Stereotactic radiotherapy for brain metastases of non-small cell lung cancer: A comprehensive review

Abstract

Lung cancer, particularly non-small cell lung cancer (NSCLC), remains a leading cause of cancer-related death globally, and a significant number of patients develop brain metastasis (BM) as the disease progresses. The presence of BM, which affects up to 60% of patients with NSCLC, is correlated with an unfavorable prognosis and markedly decreased quality of life. Standard treatment options for BMs, such as whole-brain radiation therapy and surgery, have displayed limited efficacy in controlling disease progression, and they can cause significant neurocognitive side effects. Stereotactic radiotherapy (SRT), including stereotactic radiosurgery, fractionated SRT, and stereotactic body radiotherapy, represents an advanced and precise approach for treating BM that minimizes damage to surrounding healthy tissues. This review highlights recent advances in the application of SRT for treating BM of NSCLC, focusing on its underlying biological principles and mechanisms of action as well as the quality standards necessary for effective SRT implementation. The ability of SRT to deliver substantial radiation doses in a precisely targeted manner has resulted in better local tumor management, fewer side effects, and increased patient survival rates. Future research is crucial to improve SRT procedures and successfully incorporate them into multimodal therapy plans for patients with NSCLC and BM.

Key Words: Lung carcinoma; Non-small cell lung cancer; Brain metastasis; Stereotactic radiotherapy; Blood–brain barrier; Tumor microenvironment

Core Tip: Stereotactic radiotherapy (SRT) offers a precise and effective treatment option for brain metastasis (BM) in patients with non-small cell lung cancer (NSCLC), providing better local tumor control, fewer side effects, and improved survival rates compared with the effects of traditional therapies. Integrating SRT with immunotherapy has displayed promise in enhancing intracranial progression-free survival, but further research is needed to optimize treatment protocols and refine multimodal therapy strategies for patients with NSCLC and BM.

INTRODUCTION

Lung cancer remains a significant health issue globally, causing approximately 2 million new cases and 1.8 million fatalities each year[1]. Non-small cell lung cancer (NSCLC) is the most common form of lung cancer, accounting for 85% of all diagnosed cases[2]. Advanced NSCLC is associated with poor outcomes, as evidenced by 5-year survival rates of only 15% and 5% for especially stage III and metastatic stage IV NSCLC, respectively[3]. Throughout disease progression, as many as 60% of patients with NSCLC can experience central nervous system (CNS) involvement[4]. Brain metastasis (BM) in patients with NSCLC is correlated with reduced overall survival, progression-free survival, and quality of life; however, early detection has been demonstrated to improve patient outcomes[5]. BM occurs in nearly 50% of individuals with advanced NSCLC, significantly affecting the overall morbidity associated with the disease[6].

BM is associated with several symptoms, such as headache, seizures, and changes in vision, speech, and/or performance[7]. Prior research[8] indicated that these symptoms significantly decrease patients’ quality of life. Additionally, BM associated with lung adenocarcinoma is correlated with poor prognoses, leading to an average survival of approximately 15 months. Treatment options for BM are limited, typically including surgery, radiotherapy (RT), and chemotherapy. The choice of treatment depends upon several factors, together with the patient’s general health and the degree of metastasis[9,10].

Chemotherapy is an effective treatment for BM, with response rates in the brain similar to those reported in other regions of the body[11]. Targeted systemic therapies are highly effective, especially in patients with driver mutations such as EGFR and ALK–MET mutations, and they can effectively reach the CNS[11]. Although there are insufficient prospective data to determine the best timing or combination of local therapies and systemic treatments for patients with significant CNS involvement, retrospective studies suggest that initiating local interventions early could increase intracranial progression-free survival[11,12].

The management of NSCLC with BM mostly consists of surgical intervention and RT[13]. Whole-brain RT (WBRT) and stereotactic RT (SRT) are two forms of RT. SRT includes various techniques, such as fractionated SRT (FSRT), stereotactic body RT (SBRT), and stereotactic radiosurgery (SRS)[14]. Currently, most patients typically receive SRT, whereas individuals with a significant disease load receive WBRT[15]. SRT facilitates superior local control with little toxicity[16,17].

This study examined the clinical effectiveness of SRT and the underlying mechanisms in patients with lung cancer and BM. This study compared recent improvements in SRT procedures with traditional treatments to assess the effects of SRT on local control, side effects, and survival rates. This research also explored the integration of SRT with systemic medications to develop a comprehensive and successful treatment plan for patients with NSCLC.

SRT

Currently, the standard treatment for patients with limited BMs involves a combination of surgery and postoperative RT[18,19]. For individuals with an asymptomatic BM lesion, those with multiple BMs, or those ineligible for surgery because of comorbidities or challenging anatomical lesion locations, standalone RT is also considered[20]. Nevertheless, several studies reported no substantial difference in patient outcomes between RT alone and postoperative RT in terms of local disease management and overall survival[21,22]. SRT is currently recommended by the World Health Organization for the treatment of both malignant and benign tumors, in addition to neurological and vascular diseases. This treatment is especially suitable for certain difficult-to-treat or inoperable tumors, such as malignant brain tumors (e.g., glioblastoma, metastatic brain tumors), spinal tumors, lung cancer, liver cancer, and pancreatic cancer[23]. For benign tumors, such as meningioma, pituitary adenoma, and acoustic neuroma, SBRT can also effectively control tumor growth and avoid surgical risks[24]. This treatment method is widely used for tumor control and symptom relief, as it targets the tumor with precise radiation beams and minimizes damage to surrounding healthy tissues. SRT has become part of regular practice in the radiation oncology field, and it is used outside of clinical trials and specialist academic institutions[25]. The three forms of SRT (SRS, FSRT and SBRT) are distinguished by their indications, fractionation, and quality standards[26]. WBRT has traditionally been the primary method used because of its ability to rapidly address both apparent and hidden lesions[27]. WBRT plays a significant role in managing numerous brain lesions, enhancing both endemic and remote CNS tumor management. However, WBRT is associated with several adverse effects, including cognitive issues such as drowsiness and memory loss, decreased physical ability, diminished appetite, and increased fatigue[28,29]. Additionally, irradiation can cause radiation necrosis in the healthy brain parenchyma[30]. Consequently, the implementation of RT has recently transitioned to the use of less hazardous methodologies, such as SRT, which have led to increased cognitive preservation[31].

SRS

As noted by Topkan et al[32], SRS is an effective technique that allows a substantial dose of radiation to be precisely directed to a well-defined target in a single session. This ablative and focused strategy works similarly to surgical resection while causing less damage. SRS is the best treatment option for small BMs, and it is a good option when surgery is not possible, such as in cases in which metastases are located in deep or delicate brain areas and they cannot be removed or a patient has other health problems that preclude surgery[33-35]. Linear accelerators, CyberKnife^®, and GammaKnife are the most widely utilized technologies for the radiosurgical treatment of BMs[36,37]. Schmitt et al[38] and Vellayappan et al[39] used SRS to treat BMs next to the optic nerve, brainstem, or other delicate brain structures, and they demonstrated that this approach had a better toxicity profile than other RT methods.

FSRT/MULTIFRACTION STEREOTACTIC RT

FSRT/multifraction stereotactic RT (MFSRT) is a viable approach for the management of extensive postoperative cavities after the excision of a BM[20]. This method divides radiation doses to increase the biologically effective dose (BEDs) delivered to the target lesion while simultaneously minimizing the risk of radiation necrosis in adjacent healthy brain tissue[40]. Researchers have treated patients with numerous BMs with three to five FSRT treatments[41]. FSRT/MFSRT is often used to treat lesions adjacent to vital regions, such as the brainstem[15,20]. Establishing the precise radiation doses administered by MFSRT remains difficult owing to the absence of prospective studies. Studies comparing RT approaches indicated that MFRST causes much lower rates of radiation necrosis (0%–8%) than SRS (13%–30%)[20]. Research reported that the 1-year local control rate after MFSRT alone varies between 65% and 96%[15,20]. According to Perlow et al[42], FSRT/MFSRT can provide therapeutic efficacy and cause few side effects when used after surgery. Additionally, FSRT/MFSRT can be used as an initial treatment before surgery.

Moreover, this method has been substantially applied clinically because it induces a lower rate of side effects and a higher rate of local control than SRS. Putz et al[43] reported that FSRT/MFSRT had different biological effectiveness than SRS. Although hypoxic tumor cells can persist after SRS, reoxidation-based FSRT/MFSRT achieves superior tumor control rates. Patients who undergo FSRT or MFSRT might not benefit from the SIR model because of this[44]. The development of prognostic indicators for patients with NSCLC who are receiving FSRT/MFSRT to treat brain oligometastasis is extremely important. The size of the metastatic lesion and the radiation dose are the new foci of prognostic research for FSRT/MFSRT in patients with oligometastasis[45]. Although several studies suggested different BEDs for radiation, there is no universally accepted technique for evaluating the extent of the tumor, radiation dosage, or fractionation schemes[46]. Consequently, it is essential to develop and improve prediction indices to assess the efficacy of treatment for patients with NSCLC and brain oligometastasis who are undergoing FSRT/MFSRT.

SBRT

SBRT integrates various technologies and methods, such as 3D conformal radiation, intensity-modulated RT, image guidance, motion management, and stereotactic precision. However, the hallmark of SBRT is the application of a high, ablative, or nearly ablative dose in a limited number of treatment sessions (i.e., five or fewer fractions)[47]. Although the technologies and procedures used in the implementation of SBRT are intriguing, the primary purpose of this strategy is to administer a compact dosage precisely to a designated target possessing steep slopes in all directions, a technique known as geometric avoidance[48]. In contrast to traditional RT, which leverages the difference in healing between neoplastic and healthy tissues after RT to achieve a therapeutic benefit, SBRT primarily aims to target the tumor while ideally completely sparing the surrounding normal tissue[49]. Thus, this method markedly differs from traditional RT, which often affects extensive areas of healthy tissue[50].

BIOLOGICAL PRINCIPLES OF SRT

SRS was originally designed to treat a range of cranial disorders opposed to being specifically intended for the treatment of brain tumors. In the late 1960s, SRS was successfully used to treat arteriovenous malformations (AVMs), which are congenital vascular defects in which blood flows directly from arteries to veins without passing through capillaries. AVMs are characterized by poorly developed blood channels, which are highly radiosensitive. A single SRS dose of 15–25 Gy obliterates 80%–90% of small AVMs, indicating early success in the use of SRS for treating abnormal vascular structures[50-52]. This success facilitated the use of SRS in the treatment of brain tumors and metastases[53].

MECHANISM BY WHICH SRT CONTROLS METASTASIS

The tumor microenvironment (TME) is critical at every phase of metastasis, as it shapes tumor growth, progression, and spread to distant sites[54] (Figure 1). BM is common in lung cancer, as cancer cells can infiltrate the brain parenchyma by crossing the blood-brain barrier (BBB), disrupting its defense mechanism[4,55,56]. Reactive gliosis triggers changes in astrocytes that accelerate BM growth and reduce sensitivity to chemotherapy. Additionally, various TME cells are reprogrammed to facilitate cancer spread; for example, tumor-associated macrophages, especially the M2 subtype, promote angiogenesis and immune suppression[57-59].

Figure 1 Molecular mechanisms driving organotropism and brain metastasis. VEGF: Vascular endothelial growth factor; BBB: Blood-brain barrier.

Tumor spread is influenced by factors such as blood flow, proximity, and the TME. Key processes include tumor cells crossing the BBB and undergoing epithelial-mesenchymal transition, enabling tumor cell detachment and invasion. Markers, such as CXCL12/CXCR4, E-cadherin, and MMP-9, and pathways, such as the EGFR/ERK and VEGF pathways, play important roles in metastasis. Noncoding RNAs, including specific microRNAs (e.g., miRNA-200, miRNA-378) and lncRNAs (e.g., MALAT1), contribute to metastatic adaptation in the brain by regulating the expression of tumor suppressor genes and oncogenes[60].

In NSCLC, dendritic cells (DCs) suppress T lymphocyte proliferation through regulatory T cells (Tregs), and tumor-associated neutrophils can shift to protumoral N2 phenotypes, contributing to extracellular matrix remodeling and immune evasion[61,62]. RT has complex effects on TME cells that potentially influence both treatment response and resistance. RT increases immune activation by increasing natural killer (NK) cell and CD8⁺ T lymphocyte cytotoxicity and promoting M1 macrophage differentiation while reducing Treg infiltration[63,64]. DCs also become more active in response to RT, increasing MHC molecule expression and triggering immune responses[65].

Nonetheless, RT stimulates the secretion of TGF-β, thus facilitating tumor invasion and immune evasion. In addition, inflammatory cytokines produced by CD8⁺ T cells and NK cells, such as tumor necrosis factor-alpha, interferon-gamma (IFN-γ), and interleukin-2, help establish a pro-apoptotic environment, potentially increasing the ability of the immune system to target cancer cells[34,66]. Tregs, which are resistant to radiation, impair CD8⁺ T-cell activity and support cancer-associated fibroblast differentiation and antiapoptotic signaling. High-dose hypofractionated stereotactic RT (HSRT) can counteract these processes by increasing CD8⁺ T-cell activity and reducing TGF-β secretion[67,68].

PD-L1 expression is another critical factor in the TME. Cancer cells often exploit PD-L1/PD-1 pathways to evade immune responses by inhibiting cytotoxic T lymphocytes (CTLs)[69]. In lung cancer with BM, the number of PD-L1–positive tumor-infiltrating cells is decreased, thereby reducing the efficacy of PD-L1 inhibitors compared with their efficacy in primary lung tumors[70]. RT increases PD-L1 expression in tumor cells, potentially facilitating immune evasion. However, this increase in PD-L1 expression could also increase the responsiveness of tumors to PD-L1–targeting treatments when used alongside RT[71]. High PD-L1 expression, especially in tumors with a high tumor mutational burden (TMB), generally increases the effectiveness of immunotherapies, such as nivolumab and pembrolizumab[72]. Conversely, NSCLC tumors with EGFR or ALK mutations have a lower TMB and PD-L1 expression, making them less responsive to these therapies[73].

Radiation also affects macrophage polarization, thus influencing tumor growth. Some studies revealed that low-dose radiation (10 Gy) increases the number of M1 macrophages while reducing the number of M2 macrophages and activating prosurvival pathways[74,75]. Modest radiation doses can increase IFN-γ expression, enhancing lymphocyte mobility and tumor-fighting abilities by upregulating MHC I and VCAM-1[76,77]. However, radioresistant tumors can block CTL infiltration, although RT-induced TLR upregulation and DAMP exposure increase CTL cytotoxicity[78]. During HSRT, high radiation doses increase immune-stimulating antigen production, further enhancing antitumor immunity[34].

The regulation of inflammation in the TME remains critical, as COX-2 overexpression promotes tumor growth and radioresistance. COX-2 inhibition can sensitize cancer cells to radiation, with some evidence suggesting improved survival in patients with breast or lung cancer[79,80]. However, hypoxia, which is driven by HIF-1 and VEGF, complicates the efficacy of RT. Inhibiting VEGF and related pathways using drugs such as cediranib might increase the response to RT by minimizing hypoxic cell involvement[81,82] (Figure 2). Understanding and modifying these TME interactions are crucial to counteract tumor-induced immunosuppression and optimize the efficacy of RT and systemic therapies, thereby improving both disease management and survival outcomes[83].

Figure 2  Biological activity of stereotactic radiotherapy in the treatment of brain metastasis.

QUALITY REQUIREMENTS FOR SRT

SRS demands greater targeting precision, a sharply defined dose gradient, and rigorous dose verification, differing from other forms of RT[84]. Three main factors affect positioning accuracy in SRS[85].

Mechanical precision

Modern SRS systems have sub-millimeter mechanical accuracy, which is crucial for precisely targeting small areas[86].

Imaging accuracy

CT offers high-resolution, low-distortion imaging. Conversely, magnetic resonance imaging often requires thicker slices for better signal quality, leading to potential distortions. Although 1.5T MR systems maintain distortion within approximately 0.5 mm, 3T MR systems require careful assessment to manage distortion for SRS[87-89].

Patient movement

During intracranial SRS, a fixed stereotactic frame is used to stabilize the head, whereas frameless SRS systems face challenges from involuntary movement. Modern SRS devices are equipped with monitoring systems to limit or adjust for movements within a sub-millimeter range[90,91].

The goal of SRS is to deliver steep dose gradients to exert maximum effects on targeted lesions[32,92]. High-dose-per-fraction strategies in fractionated therapy improve machine efficiency and patient throughput. Radiosurgery devices achieve precise dose distributions through different techniques. The GammaKnife converges approximately 200 beams at a focal point. Novalis uses a gantry that moves along multiple arcs, and CyberKnife delivers photons from various directions to create nonisocentric dose patterns[93,94].

Given the intense, localized doses that are administered in SRS, dose verification is essential to minimize the risk of tissue damage[95]. Elative dose distributions are accurately measured, and radiochromic films are often used for absolute dose quantification. In GammaKnife planning systems, the 1 mm/3% criterion typically yields gamma index values exceeding 97%, highlighting its precision. Accurate absorbed dose measurements, particularly with smaller fields, are critical for SRS applications[96-98].

EFFECTIVENESS OF SRT

The outcomes of SRT for BM treatment have been frequently reported across various populations. The key factors that influence prognosis include age, the number of metastases, the presence of extracranial metastases, and the Karnofsky Performance Status. According to the diagnosis-specific Graded Prognostic Assessment, patients with BM generally have a poor prognosis, with a median survival of 3–15 months[99,100]. Table 1 presents findings from various studies that assessed the effectiveness of SRT compared with that of WBRT.

Table 1 The use of stereotactic radiotherapy to treat brain metastasis of lung cancer and its effectiveness compared with whole-brain radiotherapy.

Ref.	Objective	Dosage	Key findings	Effectiveness	Toxicity	Concluding remarks
Luo et al[97]	Local and cerebral control in NSCLC patients treated with CyberKnife™ SRT	27 Gy in three fractions (69%), 18–25 Gy in one fraction (18%), 30 Gy in five fractions (9%)	Local control rate = 78.7%, cerebral control rate = 43%, median overall survival = 10.1 months	Effective for local control, minimal toxicity	Acute toxicity = 17%, severe toxicity = 2%	Suitable for patients with few BMs, close follow-up is needed
Fessart et al[99]	Survival predictors in patients with lung cancer and BM	Single 20-Gy fraction for SRT, 7–10 Gy/fraction for HFSRT	Disease control rate = 84%, median overall survival = 6.1 months	Effective with better control than WBRT	Grade III–IV toxicity = 4%	Well-tolerated, patient selection is key
Guo et al[100]	Palliative RT for BM and quality of life	WBRT = 30 Gy for 10 fractions, SRS = 20 Gy single fraction	Response rate = 50%–75%, neurological improvement rate = 75%	Improves quality of life, better than WBRT alone	Short term: Neurological symptoms; long term: Memory loss	Treatment should be individualized according to patients’ conditions
Gunnarsson et al[101]	Effectiveness of SRT in patients with lung cancer and BM	BED 10 SRT ≥ 50 Gy	Median overall survival = 19 months	Effective with controlled extracranial disease	No marked toxicity difference	SRT is effective, particularly with stable extracranial disease
Hashmi et al[102]	Cognitive deterioration in SRS vs SRS + WBRT patients	SRS = 20–24 Gy, SRS + WBRT = 18–20 Gy (SRS) + 30 Gy (WBRT)	Cognitive deterioration: 63.5% (SRS) vs 91.7% (SRS + WBRT), median survival = 10.4 months (SRS), 7.4 months (SRS + WBRT)	SRS alone results in less cognitive decline	Cognitive deterioration	SRS preferred for minimizing cognitive decline without impacting survival

NSCLC: Non-small cell lung cancer; BM: Brain metastasis; SRT: Stereotactic radiotherapy; SRS: Stereotactic radiosurgery; WBRT: Whole-brain radiotherapy; HFSRT: Hypofractionated stereotactic radiotherapy; BED: Biologically effective dose.

LIMITATIONS AND FUTURE DIRECTIONS

For larger BMs (greater than 2 cm in diameter), SRS is being used more frequently alongside conservative approaches[18]. Patients typically exhibit prominent neurological symptoms and potentially experience vasogenic edema or mass effects, which frequently necessitate immediate surgical intervention. After achieving gross total resection, postoperative SRS at a median dose of 15 Gy has been associated with increased local control and overall survival in patients with tumors averaging 8.7–9.6 mL in volume[101-103]. However, SRS is associated with some risks, including potential neurological issues because of extensive resection and symptomatic radionecrosis, particularly with a large target volume margin (> 1.0 mm)[104]. A study on NSCLC revealed that a gross tumor volume greater than 15 mL is a primary predictor of local recurrence[103]. Additionally, the rates of radionecrosis increase substantially when more than 10 mL of healthy brain tissue receives 12 Gy, with rates reported between 15% and 55%[17]. To reduce this risk, FSRS, such as that with V12 volumes exceeding 8.5 mL and doses of 30 Gy over five fractions or 27 Gy over three fractions, is advised, especially for treating metastases near critical brain areas[103].

Radiation necrosis remains a notable risk of SRS, particularly in cases involving large treatment volumes[105]. This condition can appear 1 to 2 years post-treatment, and it is often indicated by radiographic changes or symptoms such as headaches, drowsiness, seizures, and death in severe cases[106]. Recent studies investigated the combination of SRS with immunotherapies and targeted therapies, focusing on the potential synergistic benefits of pairing SRS with immune checkpoint inhibitors[107-109].

CONCLUSION

SRT represents a significant advancement in treating BMs in patients with NSCLC. This technique increases precision and minimizes collateral damage to surrounding brain tissue, thereby improving local control and extending patient survival. To maximize the benefits of SRT, further clinical studies are needed to refine the timing, radiation dosage, and fractionation protocols. Future research efforts should focus on improving predictive metrics and identifying biomarkers to develop tailored, personalized treatment for patients with lung cancer BMs. Additionally, exploring emerging technologies, such as advanced imaging techniques or novel RT methods, holds great potential for improving the effectiveness of SRT. Areas that require further clinical validation include the combination of SRT with other treatment modalities or the optimization of fractionation schedules, as such advancements could significantly enhance patient outcomes. By outlining these potential research directions, this paper can serve as a guide for future work in the field, encouraging further exploration and development to optimize efficacy and expand treatment indications.

ACKNOWLEDGEMENTS

Sincere gratitude is extended to Professor Guan Wei for her invaluable assistance and insightful guidance throughout the process of writing this paper.