Intracranial Disease in Patients with Non-Small Cell Lung Cancer: Treatment with Erlotinib

Introduction

Lung cancer affects approximately 1.6 million persons a year globally. In the West, it accounts for approximately 10–15% of new cancer cases and 20–30% of cancer deaths ( ). Metastasis to the brain is responsible for death in up to half of cancer patients. Lung cancer is the most frequent primary site of origin, making up 40–50% of cases ( ). Metastasis involving the central nervous system (CNS) affects approximately 20–40% of patients with non-small cell lung cancer (NSCLC) at some stage in their illness, and is present in about 10% at diagnosis ( ). It is highly likely that brain metastasis from NSCLC will present an increasing clinical challenge, due to improvements in initial radiological staging and longer survival following successful treatment of primary and systemic disease.

Patients developing brain metastases are not a homogeneous population. Developments in both neuro-oncology and thoracic oncology have brought about a change in perspective in recent years. First, improved clinical data have resulted in meaningful stratification of patients with brain metastasis, allowing treatment to be adapted according to therapy context and anticipated outcome. In particular, the use of magnetic resonance imaging (MRI) means the extent of intracranial lesions can be more accurately defined. Classic prognostic classification systems ( ) have been refined to take into account these data as well as primary site of origin. Second, the technical capabilities of both surgery and radiotherapy have improved including highly focused stereotactic irradiation techniques. Third, within medical thoracic oncology, a new generation of drugs has expanded the treatment options for molecularly-defined NSCLC subsets. We now have the first and second generation of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), erlotinib, gefitinib, and now afatinib, which have proven activity against brain metastases in case reports, retrospective case series and prospective clinical trials.

This chapter discusses the characteristics and standard clinical management of intracranial disease in patients with NSCLC. We focus on the pharmacologic aspects of erlotinib and preclinical evidence for intracerebral activity. We review the evidence for the activity of erlotinib in patients with brain metastases in various treatment settings. Lastly, we discuss opportunities for further research in improving the efficacy of erlotinib as a treatment for intracranial disease in NSCLC patients.

First-Line Treatment for Advanced NSCLC

Primary chemotherapy for advanced NSCLC has for a long time been centered on platinum agents, with adjunctive roles for the taxanes, gemcitabine, vinorelbine and pemetrexed. However, in the last decade, NSCLC has joined a short list of malignancies that display major vulnerability to targeted inhibition of single aberrant kinases, derived from so-called “driver” mutations. One such target is a receptor tyrosine kinase, EGFR, which activates major survival and proliferation signaling pathways. In an initial large phase III trial, the EGFR-TKI erlotinib improved survival overall in previously treated unselected NSCLC patients ( ). However, it became apparent that a subset of these patients demonstrated significant and prolonged treatment responses. These patients displayed common clinical characteristics: often female, light or never smokers, with adenocarcinoma and a greater frequency in East-Asians. Post-hoc analysis revealed that their tumors contained mutations in the tyrosine kinase domain of the EGFR gene, specifically an exon 19 deletion and a point mutation in exon 21 (L858R). Preclinical evidence confirmed that these are driver mutations, defining a specific subtype of adenocarcinoma, distinct from the more highly mutated cancers that are associated with long-term cigarette smoking ( ).

While erlotinib remains licensed for unselected patients with NSCLC in the second- and third-line setting, its major clinical benefit is in those with sensitizing EGFR mutations. Subsequent trials have addressed the role of tyrosine kinase inhibition as primary therapy in this patient subpopulation and confirmed that erlotinib is effective in the first-line treatment of EGFR -mutated NSCLC with better progression-free survival and quality of life when compared to chemotherapy ( ).

Development and Management of NSCLC Brain Metastases

Development of intracranial metastasis from NSCLC requires multiple pathophysiologic steps. After dissemination from the primary tumor, cancer cells must enter and survive in the bloodstream, arrest in the brain capillary bed, extravasate and proliferate. Stromal cells associated with the primary tumor, as well as co-opted brain microglia and astrocytes, have been shown to assist this process and are likely to be an increasing focus of therapeutic attention ( ). Establishment and propagation of a blood vessel supply has been shown to occur by a variety of mechanisms, probably varying by tumor type and disease progression; growth of brain metastasis from NSCLC is at least partly dependent on neoangiogenesis via vascular endothelial growth factor.

Intracranial metastasis is not only a distinct clinical problem in disseminated NSCLC ( ), but is also a frequent site of initial failure in patients with localized disease who have received treatment with curative intent. A review of 112 NSCLC patients found that brain metastasis was observed in 29% of all recurrences, with a median time to brain recurrence of 9 months ( ). Young age, primary tumor size and lymph node metastasis were associated with a higher risk of intracranial involvement. In one retrospective study, the predicted probabilities of developing brain metastasis from node-negative, primary adenocarcinomas measuring 2 or 6 cm were 0.14 and 0.72, respectively ( ). However, tumor size does not fully explain the development of brain metastasis with cases of small or even occult NSCLC metastasizing early to the brain, while other patients with large tumors, or locoregionally or systemically advanced disease may never establish overt intracranial growth. Prophylactic cranial irradiation (PCI) has been shown to reduce the risk of brain metastasis in high-risk NSCLC, but without disease-free or overall survival benefits ( ).

NSCLC patients with brain metastases may present with severe debility and the least-harm, symptom-based approach to maintain quality of life may be the most appropriate management. However, more commonly some permutation of surgery, whole brain radiotherapy (WBRT) and/or stereotactic radiosurgery is usual. In the presence of multiple brain metastases, the basis of treatment is WBRT, combined with short-course corticosteroid therapy to control peritumoral edema. This is historically associated with a median survival of 3–5 months with 10% of patients alive at 1 year. In the presence of three or fewer brain metastases, addition of a second treatment to WBRT (surgery or stereotactic radiotherapy) confers improved prognosis ( ). Furthermore, radiosurgery has been widely adopted as primary sole treatment for patients with oligometastatic disease to the brain. Subsequent systemic cytotoxic chemotherapy is feasible and may confer benefits in a subset of patients with good functional status and a limited number of brain metastases.