In fact, brain metastasis is the most common intracranial tumor, and 8%-10% of tumor patients have brain metastasis with neurological symptoms, and brain metastasis of lung cancer patients accounts for 40%-70% of intracranial metastases. How to make better use of these treatments to treat brain metastases, prolong patients’ survival and protect the function of central nervous system is a major issue that cannot be ignored. Lung cancer brain The incidence of brain metastasis accounts for 40%-60% of all solid tumor brain metastases, and its biological behavior is aggressive and has poor prognosis, often accompanied by a decline in the quality of life of patients. At present, the treatment for brain metastases is limited, and surgery or stereotactic radiotherapy is mostly used for isolated lesions, while for multiple lesions, whole brain radiotherapy is the main treatment. Due to the natural barrier effect of blood-brain barrier makes drug treatment has been relatively secondary. Theoretically, the blood-brain barrier will be partially destroyed after brain metastasis of lung cancer, which is conducive to the penetration of drugs. However, in clinical practice, the efficacy of both drugs sensitive to extracerebral lesions and chemotherapeutic drugs that can completely cross the blood-brain barrier, such as nitrosoureas and VM-26, is not satisfactory. The emergence of new drugs such as temozolomide, pemetrexed and small molecule tyrosine kinase inhibitors in recent years has undoubtedly brought a ray of hope for patients with brain metastases. Temozolomide is a new type of imidazotetrazine alkylating agent with complete oral absorption, high bioavailability and ability to cross the blood-brain barrier. An Italian phase II study evaluated the efficacy of standard TMZ monotherapy (150-200 mg/m2/d, d1-5, repeated every 28 days) as salvage therapy for brain metastases from non-small cell lung cancer (NSCLC). Thirty patients with NSCLC were enrolled in the study, and the results showed that the objective remission rate (ORR) of brain metastases was 10%, and the overall time to disease progression (TTP) and overall survival (OS) were 3.6 months and 6 months, respectively, with patients who achieved objective remission achieving TTP and OS of 11-19 months and 14-24 months, respectively. Another phase II study used TMZ at a low daily dose (75 mg/m2/d, d1-21, repeated every 28 days) for the treatment of relapsed refractory NSCLC, in which 39% of patients with combined brain metastases had a disease control rate (DCR) of 16.2% and TTP and OS of 2.4 and 3.3 months, respectively. Both clinical studies showed the efficacy of TMZ as a second-line or higher treatment for brain metastases from NSCLC, which warrants a phase III clinical study. TMZ combined with radiotherapy for brain metastases has also shown good efficacy. In a phase II clinical study in France, 50 NSCLC patients with brain metastases were treated with TMZ combined with cisplatin chemotherapy in sequential whole brain radiotherapy, and the results showed an ORR of 16%, TTP and OS of 2.3 months and 5 months, respectively. Two other phase II clinical studies on concurrent TMZ radiotherapy showed ORR of 45%-57.6% and OS of 12-13 months. These studies suggest that concurrent radiotherapy may be superior to sequential radiotherapy or single chemotherapy. In addition, TMZ may also have a role in the prevention of brain metastases. One study showed that only 8% (3/37 cases) of patients treated with TMZ in combination with topotecan for NSCLC eventually developed brain metastases, much lower than the 50% incidence of brain metastases reported in other literature, suggesting that TMZ may have a potential role in preventing brain metastases. the role shown for TMZ in the treatment of brain metastases from lung cancer warrants further clinical trials. Based on the performance of TMZ in brain tumors and various brain metastases, the 2009 edition of the NCCN guidelines recommends it as one of the chemotherapy options for brain tumors. The potential of pemetrexed for the treatment of brain metastases warrants further exploration: symptomatic brain metastases frequently occur during the treatment of advanced non-squamous NSCLC. Based on the therapeutic benefits of pemetrexed in non-squamous NSCLC, two randomized large clinical studies (JMDB, JMEI) were recently retrospectively analyzed to assess the occurrence of brain metastases. One study was a clinical trial of pemetrexed/cisplatin versus gemcitabine/cisplatin in first-line treatment of advanced NSCLC (ScagliottiJCO 2008, 1725 cases), and the other was a clinical study of pemetrexed versus docetaxel in second-line treatment of advanced NSCLC (HannaJCO 2004, 571 cases). The results showed that pemetrexed reduced the incidence of symptomatic brain metastases in patients with advanced NSCLC with non-squamous cancer (3.0% vs. 7.3%, P<0.001). Although this was a retrospective study and only symptomatic brain metastases could be analyzed, it still reflected that pemetrexed was effective in suppressing the incidence of brain metastases in patients with advanced NSCLC with non-squamous cancer. Another analysis of a small sample study showed the efficacy of pemetrexed in treating brain metastases in 39 cases of advanced NSCLC with an effective rate of 38.4% and a disease control rate of 69%, showing the good potential of the drug for the treatment of brain metastases, but further prospective, multicenter clinical studies are needed to confirm this. Tyrosine kinase inhibitors (molecularly targeted therapeutics: ERSA, Troche, Exatinib, etc.) have a better treatment prospect. The position of tyrosine kinase inhibitors (TKI) in lung cancer treatment has been clearly established, and they are expected to be effective therapeutic agents for brain metastasis of lung cancer because of their small molecular weight and easy to cross the blood-brain barrier. Currently, several studies have confirmed its effectiveness in lung cancer brain metastasis, among which the more studied one is gefitinib. A Japanese study reviewed 14 NSCLC patients with both intracranial and extracranial metastases. After treatment with gefitinib, seven patients (50%) achieved objective remission of extracerebral lesions, and six of them also achieved remission of intracerebral lesions, suggesting that gefitinib can cross the blood-brain barrier more completely. A prospective phase II clinical study from Italy evaluated 41 patients with NSCLC brain metastases treated with gefitinib, with an ORR of 10% for brain metastases and median progression-free survival (PFS) and OS of 3 and 5 months, respectively, with relatively long OS in patients with adenocarcinoma (P=0.04). In another prospective study from China, 40 patients were screened for brain metastases from lung adenocarcinoma confirmed by pathological biopsy and brain MRI, including 22 men and 18 women, median age 56 years, 32 never smokers, all patients had received chemotherapy, 26 had received radiotherapy and/or stereotactic radiotherapy, and all patients were treated with gefitinib until disease progression or development of intolerable toxicity. The results showed an efficiency rate of 38%, DCR of 92%, improvement or disappearance of symptoms in 48%, median PFS of 9 months and median OS of 15 months. The incidence of rash was 100%, but all were grade 1 to 2. This study showed that patients with brain metastases had better outcomes after screening than those who were not screened, as in the case of intrapulmonary or other extracerebral metastases. Several other retrospective analyses from China and Japan also showed good promise for gefitinib treatment, with ORRs of 31.8% to 32% and PFS and OS of 5 to 9 months and 9.1 to 15 months, respectively. Subgroup analysis showed better efficacy in patients with rash and EGFR mutations. Therefore, molecularly targeted therapy for brain metastases also requires individualized screening, and patients with EGFR mutations or with specific clinical features may benefit more significantly from TKI therapy. A recent study has shown that increasing the dose intensity of EGFR-TKI may control brain metastases in patients with well-controlled tumors at the primary lung site but progressive brain metastases during EGFR-TKI treatment. 2011 Journal ofThoracicOncology reported a case of high-dose erlotinib for advanced NSCLC brain metastases in a patient. Female, 52 years old, non-smoker, adenocarcinoma cells found in pleural fluid, asymptomatic multiple brain metastases present at initial treatment, and EGFR-sensitive mutation (exon 18 G719A) found on examination of malignant pleural fluid. After 1 month of first-line gefitinib treatment, he progressed again after multiple chemotherapy regimens and developed symptoms of brain metastases, and whole brain radiotherapy was performed. Erlotinib 150 mg, qd was given for 4 months and pemetrexed chemotherapy for 1 cycle, but the brain metastases still progressed with impaired mobility and aphasia. The review showed that the intracranial lesions progressed, while the extracranial lesions remained stable. After 2 weeks of treatment with high-dose erlotinib 300 mg qd, the symptoms were relieved and the head MRI showed that the intracranial lesions were reduced. Later, high-dose erlotinib treatment was maintained for 6 months. In addition, there were 2 reports in the Journal ofClinicalOncology in 2006 and 2009, respectively, on patients with refractory NSCLC brain metastases treated with high-dose EGFR-TKI, showing that both TKI achieved varying degrees of control of intracranial metastatic lesions. These studies suggest that the sensitivity of CNS metastases to high-dose EGFR-TKI may be related to increased CNS permeability due to high levels of blood levels. The use of high-dose EGFR-TKI in patients with refractory CNS metastases and failure of standard-dose EGFR-TKI therapy has yet to be confirmed in prospective studies. In addition to tyrosine kinase inhibitors, other agents such as those targeting matrix metalloproteinases, cell cycle pathways and apoptotic pathways are in preclinical or early clinical studies.