Wrona A
Department of Oncology and Radiotherapy, Medical University of Gdańsk, 7, Dębinki Street, 80-211 Gdańsk, Poland.
Cancer Radiother. 2019 Sep;23(5):432-438. doi: 10.1016/j.canrad.2019.03.009. Epub 2019 Jul 19.
Anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (3 to 5% of all non-small cell lung cancers) carries a particularly high risk of central nervous system dissemination (60% to 90%). As the use of ALK inhibitors improves treatment outcomes over chemotherapy, the determent of central nervous system metastases has become an increasingly relevant therapeutic dilemma considering young age and possible extended overall survival. The goal of brain metastases management is to optimize both overall survival and quality of life, with the high priority of neurocognitive function preservation. Unfortunately in the first year on crizotinib, the pioneering ALK inhibitors, approximately one third of these patients fail in the central nervous system, which is explained by an inadequate central nervous system drug penetration through the blood-brain barrier. Central nervous system-directed radiotherapy represents the most important strategy to control intracranial disease burden and extend the survival benefit with crizotinib. The role of whole brain irradiation in the treatment of brain metastases diminishes, as this technique is associated with the risk of neurocognitive decline. Stereotactic radiotherapy represents an alternative technique that delivers ablative doses of ionizing radiation to the limited volume of oligometastatic brain disease, offering sparing of the adjacent brain parenchyma and reduced neurotoxicity. The next generation ALK inhibitors were designed to cross the blood-brain barrier more efficiently than crizotinib and achieve higher concentration in the cerebrospinal fluid, offering prominent ability to control central nervous system spread. In the phase III ALEX trial the intracranial control was significantly better with alectinib as compared to crizotinib and it translated into survival benefit. Other next generation ALK inhibitors (i.e. ceritinib, brigatinib, lorlatinib) also demonstrated promising activity in the central nervous system.
间变性淋巴瘤激酶（ALK）阳性非小细胞肺癌（占所有非小细胞肺癌的3%至5%）发生中枢神经系统播散的风险特别高（60%至90%）。随着ALK抑制剂的使用相较于化疗改善了治疗结果，鉴于患者年轻且总体生存期可能延长，如何防治中枢神经系统转移已成为一个日益重要的治疗难题。脑转移瘤管理的目标是优化总体生存期和生活质量，重中之重是保留神经认知功能。遗憾的是，在使用第一代ALK抑制剂克唑替尼的第一年，约三分之一的此类患者在中枢神经系统出现治疗失败，这是由于药物透过血脑屏障进入中枢神经系统的能力不足所致。中枢神经系统定向放疗是控制颅内疾病负担并延长克唑替尼生存获益的最重要策略。全脑照射在脑转移瘤治疗中的作用逐渐减小，因为该技术存在导致神经认知功能下降的风险。立体定向放疗是一种替代技术，可向有限体积的寡转移脑病灶给予消融剂量的电离辐射，从而保护相邻脑实质并降低神经毒性。新一代ALK抑制剂的设计目的是比克唑替尼更有效地穿过血脑屏障，并在脑脊液中达到更高浓度，具有显著控制中枢神经系统转移的能力。在III期ALEX试验中，与克唑替尼相比，阿来替尼的颅内控制效果显著更好，并转化为生存获益。其他新一代ALK抑制剂（如色瑞替尼、布加替尼、劳拉替尼）在中枢神经系统也显示出有前景的活性。
