Brain metastases in ALK-positive NSCLC - time to adjust current treatment algorithms

Abstract

The progress in molecular biology has revolutionized systemic treatment of advanced non-small-cell lung cancer (NSCLC) from conventional chemotherapy to a treatment stratified by histology and genetic aberrations. Tumors harboring a translocation of the anaplastic-lymphoma-kinase (ALK) gene constitute a distinct genetic and clinico-pathologic NSCLC subtype with patients with ALK-positive disease being at a higher risk for developing brain metastases. Due to the introduction of effective targeted therapy with ALK-inhibitors, today, patients with advanced ALK-positive NSCLC achieve high overall response rates and remain progression-free for long time intervals. Moreover, ALK-inhibitors seem to exhibit efficacy in the treatment of brain metastases. In the light of this, it needs to be discussed how treatment algorithms for managing patients with brain metastases should be modified. By integrating systemic ALK-inhibitor therapy, radiotherapy, in particular whole brain radiotherapy might be postponed deferring potential long-term impairment by neurocognitive deficits to a later time point in the course of the disease. An early treatment of asymptomatic brain metastases might offer patients a longer time without impairment of cerebral symptoms or radiotherapeutic interventions. Based on an updated extensive review of the literature this article provides an overview on the epidemiology and the treatment of patients' brain metastases. It describes the specifics of ALK-positive disease and proposes an algorithm for the treatment of patients with advanced ALK-positive NSCLC and brain metastases.

Keywords: ALK-inhibitors; ALK-positive; brain metastases; non-small cell lung cancer.

Figure 1

(A) Proposed algorithm for the management of patients with ALK-positive NSCLC and brain metastases under treatment with 1L-ALKi. Postpone WBRT as long as possible. If BM not amenable for SRS switch to 2L-ALKi or if sparing WBI (2×20 Gy and/or hippocampal sparing) and TBP if later in the course of the disease. In case mechanism of resistance to 1L-ALKi is known, switch to appropriate 2l-ALKi if possible. BM brain metastases; SRS stereotactic radiotherapy; WBRT whole brain radiotherapy; TBP treatment beyond progression with 1L-ALK-Inhibitor; 1L-ALKi (alectinib, ceritinib, crizotinib) 2L-ALKi second line ALK-inhibitor (change to different ALK-inhibitor than 1L). (B) Proposed algorithm for the management of patients with ALK-positive NSCLC and brain metastases under treatment with crizotinib. Postpone WBRT as long as possible.If BM not amenable for SRS switch to 2nd generation ALKi or if sparing WBI (2×20 Gy and/or hippocampal sparing) and TBP if later in the course of the disease. BM brain metastases; SRS stereotactic radiotherapy; WBRT whole brain radiotherapy; TBP treatment beyond progression with crizotinib; 2nd ALKi second generation ALK-inhibitor.

Figure 1

(A) Proposed algorithm for the management of patients with ALK-positive NSCLC and brain metastases under treatment with 1L-ALKi. Postpone WBRT as long as possible. If BM not amenable for SRS switch to 2L-ALKi or if sparing WBI (2×20 Gy and/or hippocampal sparing) and TBP if later in the course of the disease. In case mechanism of resistance to 1L-ALKi is known, switch to appropriate 2l-ALKi if possible. BM brain metastases; SRS stereotactic radiotherapy; WBRT whole brain radiotherapy; TBP treatment beyond progression with 1L-ALK-Inhibitor; 1L-ALKi (alectinib, ceritinib, crizotinib) 2L-ALKi second line ALK-inhibitor (change to different ALK-inhibitor than 1L). (B) Proposed algorithm for the management of patients with ALK-positive NSCLC and brain metastases under treatment with crizotinib. Postpone WBRT as long as possible.If BM not amenable for SRS switch to 2nd generation ALKi or if sparing WBI (2×20 Gy and/or hippocampal sparing) and TBP if later in the course of the disease. BM brain metastases; SRS stereotactic radiotherapy; WBRT whole brain radiotherapy; TBP treatment beyond progression with crizotinib; 2nd ALKi second generation ALK-inhibitor.