Metastatic brain tumors include parenchymal metastases and meningeal metastases. Brain parenchymal metastases most commonly occur in the cerebral hemispheres, followed by the cerebellum and brainstem. Meningeal metastases are less common than parenchymal metastases but have a worse prognosis. 20% to 65% of lung cancer patients will develop brain metastases during the course of the disease, which is the most common type of brain metastatic tumors. Treatment for patients with brain metastases from lung cancer should be based on systemic treatment for brain metastases, including surgery, whole brain radiotherapy (WBRT), stereotactic radiotherapy (SRT) and medical treatment, which are multidisciplinary and comprehensive treatments aimed at treating metastatic lesions, improving patients’ symptoms and quality of life, and maximizing patients’ survival time.
(i) Surgical treatment
Compared with medical treatment and radiotherapy, surgery has the following advantages: (1) total removal of metastases can rapidly relieve the symptoms of intracranial hypertension and eliminate the stimulation of metastases to the surrounding brain tissue; (2) tumor tissue can be obtained to clarify the pathological diagnosis; (3) surgery can achieve local cure by removing the entire tumor.
Indications for surgical procedures.
(1) Biopsy: to clarify the histopathological and molecular pathological diagnosis in order to guide the next step of treatment. (1) Occult lung primary foci or difficult to obtain although the primary foci are clear; (2) Clear pathology of lung primary foci but atypical brain lesions or difficult to diagnose; (3) Clearly necrosis or recurrence of tumor and assessment of the effect of prior radiotherapy or internal medicine treatment.
(2) Surgical resection: whether patients with brain metastases are suitable for surgical resection needs to consider the number of tumors, tumor size, tumor site, histological type, patient’s general condition and other factors.
It is worth noting that patients with brain metastases are all advanced, and surgical selection should be cautious. Disadvantages: Intracranial tumors are difficult to be completely resected, and patients are highly prone to recurrence after simple surgical treatment.
①Patients with single intracerebral tumor, suitable site, easy to resect, and the tumor or its edema with heavy occupying effect or causing hydrocephalus are suitable for surgical resection. Although single, pathological types sensitive to radiotherapy and chemotherapy, such as small cell lung cancer (SCLC), may not be preferred for surgery, except for the following cases: metastases and/or edema with large volume, intracranial pressure loss, tumor strokes on the verge of brain herniation, and life-threatening cases should be operated urgently.
The surgical treatment of multiple brain metastases is still controversial, but it is generally believed that if the number of tumors is ≤3 and the surgery can be completely resected, the same satisfactory treatment results can be obtained as those of patients with single brain metastases. ＞WBRT or SRT should be preferred for the treatment of >3 brain metastases.
③Tumor size: Tumors with maximum diameter >3cm are generally not suitable for radiotherapy and surgery is appropriate; tumors with maximum diameter <5mm, especially located in deep brain (thalamus, brainstem, etc.) are preferable to radiotherapy or internal medicine; if the maximum diameter of tumor is 1~3cm, then surgery or other treatments are preferred according to the comprehensive assessment of patient's general condition and surgical risk.
④Tumor site: Although at present, with the help of neuronavigation and intraoperative functional localization, neurosurgeons’ techniques can reach any part of the skull, the disability rate of surgery for metastases in deep brain or functional areas is generally higher than that of surgery in superficial or non-functional areas. Therefore, surgery is not preferred in principle for brain metastases located in the brainstem, thalamus, or basal ganglia.
(ii) Radiotherapy
1.WBRT: WBRT is one of the main local treatments for brain metastases, which can relieve the neurological symptoms and improve the local control of tumor in patients with brain metastases from lung cancer.WBRT has certain control effect on intracranial subclinical lesions, but it is difficult to eradicate intracranial lesions because it is limited by the dose of normal brain tissue. For patients with NSCLC brain metastases with effective drug control, WBRT should be postponed as much as possible and left as salvage therapy.
Indications for WBRT.
(1) Salvage therapy after failure of stereotactic radiosurgery (SRS) for patients with brain metastases from non-small cell lung cancer (NSCLC).
(2) Initial treatment of patients with >3 lesions of NSCLC brain metastases in combination with local dosing of SRS; (3) Adjuvant therapy after resection of intracranial metastases in patients with NSCLC brain metastases.
(4) Combined application of WBRT with intrathecal chemotherapy for lung cancer patients with extensive meningeal metastases, and feasible whole brain and whole spinal cord radiotherapy for lung cancer patients with spinal metastases.
(5) WBRT is feasible for patients with extensive stage SCLC with brain metastases, regardless of whether they are symptomatic or not, and regardless of the number of metastatic lesions. WBRT is usually the treatment of choice for SCLC patients with brain metastases, mainly because of the high probability of multiple brain metastases.
(6) SCLC patients who have received PCI in the past and then develop multiple brain metastases may carefully choose WBRT again.
As the survival time of patients with brain metastases from lung cancer gradually increases, the neurocognitive impairment that may result from WBRT, mainly manifested as short- and long-term memory loss, reduces the quality of life of patients, which may be related to irradiation-induced damage to hippocampal structures. The results of the phase III clinical study NRGCC001 showed that the difference in intracranial median progression-free survival time and overall survival time was not statistically significant in the group receiving WBRT combined with memantine compared to the group receiving WBRT combined with memantine with hippocampal area protection, but the incidence of cognitive dysfunction was reduced by 26% in the group with hippocampal area protection compared to the group without hippocampal area protection, and the difference was statistically significant.
SRT: SRT for brain metastases includes SRS, fractionated stereotactic radiation therapy (FSRT) and large split stereotactic radiation therapy (HSRT.) SRS is defined as a single dose or 2 to 5 fractions of SRT, which has the advantages of precise localization, concentrated dose and relatively small damage.
The main indications for SRT and FSRT treatment are.
(1) Primary treatment of single metastases less than 4-5 cm in diameter (except SCLC).
(2) Primary treatment of ≤4 metastases.
(3) Salvage treatment after failure of WBRT.
(4) adjuvant therapy after resection of intracranial metastases.
(5) Patients who have received previous SRS treatment for a duration of more than 6 months and whose imaging suggests tumor recurrence rather than necrosis may be considered for SRS again.
(6) Local add-on therapy based on WBRT for limited meningeal metastases.
For brain metastases with one to four lesions, SRT alone offers a survival advantage over WBRT alone and better preservation of cognitive function. For multiple metastases, patients treated with SRT alone have a higher rate of distant intracranial failure than WBRT. for high-risk factors for intracranial metastases including >4 metastases, uncontrolled extracranial disease, metastases >6 cm3 in volume, and time between primary diagnosis and brain metastasis diagnosis <60 months, SRT in combination with WBRT is recommended for high-risk patients, and vice versa.
For large volume lesions (usually >3cm), single SRS is difficult to achieve good local control and has significantly higher treatment toxicity, so FSRT is recommended.
Since intracranial tumors are difficult to be completely resected and patients are highly susceptible to recurrence after surgical treatment alone, postoperative treatment with local intensity modulated conformal radiotherapy (for those with large operative areas) or FSRT is necessary, especially for patients with good general condition and good prognosis for extracranial disease control. In patients with isolated brain metastases, including large volume lesions, postoperative SRS or FSRT can achieve the local control of WBRT combined with surgery, while sparing 58.4% to 81% of patients from undergoing WBRT.
3. Simultaneous additive radiotherapy: For patients who are not suitable for SRS but still have a long expected survival time, WBRT combined with simultaneous additive intensity-modulated radiotherapy technique (IMRT) for metastases can be used. The efficacy of WBRT combined with simultaneous dosing of tumor lesions using IMRT or spiral tomotherapy is better than that of WBRT alone, and the difference between WBRT and SRS is not statistically significant.
(IV) Internal medicine treatment
1. Chemotherapy for patients with brain metastases from NSCLC.
Pemetrexed combined with platinum also had a controlling effect on intracranial lesions in patients with NSCLC brain metastases, and the overall survival time (OS) of patients in the chemotherapy group was significantly longer than the natural survival time. the GFPC07-01 study included patients with primary NSCLC brain metastases, applying standard dose of cisplatin combined with pemetrexed regimen for 6 cycles of chemotherapy, and WBRT was performed at the end of chemotherapy or when brain metastases progressed. The effective rate (ORR) was 41.9% for lesions and 34.9% for extracranial lesions, with a median OS of 7.4 months.
Temozolomide is a novel imidazotetrazine alkylating agent that can be converted into an active alkylating precursor in humans, which can cross the blood-brain barrier and has good efficacy in controlling brain metastases from NSCLC. For patients with NSCLC brain metastases who have received WBRT or systemic chemotherapy, temozolomide can be applied to improve DCR and prolong OS, but the reports are mostly phase II clinical studies and need to be further confirmed by large-scale phase III clinical studies.
2. Chemotherapy for patients with brain metastases from SCLC.
The two-drug regimen of platinum-containing etoposide or irinotecan is the standard first-line systemic chemotherapy regimen for SCLC patients, and it is also effective for intracranial metastatic lesions. It is recommended that first-line treatment for patients with extensive-stage SCLC with asymptomatic brain metastases can be prioritized with systemic chemotherapy, and WBRT can be considered after the completion of systemic chemotherapy or when brain metastases progress.
3.Molecular targeted therapy: Targeted therapy is an important treatment for patients with brain metastases from NSCLC.
(1) Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs): EGFR-TKIs can achieve better objective remission rates when treating patients with advanced NSCLC with EGFR gene sensitive mutations. In contrast, for patients with brain metastases from NSCLC, intracranial remission varied to varying degrees among EGFR-TKIs. There are more data for first-generation EGFR-TKIs including gefitinib, erlotinib and erlotinib, and less data for second-generation EGFR-TKIs including afatinib and daclatinib. Third-generation EGFR-TKIs including oseltinib, amatinib and vomitinib had better brain metastasis control rates than first-generation EGFR-TKIs.
(2) Mesenchymal lymphoma kinase tyrosine kinase inhibitors (ALK-TKIs): ALK-TKIs that have been approved for marketing include first-generation crizotinib, second-generation aletinib, ceritinib, and enzatinib. Crizotinib has a higher control rate of intracranial metastases in patients with ALK fusion gene-positive NSCLC brain metastases compared with chemotherapy, while the second-generation ALK-TKIs have a higher control rate of intracranial metastatic lesions than crizotinib.
(3) Pulsed therapeutic dosing aims to achieve increased intracranial drug concentration by increasing blood concentration, which in turn exerts the effect of intracranial lesion control, mainly for the generation of EGFR-TKI-targeted drugs, which are less used at present because the third-generation targeted drugs can well cross the blood-brain barrier.
4, anti-angiogenic drugs: bevacizumab is a recombinant humanized monoclonal antibody against vascular endothelial growth factor (VEGF). The ORR and DCR of intracranial lesions in patients treated with bevacizumab are better than those of extracranial lesions and do not increase the risk of bleeding in patients with brain metastases. In addition, bevacizumab is also effective for brain necrosis and brain edema caused by radiation therapy.
5.Immunotherapy: Immune checkpoint inhibitors programmed death receptor 1 (PD-1) and programmed death receptor ligand 1 (PD-L1) have certain therapeutic effects on brain metastases from lung cancer.
6.Intrathecal injection: Intrathecal injection is to inject drugs directly into the subarachnoid space to increase the concentration of drugs in the cerebrospinal fluid, thus killing tumor cells. The drug delivery routes include lumbar puncture subarachnoid cavity injection of chemotherapy drugs and intracerebroventricular chemotherapy via Ommaya reservoir. Compared with intrathecal administration via lumbar puncture, intrathecal administration via Ommaya reservoir is safer and avoids the risk of inadvertent injection of drugs into the epidural space; in patients with thrombocytopenia, epidural and subdural hematomas can be avoided. Commonly used chemotherapeutic drugs for intrathecal injection include methotrexate, cytarabine and cetipate, but the overall efficacy needs to be further determined.
(V) Symptomatic treatment
Patients with brain metastases from lung cancer often have headache, nausea, vomiting and other symptoms caused by elevated intracranial pressure. Patients with intracranial hypertension are tumor emergencies, and the first step is to actively give dehydration and diuretic treatment to reduce intracranial pressure. Glucocorticoids, especially dexamethasone, can reduce cerebral edema and improve the quality of life of patients with brain metastases. Next is symptom control, including antiepileptic and analgesic treatment. Since antiepileptic drugs cannot reduce the risk of seizures in patients with NSCLC brain metastases without seizure symptoms, they are generally used only in patients with seizure symptoms and are not used prophylactically. Patients with significant headache can be treated with analgesic symptomatic therapy.
Treatment strategies for brain metastases from lung cancer
1. Treatment strategies for NSCLC brain metastases.
(1) For patients with positive mutations such as EGFR/ALK, for one to three metastatic lesions, SRT and treatment with third-generation EGFR-TKIs or second-generation ALK-TKIs should be given. For more than 3 metastases, patients were treated with third-generation EGFR-TKIs or second-generation ALK-TKIs, and WBRT was administered after patients showed progression of intracerebral lesions or had significant symptoms.
(2) For patients with pan-negative driver genes, SRT with chemotherapy combined with anti-vascular therapy or combined immunotherapy is given for one to three metastatic lesions. For more than 3 metastatic lesions and given chemotherapy combined with anti-vascular therapy or combined immunotherapy, with significant brain symptoms combined with WBRT; WBRT was given when there was intracerebral lesion progression.
(3) Patients with single intracerebral lesion, suitable site, easily resectable, and heavy tumor or its edema-occupying effect or causing hydrocephalus can be considered for surgery as appropriate.
2. Treatment strategy for SCLC brain metastases.
For metastases with less than 3 foci, chemotherapy or chemotherapy combined with immunotherapy, and WBRT combined with metastases with simultaneous dosing; for metastases with more than 3 foci, chemotherapy or chemotherapy combined with immunotherapy combined with whole brain radiotherapy.
3.Treatment strategy of meningeal metastasis
(1) According to the genetic mutation of patients, priority should be given to drugs with good blood-brain barrier permeability for targeted therapy.
(2) The efficacy of whole brain and whole spinal cord radiotherapy is not exact.
(3) The efficacy of intrathecal chemotherapy is inaccurate.
(4) Consider Ommaya bursa decompression or drug injection therapy as appropriate.
Brain metastasis of lung cancer is an important factor affecting the quality of life and survival of patients. The treatment of brain metastasis of lung cancer requires the use of appropriate treatments to achieve the radical state of intracranial metastatic lesions as much as possible according to the patient’s general condition, tumor status (whether there is oligometastasis), genetic status, number and size of tumors, etc. The patient’s symptoms are only one factor in prioritizing or postponing the use of therapeutic measures. For patients with brain metastases controlled by effective drugs, WBRT is postponed as much as possible and WBRT can be used as salvage therapy.