Neurocognitive aspects of brain metastasis

doi:10.1016/B978-0-12-811161-1.00012-8

Handbook of Clinical Neurology

Volume 149, 2018, Pages 155-165

https://doi.org/10.1016/B978-0-12-811161-1.00012-8 Get rights and content

Abstract

Brain metastases are common, occurring in approximately 20% of cancer patients. One of the biggest concerns for these patients and their families is neurocognitive decline. Neurocognitive issues in this patient population are complex and many patients have neurocognitive impairment due to systemic therapies even before they develop brain metastases. The development of brain metastases as well as the treatment of these tumors can cause decline in neurocognitive function. Diffuse treatments such as whole-brain radiotherapy are more frequently associated with neurocognitive decline than focal interventions such as radiosurgery, surgical resection, and implantable chemotherapy wafers. For patients with brain metastases treatment decisions require a multidisciplinary approach, balancing many factors including the neurocognitive impact of treatment and the disease process itself. Finally, to continue to advance the field there needs to be continued utilization, both off and on clinical trial, of performance-based clinical outcome assessments (i.e., neurocognitive tests) to objectively assess and measure the neurocognitive outcomes of these patients.

Introduction

Patients with brain metastasis represent a very heterogeneous and large patient population: upwards of 17% of all cancer patients eventually develop disease in the brain (Nayak et al., 2012). Improvements in diagnosis and efficacy of systemic therapies will likely result in an even higher incidence of brain metastasis in the future. Treatment of patients with metastatic cancer can be complicated by the need to address disease both within and outside the central nervous system (CNS). Although many systemically administered therapies are believed to have limited penetration across the blood–brain barrier, CNS toxicities have been observed and some agents have demonstrated efficacy in terms of disease control and/or response within the CNS compartment. The historic mainstays of treatment for patients with brain metastasis have been surgery, radiosurgery, and whole-brain radiation therapy (WBRT). All of these approaches carry potential risks of off-target as well as on-target–off-tumor adverse effects that can be manifest as neurocognitive dysfunction.

Section snippets

Impact of prior therapies: chemotherapy-related neurocognitive impairment

The most common primary cancers that metastasize to the brain include lung, breast, melanoma, renal, and colorectal. However, there is variation in when during a patient's disease course brain metastasis is diagnosed. For example, patients with lung cancer frequently develop brain metastasis at the time of diagnosis or shortly thereafter; in contrast, patients with breast and renal cancer often develop brain metastasis years after initial diagnosis and treatment (Nayak et al., 2012). Given this

Impact of tumor: neurocognitive function in brain metastasis patients at diagnosis

The impact of a brain mass on neurocognitive function is primarily related to the location of the lesion, its size, rate of growth, and the extent of surrounding edema. Neurocognitive evaluation prior to any treatment has demonstrated that these baseline deficits are common in patients with brain metastasis (Sherman et al., 2002; Herman et al., 2003; Mehta et al., 2003; Meyers et al., 2004; Chang et al., 2009). Prevalence rates vary among studies, based primarily on the sensitivity of

Surgery

The resection of a single brain metastasis is frequently considered the best treatment option in patients with accessible lesions causing mass effect, good performance status, and well-controlled systemic disease (Vogelbaum and Suh, 2006). The hallmark study conducted by Patchell and colleagues (1990) randomized 48 patients with single brain metastases to surgery and WBRT (25 patients) compared with WBRT alone (23 patients) and evaluated local recurrence and survival rates. The addition of

Neurocognitive function in clinical trials: performance-based tests

Past and current clinical trials described below have used the clinical trial battery (Wefel et al., 2011a) of neurocognitive tests that includes the Hopkins Verbal Learning Test – Revised (Benedict et al., 1998), Trail Making Test (Tombaugh, 2004), and Multilingual Aphasia Examination Controlled Oral Word Association (Ruff et al., 1996). This core battery of tests has been reviewed in detail elsewhere and recommended for inclusion in trials assessing neurocognition (van den Bent et al., 2011;

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Machine learning identifies experimental brain metastasis subtypes based on their influence on neural circuits
2023, Cancer Cell
A high percentage of patients with brain metastases frequently develop neurocognitive symptoms; however, understanding how brain metastasis co-opts the function of neuronal circuits beyond a tumor mass effect remains unknown. We report a comprehensive multidimensional modeling of brain functional analyses in the context of brain metastasis. By testing different preclinical models of brain metastasis from various primary sources and oncogenic profiles, we dissociated the heterogeneous impact on local field potential oscillatory activity from cortical and hippocampal areas that we detected from the homogeneous inter-model tumor size or glial response. In contrast, we report a potential underlying molecular program responsible for impairing neuronal crosstalk by scoring the transcriptomic and mutational profiles in a model-specific manner. Additionally, measurement of various brain activity readouts matched with machine learning strategies confirmed model-specific alterations that could help predict the presence and subtype of metastasis.
Neurological complications of breast cancer
2022, Neurological Complications of Systemic Cancer and Antineoplastic Therapy
Breast cancer is the second most common malignancy in the world, the most common malignancy in women, and an important cause of global cancer-related morbidity and mortality. Nearly one in eight women living in the United States will be diagnosed with breast cancer in their lifetime. Neurological complications are quite common in this population and can arise from the cancer itself or the various treatment modalities, i.e., surgery, radiation, or chemotherapy. Ironically, with the continued refinement of anticancer therapies and consequently improved survival afforded patients, the incidence of central nervous system (CNS) metastasis has increased, likely reflecting the sanctuary site that the central nervous system provides cancer cells. CNS metastases typically occur in patients with disseminated systemic malignancy, but the CNS may also be the first or isolated site of relapse after systemic disease control is achieved. Metastases in the central and peripheral nervous systems usually carry a poor prognosis, but when breast cancer is the primary cancer, treatment is more likely to afford local control.
Brain metastasis models: What should we aim to achieve better treatments?
2021, Advanced Drug Delivery Reviews
Citation Excerpt :
Additionally, metastatic outgrowth in the brain frequently impairs patient neurocognition [88], which is a major contributor to the morbidity of this type of metastasis and might also involve additional therapeutic strategies and cognitive rehabilitation [57]. Although this problem is clinically well-documented and there are established tests to evaluate neurocognitive decline in patients with brain metastasis [286], there is no knowledge on the underlying pathophysiology rather than the mass effect, which does not always explain the variability among patients regarding the degree of cognitive impact [111]. Emerging interests to understand this aspect that applies to many brain tumors could generate additional organ-specific strategies to improve the prognosis of patients with brain metastasis [170].
Brain metastasis is emerging as a unique entity in oncology based on its particular biology and, consequently, the pharmacological approaches that should be considered. We discuss the current state of modelling this specific progression of cancer and how these experimental models have been used to test multiple pharmacologic strategies over the years. In spite of pre-clinical evidences demonstrating brain metastasis vulnerabilities, many clinical trials have excluded patients with brain metastasis. Fortunately, this trend is getting to an end given the increasing importance of secondary brain tumors in the clinic and a better knowledge of the underlying biology. We discuss emerging trends and unsolved issues that will shape how we will study experimental brain metastasis in the years to come.
Initial Approach to the Patient with Multiple Newly Diagnosed Brain Metastases
2020, Neurosurgery Clinics of North America
Citation Excerpt :
However, reduced rates of intracranial relapse do not translate into significant prolongation of overall survival or functionally independent survival in patients treated with WBRT in addition to SRS, versus SRS alone.15–18 Furthermore, WBRT is associated with significant neurocognitive decline.19 Post-WBRT patients show decreased performance on a battery of cognitive tests, such as delayed recall,20 with greater than 90% of patients showing cognitive decline in the 3 months following WBRT + SRS versus 63.5% who underwent SRS alone.16
Death Anxiety in Patients With Metastatic Non-Small Cell Lung Cancer With and Without Brain Metastases
2020, Journal of Pain and Symptom Management
Citation Excerpt :
The shortened life expectancy and adverse neurological sequelae associated with brain metastases may increase death anxiety. Cognitive decline is common in both central nervous system and non-central nervous system cancers, but the development of brain metastases and their treatment increase the risk for such decline.20–25 Cognitive decline can significantly impede daily functioning and may be a signal of disease progression to patients, heightening their death anxiety.26
Death anxiety is common in patients with metastatic cancer, but its relationship to brain metastases and cognitive decline is unknown. Early identification of death anxiety and its determinants allows proactive interventions to be offered to those in need.
To identify psychological, physical, and disease-related (including brain metastases and cognitive impairment) factors associated with death anxiety in metastatic non-small cell lung cancer (mNSCLC) patients.
A cross-sectional pilot study with mNSCLC outpatients completing standardized neuropsychological tests and validated questionnaires measuring death anxiety, cognitive concerns, illness intrusiveness, depression, demoralization, self-esteem, and common cancer symptoms. We constructed a composite for objective cognitive function (mean neuropsychological tests z-scores).
Study measures were completed by 78 patients (50% females; median age 62 years [range 37–82]). Median time since mNSCLC diagnosis was 11 months (range 0–89); 53% had brain metastases. At least moderate death anxiety was reported by 43% (n = 33). Objective cognitive impairment was present in 41% (n = 32) and perceived cognitive impairment in 27% (n = 21). Death anxiety, objective, and perceived cognitive impairment did not significantly differ between patients with and without brain metastases. In univariate analysis, death anxiety was associated with demoralization, depression, self-esteem, illness intrusiveness, common physical cancer symptoms, and perceived cognitive impairment. In multivariate analysis, demoralization (P < 0.001) and illness intrusiveness (P = 0.001) were associated with death anxiety.
Death anxiety and brain metastases are common in patients with mNSCLC but not necessarily linked. The association of death anxiety with both demoralization and illness intrusiveness highlights the importance of integrated psychological and symptom management. Further research is needed on the psychological impact of brain metastases.
Radiosurgery and Immunotherapy in the Treatment of Brain Metastases
2019, World Neurosurgery
Citation Excerpt :
Strategies in this scenario differ considerably. The available evidence in patients with more than 4 brain metastases indicates that whole brain radiotherapy enhances brain control, but this occurs at the expense of neurocognitive deterioration and is associated with questionable survival benefit.2,5,6 Because of these drawbacks, many offer SRS to patients with more than 4 brain metastases as a first-choice treatment.7-11
Radiation therapy represents a mainstay of treatment for patients with brain metastases. Recently, the widespread adoption of immune checkpoint blockade has led to keen interest in treating cancers with checkpoint inhibitors in place of, or as an adjunct to, traditional chemotherapy. However, with the exception of melanoma, immune checkpoint blockade in solid tumors has failed to achieve significant brain control in patients with brain metastases. The possibility of combining immune checkpoint blockade with radiation for the treatment of brain and other metastases represents an exciting new strategy that is in its early stages of investigation. Success with this combinatorial strategy has the potential to result in enhanced rates of brain control, less brain exposure to radiation, and improved cognitive outcomes. In this review, we discuss the mechanisms behind this synergy, describe its limitations, and suggest ways to move the field forward.

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Chapter 12 - Neurocognitive aspects of brain metastasis

Abstract

Introduction

Section snippets

Impact of prior therapies: chemotherapy-related neurocognitive impairment

Impact of tumor: neurocognitive function in brain metastasis patients at diagnosis

Surgery

Neurocognitive function in clinical trials: performance-based tests

Lancet Oncol

Lancet

International Journal of Radiation Oncology, Biology, Physics

International Journal of Radiation Oncology, Biology, Physics

Progress in Brain Research

Lancet Oncol

Int J Radiat Oncol Biol Phys

Behav Brain Res

Neuroscience

International Journal of Radiation Oncology, Biology, Physics

Archives of Clinical Neuropsychology

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Archives of Clinical Neuropsychology

Crit Rev Oncol Hematol

Lancet Oncol

Lancet Oncol

Int J Radiat Oncol Biol Phys

Surg Neurol

Pathogenesis of irradiation-induced cognitive dysfunction

Acta oncologica (Stockholm, Sweden)

Phase II trial of sunitinib as adjuvant therapy after stereotactic radiosurgery in patients with 1-3 newly diagnosed brain metastases

J Neurooncol

Phase II randomized trial of temozolomide and concurrent radiotherapy in patients with brain metastases

J Clin Oncol

Updates in the management of brain metastases

Neuro Oncol

Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. Prophylactic Cranial Irradiation Overview Collaborative Group

N Engl J Med

Hopkins verbal learning test revised: normative data and analysis of inter-form and test-retest reliability

Clinical Neuropsychologist

Bevacizumab in patients with nonsquamous non-small cell lung cancer and asymptomatic, untreated brain metastases (BRAIN): a nonrandomized, phase II study

Clin Cancer Res

Clinical outcome assessment in malignant glioma trials: measuring signs, symptoms, and functional limitations

Neuro Oncol

Response of brain metastases from breast cancer to systemic chemotherapy

Cancer

Genomic characterization of brain metastases reveals branched evolution and potential therapeutic targets

Cancer Discov

The role of Gliadel wafers in the treatment of high-grade gliomas

Expert Rev Anticancer Ther

Preservation of neurocognitive function and local control of 1 to 3 brain metastases treated with surgery and carmustine wafers

Cancer

Memantine for the prevention of cognitive dysfunction in patients receiving whole-brain radiotherapy: a randomized, double-blind, placebo-controlled trial

Neuro Oncol

Effect of radiosurgery alone vs radiosurgery with whole brain radiation therapy on cognitive function in patients with 1 to 3 brain metastases: a randomized clinical trial

JAMA

CogState computerized memory tests in patients with brain metastases: secondary endpoint results of NRG Oncology RTOG 0933

J Neurooncol

Mechanism of memantine block of NMDA-activated channels in rat retinal ganglion cells: uncompetitive antagonism

Journal of Physiology

Open-channel block of N-methyl-D-aspartate (NMDA) responses by memantine: therapeutic advantage against NMDA receptor-mediated neurotoxicity

Journal of Neuroscience

Clinical experience with crizotinib in patients with advanced ALK-rearranged non-small-cell lung cancer and brain metastases

J Clin Oncol

Therapeutic strategies in patients with non-squamous non-small cell lung cancer with brain metastases (METAL2) [Online]

Neurobehavioral sequelae of cranial irradiation in adults: a review of radiation-induced encephalopathy

J Clin Oncol

GlycineB antagonists as potential therapeutic agents. Previous hopes and present reality

Amino Acids

Neural network alterations underlie cognitive deficits in brain tumor patients

Curr Opin Oncol

Strategies for preservation of memory function in patients with brain metastases

Chin Clin Oncol

Treatment of single brain metastasis with resection, intracavity carmustine polymer wafers, and radiation therapy is safe and provides excellent local control

Clin Cancer Res

Cognition in patients with newly diagnosed brain metastasis: profiles and implications

J Neurooncol

Hippocampal dosimetry predicts neurocognitive function impairment after fractionated stereotactic radiotherapy for benign or low-grade adult brain tumors

Int J Radiat Oncol Biol Phys

Preservation of memory with conformal avoidance of the hippocampal neural stem-cell compartment during whole-brain radiotherapy for brain metastases (RTOG 0933): a phase II multi-institutional trial

J Clin Oncol