10.1093/neuros/nyy436 [DOI] [PubMed] [Google Scholar]

[coi250028r10] 10.Atalar B, Modlin LA, Choi CY, et al. Risk of leptomeningeal disease in patients treated with stereotactic radiosurgery targeting the postoperative resection cavity for brain metastases. Int J Radiat Oncol Biol Phys. 2013;87(4):713-718. doi: 10.1016/j.ijrobp.2013.07.034 [DOI] [PubMed] [Google Scholar]

[coi250028r11] 11.El Shafie RA, Tonndorf-Martini E, Schmitt D, et al. Pre-operative versus post-operative radiosurgery of brain metastases-volumetric and dosimetric impact of treatment sequence and margin concept. Cancers (Basel). 2019;11(3):294. doi: 10.3390/cancers11030294 [DOI] [PMC free article] [PubMed] [Google Scholar]

[coi250028r12] 12.Vellayappan BA, Doody J, Vandervoort E, et al. Pre-operative versus post-operative radiosurgery for brain metastasis: effects on treatment volume and inter-observer variability. J Radiosurg SBRT. 2018;5(2):89-97. [PMC free article] [PubMed] [Google Scholar]

[coi250028r13] 13.Redmond KJ, De Salles AAF, Fariselli L, et al. Stereotactic radiosurgery for postoperative metastatic surgical cavities: a critical review and International Stereotactic Radiosurgery Society (ISRS) practice guidelines. Int J Radiat Oncol Biol Phys. 2021;111(1):68-80. doi: 10.1016/j.ijrobp.2021.04.016 [DOI] [PubMed] [Google Scholar]

[coi250028r14] 14.Prabhu RS, Dhakal R, Vaslow ZK, et al. Preoperative radiosurgery for resected brain metastases: the PROPS-BM multicenter cohort study. Int J Radiat Oncol Biol Phys. 2021;111(3):764-772. doi: 10.1016/j.ijrobp.2021.05.124 [DOI] [PubMed] [Google Scholar]

[coi250028r15] 15.Asher AL, Burri SH, Wiggins WF, et al. A new treatment paradigm: neoadjuvant radiosurgery before surgical resection of brain metastases with analysis of local tumor recurrence. Int J Radiat Oncol Biol Phys. 2014;88(4):899-906. doi: 10.1016/j.ijrobp.2013.12.013 [DOI] [PubMed] [Google Scholar]

[coi250028r16] 16.Brennan C, Yang TJ, Hilden P, et al. A phase 2 trial of stereotactic radiosurgery boost after surgical resection for brain metastases. Int J Radiat Oncol Biol Phys. 2014;88(1):130-136. doi: 10.1016/j.ijrobp.2013.09.051 [DOI] [PMC free article] [PubMed] [Google Scholar]

[coi250028r17] 17.Roth O’Brien DA, Poppas P, Kaye SM, et al. Timing of adjuvant fractionated stereotactic radiosurgery affects local control of resected brain metastases. Pract Radiat Oncol. 2021;11(3):e267-e275. doi: 10.1016/j.prro.2021.01.011 [DOI] [PubMed] [Google Scholar]

[coi250028r18] 18.Prabhu RS, Patel KR, Press RH, et al. Preoperative vs postoperative radiosurgery for resected brain metastases: a review. Neurosurgery. 2019;84(1):19-29. doi: 10.1093/neuros/nyy146 [DOI] [PubMed] [Google Scholar]

[coi250028r19] 19.Lowe SR, Wang CP, Brisco A, et al. Surgical and anatomic factors predict development of leptomeningeal disease in patients with melanoma brain metastases. Neuro Oncol. 2022;24(8):1307-1317. doi: 10.1093/neuonc/noac023 [DOI] [PMC free article] [PubMed] [Google Scholar]

[coi250028r20] 20.Cheok SK, Yu C, Feng JJ, et al. Comparison of preoperative versus postoperative treatment dosimetry plans of single-fraction stereotactic radiosurgery for surgically resected brain metastases. Neurosurg Focus. 2023;55(2):E9. doi: 10.3171/2023.5.FOCUS23209 [DOI] [PubMed] [Google Scholar]

PERMALINK

Therapy, Safety, and Logistics of Preoperative vs Postoperative Stereotactic Radiation Therapy

Debra Nana Yeboa, MD

Jing Li, MD, PhD

Ruitao Lin, PhD

Sujit S Prabhu, MD

Thomas H Beckham, MD, PhD

Kristina Woodhouse, MD

Todd Allen Swanson, MD, PhD

Jeffrey S Weinberg, MD

Xuemei Wang, PhD

Xiaohan Chi, MS

Chinenye Lynette Ejezie, PhD

Dima Suki, PhD

Chenyang Wang, MD, PhD

Chibawanye Ene, MD, PhD

Ian E McCutcheon, MD

Susan McGovern, MD, PhD

Mary Frances McAleer, MD, PhD

Martin Tom, MD

Amol Ghia, MD

Subha Perni, MD

Wen Jiang, MD, PhD

Brian De, MD

Caroline Chung, MD

Betty Y S Kim, MD, PhD

Barbara J O’Brien, MD

Jason T Huse, MD, PhD

Jeffrey S Wefel, PhD

Laurence Court, PhD

Hussein Tawbi, MD, PhD

Filip Janku, MD, PhD

Nandita Guha-Thakurta, MD

J Matthew Debnam, MD

Jason Johnson, MD

Ceylan Altintas Taslicay, MD

Christopher Alvarez-Breckenridge, MD, PhD

Shaan M Raza, MD

Amy B Heimberger, MD, PhD

Franco DeMonte, MD

Robert North, MD, PhD

Tina M Briere, PhD

John F de Groot, MD

Raymond Sawaya, MD

David Grosshans, MD, PhD

Frederick F Lang, MD

Ganesh Rao, MD

Sherise D Ferguson, MD

Key Points

Question

Finding

Meaning

Abstract

Importance

Objective

Design, Setting, and Participants

Interventions

Main Outcomes and Measures

Results

Conclusions and Relevance

Trial Registration

Introduction

Methods

Study Design and Participants

Procedures and Interventions

Statistical Analysis

Results

Patient Characteristics

Figure. CONSORT Diagram of Brain Metastases Patients Enrolled.

Table 1. Descriptive Statistics of Patients Enrolled in the Preoperative and Postoperative Arms.

Treatment of Enrolled Patients

Patient Characteristics

Table 2. Descriptive Statistics of Patients Enrolled in the Preoperative vs Postoperative Trial Who Completed Both Therapies.

Radiation Therapy

Table 3. Per-Lesion Tumor Characteristics and Time to Therapy.

Timing of Therapy

Postprocedural Events in Enrolled Patients

Table 4. Descriptive Statistics of Postsurgical Procedure 30-Day Events by Randomized Group.

Discussion

Limitations