CNS Metastases in Patients With Non–Small-Cell Lung Cancer and ALK Gene Rearrangement

Despite the improved outcome with TKIs in patients with ALK gene rearrangement, CNS metastases remains a significant challenge. Approximately, 20% to 35% of such patients present with brain metastases. 2,5 Moreover, the CNS is a frequent site of disease progression in patients who receive crizotinib. The CNS is frequentlyasiteofdiseaseprogression,whereupto60%ofpatients develop metastases during treatment with crizotinib. 2,6 The most likely reason for such isolated CNS failure is incomplete penetration of the blood-brain barrier by crizotinib. Because of the low incidence of ALK gene rearrangement, the optimal treatment, outcome, and prognostic factors in patients with brain metastases who harbor this mutation are poorly understood. In the article that accompanies this editorial, Johung et al 7 have assembled a large series of patients with brain metastases from ALK gene–rearranged NSCLC.Perhaps themost salientpoint of thisstudy istheextended OS time of these patients after diagnosis of a metastasis to the brain. The median OS was 49.5 months, with an impressive 1-year and 2-year OS of 72% and 66%, respectively. Perhaps even more impressive is that 74% of this cohort presented with multiple brain metastases. These outcomes are substantially better than predicted according to the classic recursive partitioning analysis and Graded Prognostic Assessment classifications 8-12 that were created in the premolecular pathology era. A similar observation was made in NSCLC with EGFR mutations. 13 These findings suggest that, with effective systemic treatment, control of CNS disease may be crucial to improved survival. An important element of local disease control in the CNS is radiation therapy, which remains the standard of care for the majorityof the patients with brain metastases. In the current series, greater than 90% of patients received cranial radiation, approximately two-thirds received stereotactic radiosurgery (SRS), and half received whole-brain radiation therapy (WBRT). Although the combination of WBRT and SRS has consistently resulted in improved CNS control, multiple prospective phase III trials have demonstrated that the omission of WBRTwill not compromise the OSofpatientstreatedwithSRSwhohavealimitednumberofbrain metastases. 14-17 However, in patients who have multiple brain metastases, WBRT is routinely used. Despite the local control benefit from WBRT, concerns are the suboptimal local control when used without radiosurgery or surgery and the neurocognitive toxicities. A large, prospective study of 1,194 patients from Japan evaluated the efficacy of SRS alone for patients with up to 10 brain metastases. This study found that the outcome of SRS treatment alone in patients with five to 10 brain metastases is noninferior to that in patients with two to four brain metastases, and the report concluded thatSRS alone maybe asuitable option for patients with up to 10 brain metastases. 18 The negative impact of WBRT on neurocognitive function is particularly relevant in patients with ALK rearrangement because of their extended survival. Recently, two National Clinical Trials Network trials have reported encouraging findings that effectively mitigate the risk of neurocognitive decline in patients who receive WBRT. The Radiation Therapy Oncology Group (RTOG) 0614 trial demonstrated that memantine withWBRT ledtosignificantly longer time tocognitive decline, superior executive function and processing speed, and delayed recognition compared with WBRT alone. 19 The RTOG 0933 trial evaluated the feasibility of preserving memory through conformal avoidance of the hippocampal neural stem-cell compartment during WBRT by using sophisticated medical physics treatment planning. The study demonstrated significantly better