Cognitive Impairment in Lung Cancer and Brain Metastases

Introduction

Over the past few decades, advances in cancer treatments have significantly extended survival. With an increase in the number of cancer survivors, there has been a greater appreciation for potential adverse side effects of cancer treatments. Cognitive functioning in cancer patients has increasingly received research attention, particularly with the side effects of chemotherapy on cognition, which are often referred to by patients as “chemo brain” or “chemo fog.” Importantly, cognitive complaints are among the most frequently reported side effects from treatments, even in patients with non-central nervous system (non-CNS) cancers. Cognitive impairment can have detrimental impacts on patients' quality of life by affecting their functional abilities, school or occupational performance, social relationships, and participation in leisure activities.

Much of the research on cognition in cancer patients has focused on breast cancer, but several studies have observed cognitive impairments in patients with a variety of other non-CNS cancers including lung cancer. In this chapter, we will focus on cognitive impairment in patients with small cell or non-small cell lung cancer (SCLC and NSCLC, respectively) as well as those lung cancer patients who develop brain metastases. We will summarize the literature on the incidence and pattern of cognitive impairment in lung cancer and brain metastases, the brain-related changes associated with various cancer treatments, and potential approaches to prevent or treat cognitive impairment.

Epidemiology

More than one in three persons will be diagnosed with cancer in their lifetime. Most of these cancers are outside of the central nervous system (CNS). Lung cancer, including both SCLC and NSCLC, is the second most common cancer in men and women. Breast cancer is the most common in women, while prostate cancer is the most common in men. Lung cancer accounts for nearly 25% of all cancer-related deaths, which is the most common cancer-related death in the United States but also in the world. The most common lung cancer type is NSCLC, accounting for approximately 85% of cases, while the often more aggressive SCLC accounts for about 15% of cases. Lung cancer mainly occurs among older adults and the average age at diagnosis is 70. Smoking drastically increases the risk of lung cancer with approximately 85%–90% of cases attributed to smoking. Fortunately, the incidence of lung cancer cases has decreased in recent years due to more people quitting smoking.

Around 20% of cancer patients will develop brain metastases, and lung cancer is the most common primary site for brain metastases across patients irrespective of sex. Lung cancer patients often tend to present with multiple brain metastases, although they may have a solitary lesion if it is detected early. Lung cancer patients with brain metastases can often have a poor prognosis. However, prognosis varies considerably based on molecular markers, such that some patients with brain metastases from NSCLC can have differences in median survival from 12 months to even 4 years. About 20%–40% of NSCLC patients eventually develop brain metastases. Approximately 10% of SCLC patients present with brain metastases at diagnosis, while an additional 40%–50% go on to have brain metastases. At times, the brain metastasis may be discovered before lung cancer is even identified as the primary cancer. Most brain metastases are supratentorial, and they are often discovered at the junction between the gray and white matter and in watershed areas between vascular territories. SCLC has one of the highest incidences of leptomeningeal metastases, a subset of metastases growing in the lining of the brain or spine and/or disseminated in the cerebrospinal spinal fluid, which is associated with a poor prognosis. ^,

Cognitive complaints are relatively frequent in patients with both non-CNS cancers along with brain metastases. Up to 70% of adult patients with non-CNS cancers have cognitive complaints during cancer treatments and approximately 30% demonstrate cognitive impairment on formal neuropsychological assessments. Specifically in lung cancer, cognitive dysfunction appears to be common in SCLC with prevalence rates ranging from 15% to 90%. Among patients with NSCLC who had not yet received treatment, prevalence rates range from 23% to 95% having cognitive impairment at baseline. In patients with brain metastases, cognitive impairment is almost ubiquitous with approximately 90% of patients presenting with cognitive impairment prior to receiving any treatments.

In addition to brain metastases, another potential cause of CNS involvement in lung cancer is paraneoplastic neurologic syndromes (PNS). PNS are a heterogeneous group of disorders, which are often caused by an immune response to cancer and not by direct invasion, metastasis, or an effect of cancer treatments. PNS can affect any part of the nervous system. The immune response is often associated with antineuronal antibodies, and these can serve as biomarkers of the origin of the neurological syndrome and may also reveal the primary cancer. For instance, paraneoplastic limbic encephalitis (PLE) is strongly associated with the antineuronal antibody and anti-Hu, which is often found in SCLC. While PNS can occur with any type of cancer, SCLC is one of the most frequent causes of PNS. SCLC has been found to be associated with a variety of PNS: PLE, Lambert–Eaton myasthenic syndrome, paraneoplastic encephalomyelitis, paraneoplastic sensory neuropathy, and paraneoplastic cerebellar degeneration. Of these disorders, the one that may be most relevant to cognition is paraneoplastic limbic encephalitis (PLE).

PLE is a relatively rare disorder (i.e., approximately 1 in 10,000 of cancer patients; in which 50% are due to SCLC. PLE may occur as a part of a multifocal encephalomyelitis or as an isolated syndrome. Patients with PLE often present with significant cognitive impairments, seizures, and psychiatric symptoms. PLE typically presents as an amnestic syndrome characterized by pronounced memory loss along with deficits in attention, language, visuospatial skills, and executive functioning. Memory loss can be accompanied by confabulations and a lack of insight. The seizures may be generalized or focal. Common psychiatric symptoms may consist of symptoms of depression, anxiety, emotional lability, personality changes, as well as hallucinations and delusions. Overall, the diagnosis of PLE can be difficult to ascertain given the similarity of these symptoms with other cancer-related complications, including brain metastases, toxic and metabolic encephalopathies, viral etiologies such as herpes simplex encephalitis, and the side effects of various cancer treatments. The neurological symptoms of PNS can even precede the detection of the cancer, which can be more difficult to identify it as a paraneoplastic syndrome.

Causes and Mechanisms