Pellerino Alessia, Bruno Francesco, Rudà Roberta, Soffietti Riccardo
Department of Neuro-Oncology, University and City of Health and Science Hospital, via Cherasco 15, 10126, Turin, Italy.
Department of Neurology, Castelfranco Veneto and Treviso Hospital, via Sant' Ambrogio di Fiera 37, 31100, Treviso, Italy.
Curr Treat Options Oncol. 2021 Oct 25;22(12):110. doi: 10.1007/s11864-021-00911-7.
Systemic therapy for brain metastases (BM) is quickly moving from conventional cytotoxic chemotherapy toward targeted therapies, that allow a disruption of driver molecular pathways. The discovery of actionable driver mutations has led to the development of an impressive number of tyrosine kinase inhibitors (TKIs), that target the epidermal growth factor receptor (EGFR) mutations, anaplastic-lymphoma-kinase (ALK) rearrangements, and other rare molecular alterations in patients bearing metastatic non-small cell lung cancer (NSCLC) in the brain, with remarkable results in terms of intracranial disease control and overall survival. Moreover, these drugs may delay the use of local therapies, such as stereotactic radiosurgery (SRS) or whole-brain radiotherapy (WBRT). New drugs with higher molecular specificity and ability to cross the CNS barriers (BBB, BTB and blood-CSF) are being developed. Two major issues are related to targeted therapies. First, the emergence of a resistance is a common event, and a deeper understanding of molecular pathways that are involved is critical for the successful development of effective new targeted agents. Second, an early detection of tumor progression is of utmost importance to avoid the prolongation of an ineffective therapy while changing to another drug. In order to monitor over time the treatment to targeted therapies, liquid biopsy, that allows the detection in biofluids of either circulating tumor cells (CTCs) or circulating tumor DNA (ctDNA) or exosomes, is increasingly employed in clinical trials: with respect to BM the monitoring of both blood and CSF is necessary. Also, radiomics is being developed to predict the mutational status of the BM on MRI.For patients without druggable mutations or who do not respond to targeted agents, immunotherapy with checkpoint inhibitors is increasingly employed, alone or in combination with radiotherapy. Pseudoprogression after immunotherapy alone maybe a challenge for several months after the start of treatment, and the same is true for radionecrosis after the combination of immunotherapy and SRS. In this regard, the value of advanced MRI techniques and PET imaging for a better distinction of pseudoprogression/radionecrosis and true tumor progression is promising, but needs validation in large prospective datasets. Last, a new frontier in the near future will be chemoprevention (primary and secondary), but we need to identify among solid tumors those subgroups of patients with a higher risk of relapsing into the brain and novel drugs, active on either neoplastic or normal cells of the microenvironment, that are cooperating in the invasion of brain tissue.
脑转移瘤（BM）的全身治疗正迅速从传统的细胞毒性化疗转向靶向治疗，后者能够干扰驱动分子途径。可操作驱动基因突变的发现促使大量酪氨酸激酶抑制剂（TKIs）得以开发，这些抑制剂针对携带脑转移非小细胞肺癌（NSCLC）患者的表皮生长因子受体（EGFR）突变、间变性淋巴瘤激酶（ALK）重排及其他罕见分子改变，在颅内疾病控制和总生存期方面取得了显著成效。此外，这些药物可能会延迟立体定向放射外科（SRS）或全脑放疗（WBRT）等局部治疗的使用。具有更高分子特异性和穿越中枢神经系统屏障（血脑屏障、血肿瘤屏障和血脑脊液屏障）能力的新药正在研发中。靶向治疗存在两个主要问题。其一，耐药的出现较为常见，深入了解相关分子途径对于成功开发有效的新型靶向药物至关重要。其二，早期发现肿瘤进展对于避免无效治疗的延长并及时更换药物极为重要。为了长期监测靶向治疗，液体活检（可检测生物流体中的循环肿瘤细胞（CTC）、循环肿瘤DNA（ctDNA）或外泌体）在临床试验中越来越多地被采用：对于脑转移瘤而言，同时监测血液和脑脊液是必要的。此外，正研发影像组学以在MRI上预测脑转移瘤的突变状态。对于没有可靶向突变或对靶向药物无反应的患者，越来越多地单独或联合放疗使用检查点抑制剂进行免疫治疗。单独免疫治疗后的假性进展在治疗开始后的几个月内可能是一个挑战，免疫治疗与SRS联合后的放射性坏死情况也是如此。在这方面，先进的MRI技术和PET成像对于更好地区分假性进展/放射性坏死与真正的肿瘤进展具有前景，但需要在大型前瞻性数据集中进行验证。最后，在不久的将来，化学预防（一级和二级）将成为一个新领域，但我们需要在实体瘤中识别出有更高复发至脑风险的患者亚组，以及对肿瘤微环境中的肿瘤细胞或正常细胞有活性、协同参与脑组织侵袭的新型药物。
