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Anaplastic lymphoma kinase non-Small-cell lung cancer intracranial metastases

ALK inhibitors are effective in both naive and pre-treated patients with similar intracranial overall response rate (IC ORR) and IC disease control rate, irrespective of the line of therapy 1)

Nicoś et al. assessed the frequency of ALK abnormalities in 145 formalin fixed paraffin embedded (FFPE) tissue samples from CNS metastases of NSCLC using immunohistochemical (IHC) automated staining (BenchMark GX, Ventana, USA) and fluorescence in situ hybridization (FISH) technique (Abbot Molecular, USA). The studied group was heterogeneous in terms of histopathology and smoking status. ALK abnormalities were detected in 4.8% (7/145) of CNS metastases. ALK abnormalities were observed in six AD (7.5%; 6/80) and in single patients with adenosuqamous lung carcinoma. Analysis of clinical and demographic factors indicated that expression of abnormal ALK was significantly more frequently observed (P = 0.0002; χ2  = 16.783) in former-smokers. Comparison of IHC and FISH results showed some discrepancies, which were caused by unspecific staining of macrophages and glial/nerve cells, which constitute the background of CNS tissues. Their results indicate high frequency of ALK gene rearrangement in CNS metastatic sites of NSCLC that are in line with prior studies concerning evaluation of the presence of ALK abnormalities in such patients. However, they showed that assessment of ALK by IHC and FISH methods in CNS tissues require additional standardizations 2).

In Anaplastic lymphoma kinase non-Small-cell lung cancer patients; ALK inhibitors may provide a new treatment option for brain metastasis and could improve overall survival (OS). Even in patients with crizotinib-resistant disease, second generation ALK inhibitors display prominent clinical activity. There is rapidly emerging preclinical and clinical data showing improvement in this issue 3).

Song and Colaco present a case of a patient with stage IV anaplastic lymphoma kinase (ALK) positive adenocarcinoma of the lung who underwent stereotactic radiosurgery to her brain metastases and received targeted treatment. While her intracranial and extracranial disease remained well controlled, they discuss the radiation-induced necrosis she suffered as a result of the treatment, the related diagnostic dilemma involved, and the subsequent management of this late toxicity of stereotactic radiosurgery 4).

A total of 90 patients with brain metastases from ALK-rearranged NSCLC were identified from six institutions; 84 of 90 patients received radiotherapy to the brain (stereotactic radiosurgery [SRS] or whole-brain radiotherapy [WBRT]), and 86 of 90 received tyrosine kinase inhibitor (TKI) therapy. Estimates for overall (OS) and intracranial progression-free survival were determined and clinical prognostic factors were identified by Cox proportional hazards modeling.

RESULTS: Median OS after development of brain metastases was 49.5 months (95% CI, 29.0 months to not reached), and median intracranial progression-free survival was 11.9 months (95% CI, 10.1 to 18.2 months). Forty-five percent of patients with follow-up had progressive brain metastases at death, and repeated interventions for brain metastases were common. Absence of extracranial metastases, Karnofsky performance score ≥ 90, and no history of TKIs before development of brain metastases were associated with improved survival (P = .003, < .001, and < .001, respectively), whereas a single brain metastasis or initial treatment with SRS versus WBRT were not (P = .633 and .666, respectively). Prognostic factors significant by multivariable analysis were used to describe four patient groups with 2-year OS estimates of 33%, 59%, 76%, and 100%, respectively (P < .001).

CONCLUSION: Patients with brain metastases from ALK-rearranged NSCLC treated with radiotherapy (SRS and/or WBRT) and TKIs have prolonged survival, suggesting that interventions to control intracranial disease are critical. The refinement of prognosis for this molecular subtype of NSCLC identifies a population of patients likely to benefit from first-line SRS, close CNS observation, and treatment of emergent CNS disease 5).

Petrelli F, Lazzari C, Ardito R, Borgonovo K, Bulotta A, Conti B, Cabiddu M, Capitanio JF, Brighenti M, Ghilardi M, Gianni L, Barni S, Gregorc V. Efficacy of ALK inhibitors on NSCLC brain metastases: A systematic review and pooled analysis of 21 studies. PLoS One. 2018 Jul 27;13(7):e0201425. doi: 10.1371/journal.pone.0201425. eCollection 2018. PubMed PMID: 30052658; PubMed Central PMCID: PMC6063430.
Nicoś M, Jarosz B, Krawczyk P, Wojas-Krawczyk K, Kucharczyk T, Sawicki M, Pankowski J, Trojanowski T, Milanowski J. Screening for ALK abnormalities in central nervous system metastases of non-small-cell lung cancer. Brain Pathol. 2018 Jan;28(1):77-86. doi: 10.1111/bpa.12466. Epub 2017 Mar 2. PubMed PMID: 27879019.
Muhammet Hacioglu B, Kostek O, Erdogan B, Uzunoglu S, Cicin I. Targeted therapy with anaplastic lymphoma kinase inhibitors in non-Small-cell lung cancer even with brain metastasis. J BUON. 2017 May-Jun;22(3):586-591. PubMed PMID: 28730760.
Song YP, Colaco RJ. Radiation Necrosis - A Growing Problem in a Case of Brain Metastases Following Whole Brain Radiotherapy and Stereotactic Radiosurgery. Cureus. 2018 Jan 8;10(1):e2037. doi: 10.7759/cureus.2037. PubMed PMID: 29541558; PubMed Central PMCID: PMC5843383.
Johung KL, Yeh N, Desai NB, Williams TM, Lautenschlaeger T, Arvold ND, Ning MS, Attia A, Lovly CM, Goldberg S, Beal K, Yu JB, Kavanagh BD, Chiang VL, Camidge DR, Contessa JN. Extended Survival and Prognostic Factors for Patients With ALK-Rearranged Non-Small-Cell Lung Cancer and Brain Metastasis. J Clin Oncol. 2016 Jan 10;34(2):123-9. doi: 10.1200/JCO.2015.62.0138. Epub 2015 Oct 5. PubMed PMID: 26438117; PubMed Central PMCID: PMC5070549.
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