Targeting Angiogenesis for Treatment of NSCLC Brain Metastases

Abstract

Lung cancer is the leading cause of cancer-related mortality worldwide, and non-small cell lung cancer (NSCLC) accounts for about 85% of all new lung cancer diagnosis. The majority of people with NSCLC are unsuitable for surgery since most patients have metastatic disease at diagnosis. About 60% of brain metastases arise from lung cancer. Therapeutic approaches to brain metastases include surgery, whole brain radiotherapy (WBRT), stereotactic radiosurgery, chemotherapy and new biologic agents. Angiogenesis is essential for the development and progression of cancer, and vascular endothelial growth factor (VEGF) is a critical mediator of tumour angiogenesis. One of the targeted approaches most widely studied in the treatment of NSCLC is the inhibition of angiogenesis. Bevacizumab, an anti-VEGF recombinant humanized monoclonal antibody, is the first targeted agent which, when combined with chemotherapy, has shown superior efficacy versus chemotherapy alone as first-line treatment of advanced non-squamous NSCLC patients. Patients with central nervous system (CNS) metastases have initially been excluded from bevacizumab trials for the risk of cerebral haemorrhage as a result of the treatment. Nevertheless, the available data suggest an equal risk of intracranial bleeding in patients with CNS metastases treated with or without bevacizumab therapy. Several other anti-angiogenetic drugs are being investigated in the treatment of advanced NSCLC patients, but results of their activity specifically in CNS metastases are still lacking. This review will focus on the potential role of bevacizumab and other anti-angiogenetic agents in the treatment of brain metastases from NSCLC.

Anti-angiogenetic therapies for central nervous system metastases from non-small cell lung cancer

“…It is known that central nervous system (CNS) bleeding in patients with BM is an important complication. The rate of the CNS bleeding is different across the type of tumor: 1-7% in lung cancer and 70% in renal cancer (13). On the basis of these observations patients with BM are frequently not candidate to clinical studies with anti-vascular endothelial growth factor (VEGF) therapy.…”

Methods and results of locoregional treatment of brain metastases in patients with non-small cell lung cancer

“…Occurrence of BMF-NSCLC is associated with a very poor prognosis: median survival of untreated patients is about 1 month [1, 6, 8, 10, 11, 15, 17, 18, 21, 22] and of those receiving palliative corticosteroid treatment slightly over 2 months [17, 18]. Palliative whole brain radiotherapy (WBRT) prolongs median survival to 3–6 months [8, 10, 17].…”

“…The following methods are used in the treatment of BMF-NSCLC: surgery, SRS, WBRT, systemic treatments (chemotherapy, immunotherapy) and various combinations of these methods [1, 2, 4–6, 8, 9, 11, 12, 17–19, 26, 28–35]. In general, local (surgery, SRS) [1, 4, 6, 8, 17, 18, 28–30, 35] or regional (WBRT) [1, 4, 19, 28–30, 33–35] treatment is preferred, including combination of surgery and radiotherapy.…”

“…In general, local (surgery, SRS) [1, 4, 6, 8, 17, 18, 28–30, 35] or regional (WBRT) [1, 4, 19, 28–30, 33–35] treatment is preferred, including combination of surgery and radiotherapy. There is a growing importance of systemic treatment, in particular of immunotherapy [1, 2, 4, 11, 12, 30–32]. …”

Bevacizumab in Combination with Platinum-Based Chemotherapy in Patients with Advanced Non-Squamous Non-Small Cell Lung Cancer with or without Brain Metastases: A French Cohort Study (EOLE)

“…However, exploratory analyses from studies involving NSCLC patients with undiagnosed or previously treated BM at enrolment concluded that wBM patients are at similar risk of cerebral haemorrhage, regardless of bevacizumab treatment [10][11][12][13][14][15][16] . Furthermore, the BM contraindication was removed from the EU Summary of Product Characteristics in 2009 after the submission of comprehensive safety data [17] .…”