Introduction: The Clinical Challenge of Extensive Brain Metastases
The management of brain metastases (BMs) represents one of the most significant challenges in the treatment of non-small cell lung cancer (NSCLC). Approximately 20 percent to 40 percent of patients with NSCLC will develop BMs during their disease course, and a subset of these patients presents with extensive intracranial involvement, traditionally defined as having multiple lesions that are not amenable to focal treatments like stereotactic radiosurgery (SRS). Historically, the standard of care for these patients has been whole-brain radiotherapy (WBRT). While WBRT provides reasonable intracranial control, it is associated with significant long-term neurocognitive decline, which severely impacts the quality of life (QOL) for survivors.
The Need for New Strategies
As systemic therapies for NSCLC, including targeted therapies and immunotherapy, continue to extend overall survival, the preservation of neurocognitive function has become a paramount clinical goal. This has led researchers to explore fractionated stereotactic radiotherapy (FSRT), which delivers high-dose radiation to multiple targets while sparing healthy brain tissue. However, the efficacy of radiotherapy alone remains limited by tumor hypoxia and peritumoral edema. The GASTO-1053 study was designed to address these limitations by combining FSRT with bevacizumab, a vascular endothelial growth factor (VEGF) inhibitor, to leverage their synergistic potential.
Study Design and Methodology
The GASTO-1053 study (NCT04345146) was a prospective, single-arm, phase II clinical trial aimed at evaluating the efficacy and safety of combining bevacizumab (Bev) with FSRT in NSCLC patients with extensive BMs. Patients were eligible if they had extensive brain involvement deemed unsuitable for SRS by a multidisciplinary tumor board and had stable extracranial disease.
Intervention Protocol
Participants received FSRT at a dose of 40 Gy in 10 fractions or 30 Gy in 5 fractions, depending on the size and location of the lesions. Bevacizumab was administered intravenously at a dose of 7.5 mg/kg on Day 1 (prior to the start of FSRT) and on Day 21 (post-FSRT). The primary endpoint of the study was intracranial progression-free survival (IPFS). Secondary endpoints included overall survival (OS), progression-free survival (PFS), quality of life (QOL), and treatment-related toxicities.
Comparative Analysis
To provide a robust context for the findings, the researchers used propensity score matching (PSM) to create a 1:1 comparison. The Bev + FSRT study group was matched against two historical cohorts: patients treated with WBRT plus FSRT and patients treated with FSRT alone. This matching process accounted for variables such as age, performance status, and number of metastases to ensure a fair comparison of outcomes.
Key Findings: Improved Intracranial Control
The study enrolled 106 patients in the Bev + FSRT group, with a median follow-up duration of 35.8 months. The results were highly encouraging, suggesting that this combination therapy could represent a major shift in treatment paradigms.
Intracranial Progression-Free Survival (IPFS)
The median IPFS for the Bev + FSRT group was 18.3 months (95% CI, 15.2-23.3 months). When compared to the matched control groups, the improvement was statistically significant and clinically meaningful. The WBRT + FSRT group achieved a median IPFS of only 9.6 months (P < 0.001), while the FSRT alone group reached 8.9 months (P < 0.001). This doubling of the time to intracranial progression highlights the potency of adding bevacizumab to the radiotherapy regimen.
Radiographic and Physiological Responses
The study also quantified the physiological impact of the treatment on the brain environment. The Bev + FSRT combination led to a significant reduction in tumor volume (P < 0.001) and peritumoral edema volume (P = 0.004). Furthermore, dynamic contrast-enhanced MRI showed a significant decrease in vascular leakage (P < 0.001). These changes suggest that bevacizumab not only inhibits tumor growth but also stabilizes the blood-brain barrier and improves the microenvironment, which may enhance the efficacy of the radiation delivered.
Safety and Quality of Life
One of the primary concerns with combining potent anti-angiogenic agents and high-dose radiation is the risk of radiation necrosis and other intracranial toxicities. However, the GASTO-1053 study reported excellent tolerability.
Toxicity Profile
Grade 1 radiation necrosis was observed in only one patient, and there were no reports of high-grade (Grade 3 or higher) radiation-induced CNS toxicity. The use of bevacizumab at the specified dose and schedule appeared to be safe, with no unexpected systemic adverse events. This safety profile is particularly relevant given bevacizumab’s known role in treating radiation-induced brain necrosis, suggesting that its inclusion in the primary treatment may actually protect against this complication.
Improved Patient Well-being
Quality of life (QOL) was a significant secondary endpoint. Patients treated with Bev + FSRT reported significant improvements in their overall QOL scores after treatment. This improvement was most pronounced in patients who were symptomatic from their extensive BMs at the start of the study. By rapidly reducing tumor-associated edema and achieving better intracranial control without the cognitive burden of WBRT, the combination therapy effectively preserved or enhanced the functional status of the participants.
Expert Commentary: Mechanistic Insights and Clinical Implications
The success of the GASTO-1053 trial can be attributed to the biological synergy between bevacizumab and radiotherapy. Radiotherapy induces the release of VEGF, which can lead to increased vascular permeability and edema. By inhibiting VEGF, bevacizumab counteracts these effects, ‘normalizing’ the tumor vasculature. This normalization can lead to improved oxygenation of the tumor tissue, potentially overcoming hypoxia-mediated radiation resistance.
Moving Beyond WBRT
For years, the oncology community has sought ways to ‘spare the brain’ while still controlling extensive metastatic disease. The results of this study suggest that FSRT, when boosted by bevacizumab, can achieve better local control than WBRT without the associated neurotoxicity. This is a critical finding for patients who may live for years following their diagnosis, as it allows them to maintain their cognitive integrity and independence.
Limitations and Future Directions
While the results are compelling, the researchers acknowledge that GASTO-1053 was a single-arm phase II study. The use of propensity score matching helps mitigate bias, but it cannot replace the gold standard of a randomized controlled trial. Future research should also investigate the optimal timing and dosing of bevacizumab, as well as its interaction with modern systemic agents like osimertinib or immune checkpoint inhibitors, which are now frequently used in the first-line setting for NSCLC.
Conclusion
The GASTO-1053 study provides strong evidence that the combination of bevacizumab and fractionated stereotactic radiotherapy is a safe and highly effective treatment for NSCLC patients with extensive brain metastases. By significantly extending intracranial progression-free survival and improving quality of life while minimizing the risks of radiation necrosis and cognitive decline, this regimen offers a promising alternative to traditional whole-brain radiotherapy. These findings warrant validation in a large-scale randomized trial to establish this combination as a new standard of care in the management of intracranial disease in lung cancer patients.
Funding and Clinical Trial Information
This study was registered at ClinicalTrials.gov under the identifier NCT04345146. The registration date was February 22, 2020. The research was supported by various oncology research funds aimed at improving outcomes for patients with advanced lung cancer.
References
1. Zhou R, Zheng S, Wang D, et al. Efficacy and safety of combining bevacizumab and fractionated stereotactic radiotherapy for extensive brain metastases in patients with non-small cell lung cancer: a prospective phase II study (GASTO-1053). Cancer Commun (Lond). 2025;45(12):1739-1754. doi:10.1002/cac2.70078.
2. Brown PD, Ahluwalia MS, Khan OH, et al. Whole-Brain Radiotherapy for Brain Metastases: Evolution or Revolution? J Clin Oncol. 2018;36(5):483-491.
3. Jain RK. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science. 2005;307(5706):58-62.
