Introduction

Brain metastases are the most common intracranial malignancies in adults, occurring in up to 20-40% of patients with systemic cancer during the course of their disease. Improvements in systemic therapies, including targeted agents and immunotherapies, have prolonged survival in many cancer types such as lung cancer, breast cancer, and melanoma, thereby increasing the cumulative incidence of intracranial metastatic disease [1-3]. Consequently, optimizing the management of brain metastases has become a critical priority in neuro-oncology. Historically, whole-brain radiotherapy (WBRT) was the standard adjuvant treatment following surgical resection of brain metastases. While WBRT improved intracranial control, it was associated with significant neurocognitive decline and diminished quality of life. These concerns prompted a paradigm shift toward more focal strategies, particularly stereotactic radiosurgery (SRS). SRS delivers highly conformal, high-dose radiation to a defined target while minimizing exposure to surrounding healthy brain tissue [4-6]. 

Over the past two decades, SRS has emerged as a cornerstone in the treatment of limited brain metastases, either as definitive therapy or as an adjunct to surgery. The role of SRS in the perioperative setting has traditionally been postoperative, targeting the surgical cavity to reduce local recurrence. Postoperative SRS has demonstrated improved local control compared with surgery alone and reduced neurocognitive toxicity compared with WBRT. However, several limitations of postoperative SRS identified. After resection, the surgical cavity may undergo dynamic changes in size and shape, complicating target delineation and potentially increasing treatment volumes. Moreover, postoperative SRS has been associated with a risk of leptomeningeal disease (LMD), possibly due to tumor cell dissemination during surgery. Rates of radiation necrosis also remain a concern, particularly in larger cavities requiring higher radiation doses [7-9].

In response to these challenges, preoperative SRS has emerged as an alternative strategy. In this approach, SRS delivered to the intact tumor prior to surgical resection. The theoretical advantages of preoperative SRS include more precise target definition, as the gross tumor volume clearly visualized on imaging before resection. This may allow for smaller radiation margins and reduced irradiation of normal brain tissue. Additionally, irradiation of the tumor before surgical manipulation may sterilize tumor cells, potentially reducing the risk of intraoperative dissemination and subsequent LMD. Preoperative SRS may also lower the incidence of radiation necrosis, as the irradiated tissue subsequently removed during surgery [10].

Despite these proposed benefits, preoperative SRS also presents logistical and clinical considerations. Coordinating timely SRS prior to surgery requires multidisciplinary planning and may not be feasible in cases requiring urgent decompression. Furthermore, concerns remain regarding wound healing complications, optimal dosing strategies, and the lack of high-level randomized data directly comparing preoperative and postoperative approaches [11-13].

Several retrospective studies and emerging prospective data have attempted to evaluate the comparative effectiveness of preoperative versus postoperative SRS. Reported outcomes include local control, distant brain failure, LMD incidence, radiation necrosis, overall survival, and treatment-related morbidity. While some studies suggest reduced LMD and radiation necrosis with preoperative SRS, others report comparable oncologic outcomes between the two strategies. However, variability in study design, patient selection, tumor characteristics, and radiation protocols has limited definitive conclusions [14].

Given the increasing adoption of SRS in the management of resectable brain metastases and the ongoing debate regarding optimal timing, a comprehensive synthesis of available evidence warranted. This systematic review and meta-analysis aims critically compare preoperative and postoperative SRS in patients undergoing surgical resection for brain metastases, with particular focus on local control, leptomeningeal disease, radiation necrosis, distant brain failure, and overall survival. By integrating current evidence, this study seeks to inform clinical decision-making and identify areas requiring further investigation through prospective randomized trials [15-17].

Background / Literature Review

The management of brain metastases has evolved significantly over the past few decades, reflecting advances in surgical techniques, radiotherapy modalities, and systemic therapies. Historically, surgical resection combined with whole-brain radiotherapy (WBRT) was the standard approach for patients with limited brain metastases. WBRT, while effective in controlling both local and distant intracranial disease, was associated with significant neurocognitive decline, including deficits in memory, attention, and executive function. These adverse effects prompted research into more localized radiotherapy approaches, such as stereotactic radiosurgery (SRS), which delivers high-dose radiation precisely to the tumor or surgical cavity while sparing surrounding normal brain tissue [18-20].

Postoperative SRS emerged as a preferred strategy for adjuvant therapy following resection of brain metastases. Multiple retrospective and prospective studies have demonstrated that postoperative SRS improves local control rates compared with surgery alone, while significantly reducing the cognitive decline observed with WBRT. However, postoperative SRS is not without limitations. Surgical cavities can change in size and shape after resection, making accurate target delineation challenging and often necessitating larger treatment volumes. Furthermore, postoperative SRS has been associated with a risk of leptomeningeal disease (LMD), presumably due to intraoperative tumor cell dissemination. Radiation necrosis remains a notable complication, particularly for larger cavities requiring high-dose treatment [21-23].

Preoperative SRS recently been proposed as an alternative approach to address these limitations. In this method, SRS delivered to the intact tumor prior to surgical resection. Preoperative SRS allows for precise target delineation and potentially smaller irradiation margins. Some studies suggest that sterilizing tumor cells before surgery may reduce LMD rates and decrease radiation necrosis since the irradiated tissue subsequently removed. Initial cohort studies have shown promising results in terms of safety and local control; however, the literature limited by small sample sizes, heterogeneity in tumor histologies, and variability in radiation dosing protocols [24-26].

Several comparative studies have attempted to assess the advantages and disadvantages of preoperative versus postoperative SRS. Retrospective analyses indicate that preoperative SRS may lower the incidence of LMD and symptomatic radiation necrosis while maintaining comparable local control rates. A growing body of multicenter observational studies has further explored treatment-related outcomes, including overall survival, distant brain failure, and perioperative complications. Despite these efforts, high-level evidence remains scarce, and randomized controlled trials directly comparing preoperative and postoperative SRS are still lacking [27-29].

In addition, the choice of preoperative versus postoperative SRS influenced by multiple patient- and tumor-related factors. Tumor size, location, histology, systemic disease status, and the urgency of surgical intervention all play a role in treatment planning. Multidisciplinary coordination between neurosurgeons, radiation oncologists, and medical oncologists is critical to optimize outcomes. As precision medicine advances, individualized treatment strategies considering molecular and genetic tumor characteristics may further refine the decision-making process [30-32].

Overall, the current literature suggests that both preoperative and postoperative SRS are effective adjuvant strategies following resection of brain metastases, with preoperative SRS showing potential benefits in reducing LMD and radiation necrosis. However, variations in study design, patient selection, and treatment protocols underscore the need for systematic evaluation and meta-analytic synthesis to guide clinical practice.

Methods

This systematic review and meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A comprehensive literature search conducted in PubMed, Scopus, Web of Science, and Cochrane Library databases from inception to December 2025. Search terms included “brain metastases,” “stereotactic radiosurgery,” “preoperative radiosurgery,” “postoperative radiosurgery,” “surgical resection,” and related synonyms. References of relevant studies and review articles also screened to identify additional eligible studies.

Inclusion criteria were: (1) studies comparing preoperative and postoperative SRS in adult patients undergoing surgical resection of brain metastases, (2) reporting at least one relevant clinical outcome (local control, leptomeningeal disease, radiation necrosis, distant brain failure, or overall survival), and (3) original research including retrospective or prospective cohort studies. Exclusion criteria included case reports, reviews, editorials, studies with fewer than 10 patients per group, and studies lacking clear outcome data.

Data extraction was performed independently by two reviewers, collecting information on study design, patient demographics, tumor characteristics, treatment parameters, follow-up duration, and clinical outcomes. Discrepancies were resolved through discussion or consultation with a third reviewer. Risk of bias was assessed using the Newcastle–Ottawa Scale for observational studies.

For the meta-analysis, outcome measures pooled using a random-effects model to account for inter-study heterogeneity. Heterogeneity quantified using the I² statistic, with values above 50% indicating substantial heterogeneity. Subgroup analyses conducted based on tumor histology, treatment timing, and SRS dose. Publication bias evaluated using funnel plots and Egger’s test. Statistical analyses performed using Review Manager (RevMan) version 5.4 and STATA version 17.

Figure 1. The Method figure

 Results

 Table 1. Local Control Rates (Preoperative vs. Postoperative SRS)

Table 1 summarizes comparative local control rates between preoperative and postoperative SRS in patients undergoing resection of brain metastases. Across multiple studies, local control for preoperative SRS ranged from 88% to 94%, while postoperative SRS achieved 87%-92%. Pooled analysis shows a slight advantage for preoperative SRS (91.5% vs. 89.5%), although differences are not statistically significant in most studies.

The relative consistency of local control indicates that both preoperative and postoperative SRS effectively eradicate microscopic residual disease at the resection site. Preoperative SRS may have theoretical advantages due to irradiation of intact tumor tissue, allowing for precise target delineation and sterilization of tumor cells prior to surgical manipulation. This could reduce the risk of residual microscopic disease, potentially explaining the modest trend toward higher local control in preoperative SRS.

Postoperative SRS, on the other hand, must contend with the challenges of dynamic cavity changes after resection. Variability in cavity volume and morphology can result in marginal misses or larger irradiation volumes, which might affect both efficacy and toxicity. Nevertheless, these data suggest that local control remains excellent with either approach, highlighting that surgical resection followed by timely SRS preoperative or postoperative provides robust oncologic management for resectable brain metastases.

Table 2. Leptomeningeal Disease (LMD) Incidence

Table 2 demonstrates a clear advantage of preoperative SRS in reducing leptomeningeal disease. Pooled LMD rates for preoperative SRS were 3.5% compared with 12.5% for postoperative SRS a relative reduction of approximately 72%.

This difference likely stems from the timing of irradiation. Preoperative SRS targets the intact tumor, potentially sterilizing tumor cells that might otherwise disseminate during surgery. In contrast, postoperative SRS is applied after surgical manipulation, when tumor cells may have already been displaced into cerebrospinal fluid pathways, increasing the risk of LMD.

The clinical significance is substantial. LMD is associated with poor prognosis and limited treatment options. Reducing LMD incidence not only improves survival potential but also minimizes the need for additional interventions such as WBRT, which carries neurocognitive risks. These findings underscore the potential advantage of preoperative SRS in high-risk patients, especially those with tumors near ventricular spaces or dural surfaces.

Table 3. Symptomatic Radiation Necrosis

Symptomatic radiation necrosis is a major complication of SRS, resulting in edema, neurological deficits, and sometimes the need for reoperation or corticosteroid therapy. Table 3 shows pooled rates of 4.5% for preoperative SRS versus 11.5% for postoperative SRS.

Preoperative SRS may reduce radiation necrosis by irradiating tumor tissue that subsequently removed. This approach limits the exposure of normal brain tissue to high-dose radiation. Conversely, postoperative SRS often requires larger margins to account for the surgical cavity and its irregular shape, increasing the risk of necrosis.

Lower necrosis rates with preoperative SRS translate into better functional outcomes and reduced corticosteroid dependence. In practice, this advantage may make preoperative SRS preferable in patients with eloquent or critical brain regions at risk for radiation injury.

Table 4. Distant Brain Failure (DBF)

Distant brain failure reflects the emergence of new metastases away from the resection cavity. Table 4 shows modest differences between preoperative and postoperative SRS, with pooled rates of 22% and 24.8%, respectively.

These data suggest that the timing of SRS primarily affects local outcomes and complications rather than distant disease control. DBF is more influenced by systemic disease burden, tumor biology, and the extent of micro metastatic spread than by the perioperative radiotherapy approach. Nevertheless, early control of the primary lesion with preoperative SRS does not compromise distant intracranial control and may allow for better integration with systemic therapies.

Table 5. Overall Survival (OS)