Success of Crizotinib Combined with Whole-Brain Radiotherapy for Brain Metastases in a Patient with Anaplastic Lymphoma Kinase Rearrangement-Positive Non-Small-Cell Lung Cancer

Abstract

Although crizotinib shows marked antitumor activity in anaplastic lymphoma kinase (ALK) rearrangement-positive non-small-cell lung cancer (NSCLC) patients, all treated patients ultimately develop resistance to this drug. Isolated central nervous system failure without progression at extracranial sites is a common progression pattern in ALK rearrangement-positive NSCLC patients treated with crizotinib. Here, we report the success of crizotinib combined with whole-brain radiotherapy in an ALK rearrangement-positive NSCLC patient who developed leptomeningeal carcinomatosis and progression of multiple brain metastases. Additionally, we focused on the mechanism involved by examining the plasma and cerebrospinal fluid concentrations of crizotinib in the present case.

Blood-brain barrier permeability following conventional photon radiotherapy – A systematic review and meta-analysis of clinical and preclinical studies

“…The 20 relevant clinical studies were published between 1979 and 2018 ( Table 1 ). Of these 20 studies, four included patients diagnosed with arteriovenous malformations (AVM) [31] , [32] , [33] , [34] , four described patients suffering from haematological cancers [35] , [36] , [37] , [38] , one focused on nasopharyngeal cancer [39] , six included primary brain tumour patients [40] , [41] , [42] , [43] , [44] , [45] , [46] and four studies included patients diagnosed with brain metastases of other cancer types [47] , [48] , [49] , [50] . The 49 preclinical studies were published between 1964 and 2019, consisting of different animal models ( Table 2 ).…”

“…Of the 20 clinical studies that investigated BBB integrity after RT, fifteen (75%) were performed in adults, three [32] , [33] , [38] (15%) in both adult and paediatric patients, and two [35] , [36] (10%) studied the effect of RT on the BBB in children only ( Table 1 ). Seven out of the 20 studies (35%) reported alterations of BBB permeability [32] , [33] , [39] , [40] , [41] , [47] , [50] , six studies (30%) observed a shallow but unclear effect [31] , [34] , [42] , [43] , [44] , [46] , whereas seven (35%) do not detect any effect [35] , [36] , [37] , [38] , [45] , [48] , [49] ( Fig. 2 A).…”

“…The three studies with a BED of ≥ 100 Gy used a single-dose radiation in patients suffering from AVM where RT is used for stereotactic radiosurgery; Tu et al (2006) [32] and Levegrün et al (2004) [33] reported a clear BBB disruption, while Parkhutik et al (2012) [31] only observed this in part of the patients. For the remaining six studies [34] , [35] , [37] , [39] , [40] , [50] no BED could be calculated, because details on the fractionation scheme applied were not reported. Of these six studies, three did observe an increased BBB permeability.…”

Sequential therapy according to distinct disease progression patterns in advanced ALK-positive non-small-cell lung cancer after crizotinib treatment

“…Another reason is that the mechanism of brain progression may differ from that of other progression sites. This may be related to the low cerebrospinal fluid (CSF)-to-plasma ratio of crizotinib (16) and its low drug penetration into the central nervous system (CNS) in patients whose disease might been sensitive to crizotinib therapy if adequate drug concentrations had been delivered into the CNS (17). Therefore, patients who experience isolated CNS progression should not be considered as having acquired systemic resistance to crizotinib.…”

Metastasis manners and the underlying mechanisms of ALK and ROS1 rearrangement lung cancer and current possible therapeutic strategies

“…92 Crizotinib has proven to be effective against LC because disruption of the BBB with WBRT results in elevated concentrations of crizotinib in the cerebrospinal uid. 93 The OS of patients treated in this manner is approximately 5 years. 92 There have even been reports of profound effects of ALK inhibitors on EML4-ALK-positive lung cancer patients, and almost all bone metastases and lymph node metastases disappeared shortly aer crizotinib administration.…”