Abstract
Brain metastases (BMs) represent the most frequent event during the course of Non-Small Cell Lung Cancer (NSCLC) disease. Recent advancements in the diagnostic and therapeutic procedures result in increased incidence and earlier diagnosis of BMs, with an emerging need to optimize the prognosis of these patients through the adoption of tailored treatment solutions. Nowadays a personalized and multidisciplinary approach should rely on several clinical and molecular factors like patient’s performance status, extent and location of brain involvement, extracranial disease control and the presence of any “druggable” molecular target. Radiation therapy (RT), in all its focal (radiosurgery and fractionated stereotactic radiotherapy) or extended (whole brain radiotherapy) declinations, is a cornerstone of BMs management, either alone or combined with surgery and systemic therapies. Our review aims to provide an overview of the many modern RT solutions available for the treatment of BMs from NSCLC in the different clinical scenarios (single lesion, oligo and poly-metastasis, leptomeningeal carcinomatosis). This includes a detailed review of the current standard of care in each setting, with a presentation of the literature data and of the possible technical solutions to offer a “state-of-art” treatment to these patients. In addition to the validated treatment options, we will also discuss the future perspectives on emerging RT technical strategies (e.g., hippocampal avoidance whole brain RT, simultaneous integrated boost, radiosurgery for multiple lesions), and present the innovative and promising findings regarding the combination of novel targeted agents such as tyrosine kinase inhibitors and immune checkpoint inhibitors with brain irradiation.
Highlights
In Non-Small Cell Lung Cancer (NSCLC), the development of immune checkpoint inhibitors (ICIs) and targeted agents [ Epidermal Growth Factor Receptor (EGFR) and Anaplastic Lymphoma Kinase (ALK) Tyrosine Kinase Inhibitors (TKIs)], redesigned this scenario, for the ability of these novel drugs to permeate in the Central Nervous System (CNS)
The new generation of targeted agents, such as osimertinib for EGFR-mutated [61, 62] and alectinib or lorlatinib for ALKrearranged [63, 64] NSCLC, significantly improved intracranial response rate compared to traditional ChT or first-generation TKIs, with responses durable over time
whole brain radiotherapy (WBRT) + SRS in NSCLC oligometastases with favourable prognosis deserves further evaluation
Summary
Brain metastases (BMs) represents the most frequent Central Nervous System (CNS) neoplasm and Non-Small Cell Lung Cancer (NSCLC) accounts for approximately 50% of the lesions. Single BM represents the most favorable disease presentation in the setting of BMs. Several randomized controlled trials (RCTs) demonstrated that the radical management of the single lesion with focal treatments, either surgery or RT, in addition to the historical WBRT approach, improves both local control (LC) and overall survival (OS) [9,10,11]. Maximum tolerated doses were 24 Gy, 18 Gy, and 15 Gy for tumors < 20 mm, 21–30 mm, and 31–40 mm in maximum diameter, respectively [23, 24] This risk adaptive approach is currently adopted in clinical practice, for larger lesions (>2 cm) 18-15 Gy or less in single fraction could be detrimental in terms of LC. Treated patients experienced a higher rate of early (0-3 months) local recurrence, but the relative benefit of SRS decreased with time [36]
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