Throughout my career in clinical oncology, I have watched the lung cancer treatment landscape evolve and transform – radiation, chemotherapy or invasive surgery are, for many, no longer the only treatment options as they were for all patients 20 years ago.1 Researchers are making progress every day, delivering more therapies targeted to specific molecular profiles, and developing tests to match patients to therapies that have the highest potential to offer the most tolerable and durable clinical benefit.
We are living in a new generation of lung cancer research: our understanding is rapidly improving, and there is an unprecedented level of information available to physicians and patients about the diagnosis, driving mutations associated with primary lung cancer tumours, molecular testing and targeted therapies. This knowledge has led to longer-lasting responses to treatment, but as a result, patients are more likely to experience disease progression due to secondary metastases. Awareness surrounding effective treatment options for Central Nervous System (CNS) metastases is still limited, despite their affecting up to 50% of patients with non-small cell lung cancer (NSCLC).2,3
An introduction to CNS metastases
Lung cancer is one of the most common of all cancers to spread to the central nervous system (CNS). Parenchymal brain metastases (BM) and leptomeningeal metastases (LM) are both forms of CNS metastases associated with advanced (Stage IV) non-small cell lung cancer (NSCLC).4 Although these can occur within a patient at the same time, it is important to note that these are separate conditions. BM are a more common complication of advanced cancer, occurring in 20-40% of patients, and form when primary tumour cells disseminate through the blood stream and proliferate within the brain.4,5,6 This incidence increases to around 50% of patients during the course of treatment with targeted therapies.2,3 LM disease is less common; developing in up to 5% of patients,7 and occurs when tumour cells spread from another part of the body to the meninges that surround the brain and spinal cord.8 The expected overall survival of patients with LM disease is extremely short, generally 3 to 6 months.9,10
Depending on where these tumours develop in the brain or along the spinal cord, motor and neurological symptoms may vary significantly patient-to-patient. Current treatments such as chemotherapy and radiation may treat symptoms, but are not able to cure the disease or provide long-lasting benefit. And in many cases, the side effects have an intolerable effect on quality of life.11 It is impossible to ignore that patients diagnosed with CNS metastases are confronted with poor prognosis and survival rates.11
The blood-brain barrier
There are two main reasons CNS metastases are notoriously hard to treat. The first is their positioning, within the brain or alongside the spinal cord, which makes them difficult, if not impossible, to remove surgically. The second is the challenge presented by the blood-brain barrier, a membrane that selectively regulates molecules entering the brain from the blood.12,13 A large portion of lung cancer treatments today demonstrate poor CNS activity as they struggle to penetrate this barrier, and therefore fail to gain access to the tumour via the cerebral spinal fluid (CSF, the fluid which surrounds the brain and spinal cord) on the other side.14,15,16 While some new therapies are beginning to show promise, more research is needed in this area of high unmet medical need.
Gaining scientific momentum
The blood-brain barrier is an important site of molecule exchange between the brain and the blood stream, and essential to maintaining a highly controlled microenvironment which allows neural signalling to take place within the CNS.16 Today, even as oncology scientists and academics are investigating multiple different ways to overcome this biological hurdle, the permeability of the blood-brain barrier remains a significant challenge. Many clinical studies investigating CNS activity in patients treated with targeted medicines are currently underway, and research is revealing a number of ways in which treatments could be optimised, such as combining targeted medicines with radiation or chemotherapy.17
As a clinical lead in the field of lung oncology, it is inspiring to observe the drive and determination of the scientists around me, who are striving to help patients dependent on a breakthrough in clinical research.
Developing an effective treatment for conquering the poor prognosis and survival outcomes attributed to CNS metastases depends on numerous key players. As part of our ongoing commitment to eliminating cancer as a cause of death, we are proud to collaborate with numerous research centres, academic institutions, health authorities and industry partners.
These advancements, however, could not be made at such an accelerated rate without the continued support of our patient advocacy group partners and patients – our continual driving force. With this open and ongoing exchange of information between researchers and patients, we are able to understand what matters most to patients, and continuously evolve and pinpoint the areas of highest unmet need, including CNS metastases. Being able to deliver the right treatment targeted to an individual’s disease and achieve significant clinical benefit remains the most integral motivation to our work.
- Langer CJ & Mehta MP. Current Management of Brain Metastases, With a Focus on Systemic Options. J Clin Onc. 2005;23:25:6207-6219.
- Rangachari, et al. Brain Metastases in Patients with EGFR-Mutated or ALK-Rearranged Non-Small-Cell Lung Cancers. Lung Cancer. 2015;88:108–111.
- Baik CS, et al. Targeted Therapy for Brain Metastases in EGFR-Mutated and ALK-Rearranged Non–Small-Cell Lung Cancer. Journal of Thoracic Oncology. 2015;10:1268–1278.
- Preeusser M, et al. Brain metastases: Pathophysiology and Emerging Targeted Therapies. Acta Neuropathol. 2012;123:205-222.
- Eichler AF, et al. EGFR Mutation Status and Survival after Diagnosis of Brain Metastasis in Non-Small Cell Lung Cancer. J Clin Onc. 2010;28:15(Suppl 1).
- National Institutes of Health. Adult Central Nervous System Tumors Treatment–Health Professional Version (PDQ®) Metastatic Brain Tumors. http://www.cancer.gov/types/brain/hp/adult-brain-treatment-pdq. Accessed May 2017.
- Chamberlain MC, et al. Carcinoma Meningitis Secondary to Non-small Cell Lung Cancer: Combined Modality Therapy. Arch Neurol. 1998;55:506-512.
- Schneck MJ, et al. Leptomeningeal Carcinomatosis. Practice Essentials. Available at http://emedicine.medscape.com/article/1156338-overview. Accessed May 2017.
- Liao B, et al. Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors for Non-Small Cell Lung Cancer Patients with Leptomeningeal Carcinomatosis. J Thoracic Oncology. 2015. 10(12);1754-1761.
- Reiss JW, et al. Prolonged survival of patients with non-small-cell lung cancer with leptomeningeal carcinomatosis in the modern treatment era. 2014. Clin. Lung Cancer. 15(3):202-6.
- Peters S, et al. The impact of brain metastasis on quality of life, resource utilization and survival in patients with non-small-cell lung cancer. Can Treatment Rev. 2016;45:139-162.
- De Vries NA, et al. Restricted Brain Penetration of the Tyrosine Kinase Inhibitor Erlotinib Due to the Drug Transporters P-gp and BCRP. Invest New Drugs. 2012;30(2):443-9.
- Ballabh P. et al. The blood–brain barrier: an overview: Structure, regulation, and clinical implications. Neur. Dis. 2004;16(1):1-13.
- European Medicines Agency CHMP assessment report for Giotrif. 2013.
- Zhao J, et al. Cerebrospinal Fluid Concentrations of Gefitinib in Patients with Lung Adenocarcinoma. Clin Lung Cancer. 2013:14(2):188-93.
- Abbott NJ, et al. Structure and function of the blood–brain barrier. Neuro Dis. 2010;37(1):13-25.
- Berger LA, et al. CNS metastases in non-small-cell lung cancer: Current role of EGFR-TKI therapy and future perspectives. Lung Cancer. 2013; 80(3):242-248