Stereotactic Radiosurgery and Immunotherapy for Brain Metastases: Practical Integration, Timing, and Toxicity

1. Introduction

Brain metastases occur in up to 20–40% of patients with advanced solid malignancies and remain a major cause of neurologic morbidity and mortality [1]. The incidence is particularly high in melanoma, non-small cell lung cancer (NSCLC), and renal cell carcinoma, reflecting tumor biology and improved systemic therapies that prolong survival [2]. Although breast cancer is also a common source, it is not emphasized here due to the evolving role of immune checkpoint inhibitors (ICIs) in this setting [3,4]. Over the past decade, management has shifted toward focal therapies such as stereotactic radiosurgery (SRS) rather than whole-brain radiotherapy (WBRT) in appropriately selected patients [5].

SRS is now a standard treatment for limited brain metastases, delivering highly conformal, ablative doses with high local control while preserving neurocognitive function compared with WBRT [6]. Concurrently, ICIs have transformed systemic therapy for melanoma, NSCLC, and other malignancies with central nervous system involvement [7]. As a result, patients increasingly receive both SRS and ICIs during their treatment course [8].

This convergence raises a key clinical question: how should SRS and ICIs be optimally integrated, and does treatment timing influence outcomes and toxicity? The rationale for combination is biologically compelling. Radiation enhances tumor immunogenicity through antigen release, dendritic cell activation, and T-cell priming, potentially synergizing with checkpoint blockade [9]. However, this immune activation may also increase inflammatory toxicity, including RN and edema [10].

Despite expanding clinical experience, optimal sequencing remains uncertain. Current evidence is largely retrospective and heterogeneous, with variable definitions of “concurrent” therapy and differences in histology and treatment regimens. Nonetheless, consistent patterns suggest improved intracranial outcomes with concurrent treatment and highlight important toxicity differences between single-agent and dual ICI strategies [11,12].

This narrative review provides a clinically focused synthesis of the evidence on SRS–ICI integration in brain metastases, emphasizing biologic rationale, treatment timing, efficacy, and toxicity. We also propose a practical framework for clinical decision-making and highlight key areas for future research.

2. Methods of Literature Review

This narrative review was conducted using focused searches of PubMed, Embase, and Scopus. Search terms included combinations of “brain metastases,” “stereotactic radiosurgery,” “stereotactic radiotherapy,” “immune checkpoint inhibitors,” “PD-1,” “PD-L1,” “CTLA-4,” “timing,” “concurrent,” “sequential,” and “radionecrosis.”

Priority was given to multicenter studies, contemporary retrospective analyses, prospective trials, and meta-analyses published between 2016 and 2026. Studies evaluating treatment timing, local control, overall survival, and RN were included, with emphasis on melanoma and NSCLC cohorts.

3. Biological Rationale for Combining SRS and Immunotherapy

The rationale for combining SRS with immune checkpoint inhibitors (ICIs) is based on radiation induced immune modulation [9]. High-dose focal radiation can induce immunogenic cell death, promoting antigen release, enhanced antigen presentation, and subsequent dendritic cell activation and T-cell priming, effectively transforming the irradiated lesion into an in situ vaccine–like stimulus [13,14].

Radiation also modulates the tumor microenvironment by increasing major histocompatibility complex (MHC) expression, enhancing T-cell infiltration, and altering cytokine signaling [15]. These effects may augment ICI efficacy, which functions by relieving inhibitory signals on T cells and sustaining antitumor immune responses [16]. This biologic synergy supports combining SRS and ICIs, particularly when delivered in close temporal proximity [17,18,19] .

However, these same mechanisms may also increase toxicity. Radionecrosis (RN) is a multifactorial process involving vascular injury, hypoxia, and immune-mediated inflammation [20]. ICIs may amplify these pathways, particularly with dual checkpoint blockade, potentially increasing the risk of treatment-related toxicity [10].

4. Clinical Evidence on Treatment Timing

4.1. Definition of Concurrent Treatment

A major limitation in the literature is the lack of a standardized definition of “concurrent” treatment. Definitions vary across studies, ranging from within 1, 2, or 4 weeks to within one pharmacokinetic half-life of the ICI agent [18].

Despite this variability, most studies adopt a practical definition of concurrent therapy as SRS delivered within approximately 2–4 weeks of ICI administration [8,12]. Some analyses suggest that shorter intervals, particularly within 2 weeks or one half-life, may be associated with improved intracranial response, although optimal timing remains uncertain [18].

4.2. Evidence in Melanoma

Radiation may potentiate ICI through enhanced antigen presentation and T-cell activation, providing a biological rationale for combining SRS with ICI [21]. Dual ICI remains the systemic backbone in melanoma, with Tawbi et al. demonstrating intracranial response rates of 55–57% and durable control [22]. Subsequent SRS-ICI studies consistently show improved intracranial control. Kotecha et al. reported that timing influences efficacy more than toxicity, with concurrent ICI improving response and low RN(3–5%) [18], while Carron et al. confirmed low toxicity with anti–PD-1 therapy (adverse radiation effect 4–5%, symptomatic <3%) [23].

Regimens incorporating CTLA-4 inhibition, particularly dual ICI, are associated with higher RN rates, although estimates vary. Minniti et al. reported moderate RN (15–25%) with concurrent nivolumab/ipilimumab (15–25%) [24]. In contrast, Tang et al. demonstrated significantly improved local control (92% vs 64%) without excess toxicity or increased RN [25]. Fu et al. similarly observed improved survival with concurrent SRS–ICI (37.1 vs 11.4 months) without increased radiation toxicity (2–3%) [26]. More recent data from Messing et al. show excellent local control (~90%) with low symptomatic RN (7%), while identifying prior systemic therapy as a prognostic factor [27]. Conversely, Vaios et al. reported higher RN rates with dual ICI (20–25%) [10], whereas Mandalà et al. demonstrated survival benefit with moderate RN (10%) [28]. Key retrospective studies are summarized in Table 1.

Overall, the evidence is heterogeneous and predominantly retrospective but supports close temporal integration of SRS with ICI to optimize intracranial control. ICI regimen and prior therapy exposure appear to be key determinants of toxicity and outcomes, underscoring the need for prospective validation.

4.3. Evidence in Non-Small Cell Lung Cancer (NSCLC)

Non–small cell lung cancer (NSCLC) has a growing but less mature evidence base for SRS–ICI integration compared with melanoma. Early-phase prospective studies demonstrate feasibility, safety, and encouraging intracranial control, although they were not designed to define optimal sequencing [29,30,31,32].

Across retrospective cohorts, SRS combined with ICI consistently improves intracranial control and, in selected studies, overall survival, with outcomes influenced by timing and patient selection. Foundational studies by Chen et al. and Schapira et al. showed that concurrent SRS–ICI (within 2–4 weeks) is associated with improved survival and intracranial control compared with nonconcurrent approaches [12,33]. Larger analyses, including Yomo et al., confirmed a survival advantage (mOS ~16.9 vs. 12.0 months) and improved intracranial PFS without increased toxicity [34], consistent with findings from Bashir et al. [35].

Some studies highlight differential response patterns. Shepard et al. found no survival benefit but significantly higher complete response rates (50% vs. 15.6%) with concurrent ICI [36], while Singh et al. demonstrated greater tumor shrinkage in larger lesions (>500 mm³), suggesting size-dependent synergy [37]. Additional data show improved distant intracranial control with concurrent therapy, with shorter treatment intervals (≤7 days) associated with superior outcomes [38,39]. More recent studies (Dohm et al., Frehner et al., Lu et al.) support improved intracranial response with upfront or concurrent SRS, although overall survival differences remain inconsistent, indicating a potential role for selective or deferred radiation in asymptomatic patients [40,41,42]. Key retrospective studies are summarized in Table 2.

Importantly, radionecrosis and adverse radiation effects remain low (~3–10%) and are not consistently increased with ICI. Emerging evidence suggests that dosimetric factors, rather than ICI itself, are the primary determinants of toxicity [43].

4.4. Evidence from Pooled and Meta-Analyses

Pooled and meta-analytic evidence supports combining SRS with ICI, with stronger and more consistent benefit in melanoma than NSCLC. In melanoma, systematic reviews highlight a shift toward multimodal, patient-specific strategies integrating SRS, immunotherapy, and systemic therapy [44]. In melanoma, meta-analyses demonstrate significant survival benefit with SRS–ICI, particularly with anti–PD-1 regimens [45], while Bayesian network analyses rank SRS + ICI as the most effective strategy for overall survival and intracranial control, albeit with increased radionecrosis (RN) risk [46]. Timing analyses further suggest that concurrent SRS–ICI (within 4 weeks) improves survival and intracranial outcomes compared with nonconcurrent approaches [11,47].

Contemporary pooled data report high local control (80–85%) and favorable 1-year survival (65–70%), with RN rates of approximately 10–12% in the modern immunotherapy era [48]. Importantly, large multicenter analyses indicate that RN risk is primarily driven by dosimetric factors, particularly V12 Gy, rather than treatment timing, supporting the safety of concurrent approaches when appropriate constraints are applied [8].

In NSCLC, pooled data suggest a more nuanced interaction. Chu et al. found no significant difference in survival between ICI alone and ICI combined with cranial radiotherapy, although concurrent treatment reduced distant brain failure [49]. In contrast, Yang et al. demonstrated improved overall survival with combined radiotherapy and ICI compared with radiotherapy alone, with concurrent treatment emerging as the optimal strategy without increased toxicity [50]. These findings reflect different clinical questions—whether radiotherapy augments ICI or vice versa—and collectively support a model in which immunotherapy drives survival, while SRS improves intracranial disease control.

Overall, SRS–ICI integration provides the greatest benefit in melanoma, particularly with concurrent delivery. In NSCLC, immunotherapy is the primary driver of survival, while SRS optimizes intracranial control. Major pooled analyses are summarized in Table 3.

4.5. Comparative Considerations: Melanoma vs. NSCLC

Important distinctions exist between melanoma and NSCLC in the context of SRS–ICI integration. In melanoma, evidence consistently supports a synergistic benefit, particularly with concurrent treatment [11,45,46]. In NSCLC, outcomes are more heterogeneous, with immunotherapy driving survival and radiotherapy contributing primarily to intracranial control in a context-dependent manner [49,50]. Molecular subgroups further influence treatment decisions; tumors with actionable driver mutations (e.g., EGFR, ALK) often respond well to CNS-penetrant targeted therapies [51] and these mutations are less responsive to ICI [52], limiting the role in SRS–ICI integration in this entity. In these cases, SRS is typically reserved for oligoprogressive or symptomatic disease.

5. Role of Dosimetry and Treatment Factors

Radionecrosis following stereotactic radiosurgery is multifactorial and cannot be explained by treatment timing alone. Although much of the literature focuses on the temporal relationship between SRS and ICI, accumulating evidence suggests that radiation dose volume parameters remain the primary determinants of toxicity, particularly in the setting of combined modality therapy.

Among dosimetric parameters, the volume of normal brain receiving 12 Gy (V12 Gy) is the most robust and consistently validated predictor of radionecrosis. In a large multicenter analysis by Lehrer et al. including 657 patients and over 4,000 brain metastases, V12 Gy was independently associated with radionecrosis risk not the timing of ICI administration (8). Increasing V12 Gy correlates with stepwise toxicity, with low-risk (<12 cm³), intermediate-risk (12–20 cm³), and high-risk (>20 cm³) groups demonstrating progressively higher rates [8]. These findings underscore that dosimetric optimization remains the primary determinant of radionecrosis risk, even in the era of immunotherapy.

Additional dosimetric and treatment related factors contribute to the risk of radionecrosis. Treatment of larger lesions (typically >2 cm) requires higher integral dose and results in greater exposure of surrounding normal brain tissue [43,53,54]. In patients with multiple brain metastases, cumulative treated volume increases overall brain dose and expands the low-dose radiation bath [55]. Prior cranial irradiation, including previous SRS or WBRT, further reduces normal tissue tolerance and may further increase the risk of radionecrosis [56].

Clinical factors are equally relevant. Baseline edema, corticosteroid use, and lesion location particularly in eloquent or deep brain regions may influence both the development and clinical impact of radionecrosis [57,58]. These factors may interact with immunotherapy, as immune activation can amplify inflammatory responses.

The addition of ICIs introduces further complexity. While single agent ICIs do not appear to substantially increase radionecrosis risk [23], emerging data suggest that dual checkpoint blockade may enhance inflammatory toxicity, making dosimetric optimization even more critical [10].

Overall, these findings support a shift in clinical thinking. Radionecrosis risk should not be viewed primarily through treatment timing, but rather through an integrated framework of dosimetry, lesion characteristics, prior treatment, and immunotherapy regimen. In particular, the combination of high risk dosimetric features (e.g., elevated V12 Gy or large target volume) with clinical modifiers such as dual checkpoint blockade or significant perilesional edema defines a higher risk population in whom treatment modification strategies, including dose optimization and hypofractionation, should be considered.

6. Fractionation and Risk Mitigation Strategies

Hypofractionated stereotactic radiotherapy is commonly employed to mitigate the risk of radionecrosis, particularly for lesions >2 cm or when V12 Gy exceeds approximately 10 cm³ [54], or those receiving dual immune checkpoint inhibition [8]. Although prospective data remains limited, this approach is widely adopted in clinical practice. By reducing peak dose to normal brain tissue, fractionation may help offset the increased inflammatory effects associated with concurrent immunotherapy.

7. Radiographic Assessment and Diagnostic Challenges

Distinguishing pseudoprogression, radionecrosis, and true tumor progression after SRS in patients receiving immune checkpoint inhibitors remains a major diagnostic challenge, as all may present with enlarging contrast enhancing lesions on MRI [59,60]. Pseudoprogression typically occurs early in first few months (approximately 6 months), whereas radionecrosis is a delayed effect, often developing 6–12 months post SRS [61,62,63]. The combined inflammatory effects of SRS and immunotherapy further complicate interpretation. The iRANO criteria recommend confirmatory imaging within 6 months of ICI initiation [64]. Advanced imaging modalities, including perfusion MRI and amino acid PET, improve diagnostic accuracy, though uncertainty often necessitates multidisciplinary evaluation and serial imaging [59].

8. Management of Radionecrosis

Management of radionecrosis after SRS follows a stepwise, symptom-guided approach. Asymptomatic cases may be observed with serial imaging, while symptomatic patients are treated with corticosteroids using the lowest effective dose and gradual taper. Bevacizumab is effective in steroid-refractory cases, with response rates exceeding 80% and significant radiographic improvement [65,66,67]. Surgical resection or laser interstitial thermal therapy (LITT) is reserved for refractory or diagnostically uncertain cases, providing tissue confirmation and durable control [68]. Emerging data suggest comparable efficacy between bevacizumab and LITT [69]. Management should be individualized based on symptoms, lesion characteristics, and diagnostic certainty.

9. Limitations of Current Evidence

The current literature is limited by its predominantly retrospective nature, heterogeneity in study design, and variability in definitions of concurrent treatment. Confounding by indication and challenges in distinguishing radionecrosis from tumor progression further complicate interpretation.

10. Practical Clinical Implications

The integration of SRS and immune checkpoint inhibitors requires a structured, risk-adapted approach incorporating immunotherapy regimen, dosimetry, and clinical factors.

10.1. Immunotherapy Regimen

The distinction between single agent and dual checkpoint inhibition is critical. Concurrent SRS with single agent ICI appears safe and may improve intracranial outcomes without significantly increasing radionecrosis risk. In contrast, dual checkpoint blockade is associated with a higher incidence of symptomatic radionecrosis and should prompt more cautious integration strategies.

10.2. Timing Considerations

For single-agent ICI, concurrent or near-concurrent SRS (within approximately 2–4 weeks) is reasonable and may enhance response and local control. With dual ICI, the risk of radionecrosis is higher and optimal sequencing remains uncertain; when feasible, delaying SRS by ≥4 weeks or using fractionated SRS should be considered, particularly for larger or high-risk lesions.

10.3. Dosimetric Risk

Radiation dose volume parameters, particularly V12 Gy, remain the dominant predictors of radionecrosis. Efforts should be made to minimize normal brain dose, with V12 Gy thresholds serving as a practical guide for risk stratification.

10.4. Fractionation Strategy

Radiation dose–volume parameters, particularly V12 Gy, remain the dominant predictors of radionecrosis and should guide risk stratification and treatment planning.

10.5. Additional Clinical Modifiers

Corticosteroid use, baseline edema, prior cranial irradiation, and cumulative intracranial disease burden further influence both efficacy and toxicity and should be incorporated into decision-making.

10.6. Integrated Clinical Approach

Treatment decisions should be guided by a composite assessment of ICI regimen, lesion characteristics, and dosimetry, with selective use of fractionation and minimization of corticosteroids. Coordination of systemic and local therapy should prioritize both efficacy and toxicity mitigation rather than timing alone.

A practical decision framework for integrating SRS with single-agent or dual ICI is summarized in Figure 1.

11. Future Directions

Future directions include prospective trials to define optimal timing and sequencing, alongside strategies such as dose de-escalation and fractionation to reduce toxicity [43,70]. Emerging biomarkers including neutrophil to lymphocyte ratio, early CD8⁺ T-cell activation, tumor aneuploidy, and immuno-inflammatory signatures may help identify patients most likely to benefit from combined therapy and guide immunotherapy selection [15,71]. Additional areas include exploiting the abscopal effect [72], novel immune targets, advanced imaging, and multimodality approaches [73,74,75].

12. Conclusions

The integration of SRS and immune checkpoint inhibitors represents a major advance in the management of brain metastases. Concurrent SRS with single-agent ICI appears feasible and may enhance intracranial control without significantly increasing toxicity. In contrast, dual checkpoint blockade and higher dose–volume exposure (particularly V12 Gy) define a higher-risk population for radionecrosis, necessitating more cautious, individualized strategies. Optimal integration requires consideration of not only timing, but also immunotherapy regimen, lesion characteristics, fractionation, and dosimetric parameters. Prospective studies are needed to define these relationships and guide evidence-based clinical decision-making.