Brain Metastases from Primary Tumors Volume 1

Epidemiology, Biology, and Therapy

M. A. Hayat

• Publisher: Academic Press
• Year: 2014
• eBook ISBN:
  9780128010952
• Topic: Medicine
• Subtopic: Neurology

With an annual rate of more than 12 million global diagnoses and 7.6 million deaths, the societal and economic burden of cancer cannot be overstated. Brain metastases are the most common malignant tumors of the central nervous system, yet their incidence appears to be increasing in spite of the advancement of cancer therapies. While much is known about primary cancers (including primary brain tumors), less work has been done to uncover the roots of metastatic disease. Brain Metastases from Primary Tumors Volume 1 fills that gap, serving as the first reference to focus primarily on the link between primary cancers and brain metastases. This link is explored for the most common cancer types – lung, breast, and melanoma. Additionally, biological background as well as therapy for CNS metastases is addressed. Age and gender related trends are also discussed, as is the use of biomarkers for early detection. - The only comprehensive reference detailing the link between primary cancers and brain metastases - Aids the target audience in determining the incidence of brain metastases in patients with a primary cancer - Provided education about the potential use of biomarkers for early detection, diagnosis and prevention of the spread of primary cancer to the brain - Documents temporal and gender-related trends in brain metastases from other cancers - Edited work with chapters authored by leaders in the field around the globe – the broadest, most expert coverage available

Part I

General Applications

Outline

Chapter 1 Brain Metastases

Chapter 2 Epidemiology of Central Nervous System Metastases

Chapter 3 Involvement of the CXCL12/CXCR4/CXCR7 Axis in Brain Metastases

Chapter 4 Non-Uniform Distribution of Metastatic Intracranial Tumors in Cancer Patients

Chapter 5 Targeting Angiogenesis, Enhancing Radiosensitization and Crossing the Blood–Brain Barrier for Brain Metastases

Chapter 6 Second Malignancies in Children Following Treatment for Neuroblastoma

Chapter 7 The Role of Chemotherapy in Metastatic Brain Tumors

Chapter 8 Multiple Metastases to the Brain from Primary Cancers: Whole Brain Radiotherapy

Chapter 9 Synovial Sarcoma Metastasized to the Brain

Chapter 1

Brain Metastases

Albert S. Braverman

Brain metastases (BM) most frequently arise from hematogenous dissemination of lung and breast carcinomas. Those from lung present early with neurologic deficits, while breast BM occur late, after systemic metastases. Focal deficits are the most frequent complication, while seizures are uncommon. Magnetic resonance imaging (MRI) can detect most BM and is especially sensitive to posterior fossa lesions. They can be distinguished from primary brain tumors, and careful staging can often detect a peripheral source of BM, so that brain biopsy is usually unnecessary. Analysis of spinal fluid for Epstein–Barr virus DNA helps to rule primary brain lymphomas in or out. Breast BM usually arise from tumors overexpressing epidermoid growth factor receptor 2 (HER2), or those which are negative for hormone receptor and HER2 (triple negative), suggesting that specific tumor cell markers are involved. Otherwise, specific markers have not been reliably detected by human and animal studies. Unlike primary brain tumors, BM do not usually induce de novo angiogenesis. Although parenchymal permeation (ring enhancement) may disrupt the blood–brain barrier, systemic therapies are not usually effective, except in germ cell tumor BM. Resection is indicated in certain solitary BM and those refractory to radiation, especially if it is not likely to exacerbate local deficits. Whole brain radiation therapy is the mainstay of treatment, producing remissions in most patients, which are sometimes durable. Radiation encephalopathy is a late complication which most patients do not survive to experience. Stereotactic radiotherapy improves outcome, but may result in symptomatic radiation necrosis when combined with whole brain radiation. There is a role for prophylactic radiotherapy in certain lung cancers.

Keywords

brain metastases; blood–brain barrier; lung carcinoma; breast carcinoma; neurologic deficit linear accelerator

Outline

Introduction 3

Origin of Primary Tumors 3

Neoplastic Cell Meningitis 4

Diagnosis 5

Pathogenesis 6

Therapy 7

Surgery 7

Radiation 7

Systemic Therapy 8

Intrathecal Therapy 8

The Future 9

References 9

Introduction

Metastases to the brain are among the most clinically significant, because even a single one is likely to cause serious disability. Because most may be at least partially protected from otherwise effective systemic therapies by the blood–brain barrier, they present special management problems. But whether their pathogenesis differs from that of metastases at other sites is not known.

Origin of Primary Tumors

Since the first successful systemic treatment of a disseminated neoplasm – acute lymphoblastic leukemia (ALL) in children – the CNS has been recognized as a refuge for neoplastic cells. Permeation of the meninges at the base of the skull and spinal canal is mainly seen in certain types of lymphomas, though these occasionally produce nodular brain lesions. Such lesions are usually derived from epithelial neoplasms. Most are the result of hematogenous dissemination. The exceptions are those from prostatic carcinoma, and some breast cancers, where tumor reaches the brain from skull lesions, or the dura attached to involved bone. This occurs only rarely in myeloma and lymphomas.

Of all epithelial tumors, both small and non-small cell lung cancer are associated with the highest incidence of brain metastases (BM), which occur in 30–60% of cases, and become manifest early in the course of the disease, often even before the primary tumor is diagnosed (Barnholtz-Sloan et al., 2004). Lung metastases may be especially likely to elicit edema, with ring enhancement and disruption of the blood–brain barrier, so that they produce focal deficits and other symptoms early (Hengel et al., 2013). Melanomas and renal cell carcinomas are also associated with a high incidence of BM (Schouten et al., 2002), but they are less common than breast or lung cancer.

Breast cancer is the second most common source of brain metastases, being a very common tumor in America; they ultimately develop in 35% of patients with metastatic disease (DiStefano et al., 1997). They mainly occur in HER2+and triple negative breast cancer, arising less frequently from hormone receptor positive tumors (Lin and Winer, 2007; Foulkes et al., 2010). Their natural history differs from those due to lung cancer. They are not usually symptomatic until late in the course of the disease, after metastases to bone and lung become detectable. The number of metastases per brain in breast cancer patients appears, in some, but not all studies (Delattre et al., 1988; Hengel et al., 2013), significantly greater than those in the brains of lung cancer patients. But this may be, in part, due to gender; female lung cancer patients have been reported to have more metastases per brain than males (Yawn et al., 2003). The incidence of cerebellar metastases is highest in breast cancer patients (Yoshida and Takahashi, 2009), but this does not necessarily indicate a predilection for cerebellar involvement. The incidence of breast metastases in the cerebellum correlates strongly with the total number of brain metastases present (Hengel et al., 2013). Thus, the occurrence of metastases in a given brain region may be a function of the total number of BM which have occurred.

Most lung cancer patients present with incurable disease, and systemic therapies are only effective in a minority. But the majority of breast cancer patients are potentially curable at presentation, especially with adjuvant therapies. Breast cancer metastases at any site are far more sensitive to systemic chemotherapy than those from lung cancer, and also respond to endocrine therapy in tumors expressing hormone receptors. Such treatments may delay overt progression of micrometastases for years, and 50% of patients with bone and lung metastases may be controlled by systemic therapy for many months. But the drugs used in systemic therapies may not reach the brain, so that metastases there may accumulate while other metastases are suppressed by therapy (Hengel et al., 2012). Thus, in breast cancer, the brain may be a refuge for metastatic disease.

Neoplastic Cell Meningitis

The leptomeninges are most often involved in ALL and certain lymphomas. This is assumed to be present in all ALL cases. It is rare in acute myeloblastic leukemia, though it occasionally occurs in the monoblastic subsets (M4 and M5). The lymphomas include Burkitt’s, T-cell, and a subset of especially aggressive and high stage diffuse large B-cell lymphomas. In the latter group, the presence of the typical 8;14 (myc) chromosome translocation should be ruled out, regardless of whether typical Burkitt’s histology is observed, because a posi- tive result implies an increased risk of meningeal involvement. Carcinomatous meningitis involvement is far less common. It is most frequently observed in small cell and breast carcinomas.

In fact, few such patients have a typical meningeal syndrome. They are usually alert, and without neck stiffness. The meninges at the bases of skull and cord are the most frequent sites of involvement. The usual clinical syndrome is that of mononeuritis multiplex, due to entrapment of nerve roots by meningeal growth. Ophthalmoplegias due to cranial nerve involvement are common, as are symptoms of lumbar root involvement.

Diagnosis

Early BM are often clinically silent but, ultimately, cause focal neurologic deficits of gradual onset; they are sometimes associated with more diffuse problems, such as amnesia or dementia. Only occasionally do they present with seizures, and most never cause them. Nevertheless, anti-epileptic therapies are frequently prescribed. This may be based on experience with primary intracerebral brain tumors, surgical resection of which can result in epileptogenic foci. Although brain imaging is usually performed for brain-related symptoms, it is also indicated in all lung cancer patients regardless of whether symptoms are present (Gore et al., 2010). Asymptomatic metastases are often discovered in this way (Yokoi et al., 1999).

BM which have caused neurologic deficits are almost always detectable by imaging, which can usually readily distinguish them from primary brain tumors. The former are typically sharply circumscribed, though they often display ring enhancement (Barajas and Cha, 2012). Primary intracerebral brain tumors are diffusely permeative at their margins. In fact, when adequate imaging fails to demonstrate BM, a different cause for focal deficits is likely.

Pre-contrast computed tomography (CT) scanning cannot rule out BM, but o...

Table of contents

• Cover
• Front-matter
• Table of Contents
• Copyright
• Preface
• Contributors
• List of Illustrations
• List of Tables
• Chapter 1 : Brain Metastases
• Chapter 2 : Epidemiology of Central Nervous System Metastases
• Chapter 3 : Involvement of the CXCL12/CXCR4/CXCR7 Axis in Brain Metastases
• Chapter 4 : Non-Uniform Distribution of Metastatic Intracranial Tumors in Cancer Patients
• Chapter 5 : Targeting Angiogenesis, Enhancing Radiosensitization and Crossing the Blood–Brain Barrier for Brain Metastases
• Chapter 6 : Second Malignancies in Children Following Treatment for Neuroblastoma
• Chapter 7 : The Role of Chemotherapy in Metastatic Brain Tumors
• Chapter 8 : Multiple Metastases to the Brain from Primary Cancers: Whole Brain Radiotherapy
• Chapter 9 : Synovial Sarcoma Metastasized to the Brain
• Chapter 10 : Multiple Small Brain Metastases with Limited Focal Brain Edema from Non-Small Cell Lung Cancer with Epidermal Growth Factor Receptor Mutations
• Chapter 11 : Brain Metastasis of Patients with Lung Adenocarcinoma: Epidermal Growth Factor Receptor Mutations and Response to Whole-Brain Radiation Therapy
• Chapter 12 : Metastatic Spread of Lung Cancer to Brain and Liver: Role of CX3CR1
• Chapter 13 : Solitary Brain Metastasis from Non-Small Cell Lung Cancer: Treatment with Linac-Based Stereotactic Radiosurgery
• Chapter 14 : Brain Metastases from Non-Small Cell Lung Cancer: Clinical Benefits of Erlotinib and Gefitinib
• Chapter 15 : Bispecific Targeted Toxin DTATEGF Against Metastatic NSCLC Brain Tumors
• Chapter 16 : Intracranial Disease in Patients with Non-Small Cell Lung Cancer: Treatment with Erlotinib
• Chapter 17 : Radiation Management of Synchronous Brain Metastases from Non-Small Cell Lung Cancer
• Chapter 18 : Brain Metastasis after Prophylactic Cranial Irradiation in Patients with Small Cell Lung Cancer
• Chapter 19 : Brain Metastasis from Small-Cell Lung Cancer with High Levels of Placental Growth Factor
• Chapter 20 : Brain Metastases from Lung Cancer
• Chapter 21 : Lambert–Eaton Myesthenic Syndrome and Brain Metastasis from Occult Small Cell Lung Carcinoma: A Clinician’s Perspective
• Index
• A