Nitroglycerin Plus Whole Intracranial Radiotherapy for Brain Metastases in Non-small Cell Lung Cancer Patients: a Phase II Open Randomized Clinical Trial

Non-small cell Lung cancer (NSCLC) is the most frequent type of lung cancer worldwide. Brain metastases (BM) are the most frequent neurological complications related to NSCLC and it is estimated that 20% to 40% of these patients will present them at some point during the progression of their disease, leading to a poor prognosis.

As only a selected group of NSCLC patients with single metastases or small lesions are candidates for surgical resection or SBRT, the standard treatment for multiple BM is whole-brain radiation therapy (WBRT). Although 80% of the patients who receive WRBT can initially respond to treatment, 50% of these patients will have disease progression. This further has been related to genetic and environmental factors that may lead to radio-resistance, which is the capacity of a cell to stand the effects of radiant energy. To face this problem, other options such as chemotherapy or radio-sensitizers have shown slight benefit in terms of progression-free survival (PFS) but not in overall survival (OS).

Different studies have suggested tumor microenvironment (TME) has an important role in treatment response of BM-derived from melanoma and NSCLC. The demand for O2 by tumors during cancer is an unsteady phenomenon, caused by continuous metabolic profile changes, immune response activity, and TME interactions. Hypoxia occurs in most tumors and plays an important role in tumor progression. In NSCLC exists a clear relationship between hypoxia and radioresistance. Hence, there is interest into modulate TME hypoxia to improve treatment response. Hypoxia regulates the expression of genes that encode growth factors such as endothelin-1 (ET-1), growth factor-derived platelets-B (PDGF) and vascular endothelial growth factor (VEGF), as well as genes that regulate the production of gas molecules such as nitric oxide (NO) and carbon monoxide (CO). The hypoxia-inducible factor (HIF) is a transcription factor that regulates the cellular response to hypoxia, functioning as a regulator of oxygen homeostasis. Several studies have shown that over-expression of HIF-1α is capable of inducing resistance to chemotherapy, radiotherapy and decreasing overall survival in NSCLC primary tumors.

The administration of nitric oxide donors, such as nitroglycerin, reduces the tumor resistance related to hypoxia by inducing the direct proteolysis of HIF-1α. In tumor cells increases oxygen pressure, increased blood flow, activation of p53 and apoptosis have shown a synergistic effect with ionizing irradiation in an experimental model. According to several randomized phase II studies, the addition of transdermal nitroglycerin to vinorelbine and cisplatin treatment can significantly improve the OS and time to progression in patients with locally advanced non-small cell lung cancer. However, in phase III the addition of nitroglycerin to carboplatin-based did not show benefit in PFS, OS and health-related quality of life (PMID: 26347110). Therefore, the aim of this study was to assess, if the addition of transdermal NTG to standard WRBT treatment among stage IV NSCLC patients with BM, could have a significant impact in PFS and OS as primary end-point and disease control rate (DCR) and overall response rate (ORR) as secondary endpoints.

METHODS Experimental design We conducted a phase II clinical trial with a parallel design study among patients treated at the Instituto Nacional de Cancerología from January 2014 to May 2017. The Median follows up was 18 months. Patients with histologically confirmed NSCLC and documented BM defined as the presence of one or more intra-axial enhancing lesions on gadolinium-enhanced brain magnetic resonance imaging (MRI) were included. Candidate patients who underwent radiosurgery or surgical resection were excluded.