Radiation Therapy for Patients with Brain Metastases from Non-Small Cell Lung Cancer without Driven Gene Mutation
Brain metastasis (BM) is a common complication in the progression of non-small cell lung cancer (NSCLC). Without radiotherapy, the overall survival (OS) of patients diagnosed with BM is only 3.6 months. However, advancements in treatment have extended the median survival time (MST) to approximately 16 months. For patients with specific genetic mutations, such as epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) gene rearrangements, targeted therapies are available. However, for patients without these driven gene mutations, radiation therapy remains the cornerstone of treatment.
Whole-brain radiotherapy (WBRT) has been the standard treatment for BM for decades. Despite its efficacy, WBRT is associated with significant neurological decline, which has led to the development of alternative strategies. One such approach is hippocampal-sparing WBRT (HS-WBRT) with simultaneous integrated boost (SIB). This technique aims to preserve cognitive function while maintaining local control. Studies have shown that HS-WBRT with SIB achieves a 1-year intracranial local control rate (LCR) of 67%, with only mild adverse effects. Another phase II trial reported a local recurrence rate of 8.8% and an intracranial recurrence rate of 21.3% at 1 year, with a reduced probability of delayed recall decline.
For patients with a limited number of BM lesions (1–4), stereotactic radiosurgery (SRS) is recommended due to its efficacy and minimal impact on cognitive function. A retrospective study found that SRS resulted in overall LCRs of 75% at 1 year and 66% at 2 years. The number of BM lesions significantly affects patient survival, and tumor volume is a critical factor in determining the choice of radiotherapy. For instance, patients with a lower peritumor edema/gross tumor volume ratio are more likely to receive additional WBRT.
The applicability of SRS for patients with more than four BM lesions has been explored in several clinical trials. One study found that patients with more than ten brain lesions treated with SRS alone had a MST of 6.5 months. The median time to central nervous system (CNS) failure did not differ significantly between patients who received initial WBRT and those who did not. However, as the number of BM lesions increases, patients are more likely to undergo salvage WBRT rather than SRS. The combination of SRS and WBRT has been shown to prolong MST and improve LCR. For example, one study reported a MST of 10.3 months for patients treated with SRS plus WBRT, compared to 7.3 months for those treated with WBRT alone. Similarly, the median time to intracranial tumor progression was 10 months for the combination therapy versus 7 months for WBRT alone. These findings are supported by another study, which found no significant difference in neurotoxicity between the two treatment groups.
In addition to SRS and WBRT, other radiation therapy techniques are emerging. Hypofractionated stereotactic radiotherapy (HSRT) has been shown to control intracranial tumors effectively and provide survival benefits. HSRT is associated with a lower incidence of acute complications and better LCR compared to SRS. Volumetric-modulated arc therapy (VMAT) has also demonstrated significant improvements in LCR, particularly for smaller BM lesions (diameter ≤2 cm). VMAT is associated with a lower incidence of high-grade radionecrosis compared to SRS plus WBRT, especially in elderly patients, and the survival profile does not differ as the number of metastases increases.
Chemotherapy has traditionally been considered less effective for BM due to the blood-brain barrier (BBB). However, recent studies have shown that combining radiation therapy with chemotherapy can improve patient survival. Radiation therapy may alter the BBB, increasing drug permeability, while prior chemotherapy can enhance the response to radiation. For example, systemic therapy added to radiotherapy has been shown to significantly improve OS. The number of cycles of pemetrexed combined with radiation therapy is positively correlated with longer OS. Temozolomide, another chemotherapeutic agent, has good BBB penetration. While the addition of temozolomide to WBRT improves the objective response rate, it does not prolong OS.
Immunotherapy is an emerging treatment option for BM. A case report described a patient with a single BM lesion who was treated with pembrolizumab for 20 months following SRS, chemotherapy, and maintenance treatment. The lesions were well controlled, and no new tumors appeared. The combination of programmed death-1 (PD-1) inhibitors and SRS has been shown to prolong OS and achieve a higher LCR of brain lesions compared to sequential treatment or SRS alone. However, more clinical trials are needed to explore the efficacy and safety of immunotherapy combined with radiotherapy for BM in NSCLC.
Surgery is another treatment option, particularly for symptomatic and limited BM. Radical resection of brain lesions provides a high LCR. Postoperative local radiotherapy has been shown to be more favorable than WBRT or WBRT with SIB.
In conclusion, radiation therapy continues to play a crucial role in the treatment of BM from NSCLC. While WBRT and SRS are effective, their combination or sequential use may offer better outcomes. Emerging techniques such as HS-WBRT, HSRT, and VMAT, as well as the integration of chemotherapy and immunotherapy, are expanding the treatment landscape. The goal of BM treatment should not only be to achieve local control but also to improve patients’ quality of life. Proper combination or sequential treatment strategies are essential for optimizing outcomes.
doi.org/10.1097/CM9.0000000000001044
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