Brain metastases represent the most common etiology of malignant intracranial tumors. Although it is impossible to provide precise global statistical data, population-based studies [1][2] show that 10–30% of patients diagnosed with cancer encounter this complication at some point in their disease course. The widespread availability of healthcare services and magnetic resonance imaging (MRI), along with the increasing survival rates of oncology patients, accounts for the rising incidence of brain metastases. CNS metastases increase morbidity through numerous mechanisms: worsening neurological symptoms, seizures, cognitive decline, and reduced quality of life and overall survival—a partial list of the challenges these patients face.
While the role of systemic therapies in managing intracranial metastases is growing, local treatment modalities—surgery and radiotherapy—remain primary. When selecting a treatment strategy, in addition to the number, location, and volume of metastases, we consider whether the patient is symptomatic and evaluate their general performance status.
Traditionally, patients are categorized based on complexity into one of three groups:
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Limited (1–4 metastases; stereotactic radiotherapy can be planned)
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Non-limited (≥5 metastases; the primary treatment method is whole-brain radiation therapy)
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Extensive brain metastatic disease (due to disease severity, symptom palliation and steroid therapy only are recommended)
In limited disease, when dealing with single, symptomatic metastatic lesions, surgical intervention is often the method of choice, provided it is technically feasible. Surgery provides faster relief from mass effect and symptoms, while also yielding tissue for pathological verification.
When intervention is technically impossible, contraindicated, or in cases of non-limited disease, radiotherapy becomes the mainstay of treatment, typically choosing between two techniques:
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SRS/SRT (Stereotactic Radiosurgery / Stereotactic Radiotherapy): High-dose irradiation targeted strictly to metastatic sites.
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WBRT (Whole Brain Radiation Therapy): Irradiation of the entire brain.
With advances in radiation therapy, the definition of limited intracranial disease has become outdated in many institutions, and having more than 4 metastases is no longer a restriction for stereotactic radiation therapy. But how justified is this approach? Does a patient derive real benefit from treating 10 or 15 metastases individually? To answer this question, we examine a randomized, multicenter, phase 3 study published in 2025 that compared WBRT and SRS/SRT. [3]
This study enrolled patients with 5–20 brain metastases, good performance status, no leptomeningeal disease, and no prior cranial radiotherapy. Since most patients require post-operative cavity irradiation following surgical resection, patients managed surgically at baseline were eligible for inclusion. Between 2017 and 2024, approximately 200 such patients were randomized—half received WBRT (with hippocampal avoidance) and the other half received SRS/SRT.
In patients treated with stereotactic radiosurgery, overall performance status, neurocognitive functioning, and the ability to perform daily tasks were significantly better compared to those who received whole-brain radiation. There was no difference in overall survival between the two groups. Furthermore, as expected, SRS/SRT proved superior in achieving local control of existing metastases; however, it fell significantly short of WBRT in preventing the emergence of new metastases and, more importantly, carried a higher risk of radiation necrosis (though this difference was largely driven by subclinical, radiologically detected necrosis rather than symptomatic complications).
In modern evidence-based medicine, any intervention aims to increase overall survival or quality of life; in other words, after our intervention, the patient should live longer and/or better. According to the data from this study, overall survival is identical whether using total or targeted brain irradiation. However, the difference lies in the quality of life, where SRS/SRT holds a clear advantage: following stereotactic therapy, patients live with fewer symptoms, maintain a higher degree of independence, and generally suffer less from memory impairment.
What conclusions can be drawn from this study? Given that the majority of patients enrolled had more than ten metastases, and the advantage of stereotactic radiotherapy was consistent across all subgroups—regardless of sex, age, pre-treatment neurological symptoms, or steroid dose—this trial poses a major challenge to the historical paradigm. It proves that non-limited disease does not automatically imply the necessity of WBRT.
What do the guidelines recommend? Guidelines offer virtually no strict recommendations leaning toward a specific tactic based solely on the number or size of metastases, as dozens of other variables dictate the patient’s condition and prognosis. Unlike historical definitions, the latest edition of the NCCN Guidelines [4] offers a more real-world-adapted definition: a patient belongs in the “limited” brain metastases group if we anticipate cognitive function preservation and at least equal benefit from SRS/SRT as from whole-brain radiation. In all such cases, stereotactic radiotherapy is recommended.
Author: Mikheil Atskvereli, MD, Radiation Oncologist
