Brain Metastases from Primary Tumors, Volume 2: Epidemiology, Biology, and Therapy

Brain Metastases from Primary Tumors

Epidemiology, Biology, and Therapy

M.A. Hayat

Distinguished Professor Biology Department Kean University Union, NJ, USA

Table of Contents

Cover

Title page

Copyright

Preface

Contributors

Volume 1– Contributions

I: General applications

Chapter 1: Brain Metastasis from Solid Tumors

Abstract

Introduction

Pathophysiology

Clinical presentation

Diagnosis

Prognostic factors

Treatment options

Future prospects and research approaches

Chapter 2: The Role of Surgical Resection for Metastatic Brain Tumors

Abstract

Introduction

Surgical resection

Clinical evidence

Tumor characteristics

Patient selection for surgery

Making surgery safe

Conclusion

Chapter 3: Whole-Brain Radiotherapy for Brain Metastases: Is the Therapeutic Window Enlarging?

Abstract

Introduction

Toxicity

Preventing and treating toxicity

Summary

II: Non-Small cell lung cancer

Chapter 4: Brain Metastasis in Patients with Non-Small Cell Lung Cancer: Response to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors

Abstract

Introduction

EGFR mutation in NSCLC

EGFR-TKI efficacy in NSCLC with CNS metastases

Conclusion

Chapter 5: Brain Metastasis from Non-Small Cell Lung Cancer: Use of Epidermal Growth Factor Receptor and HER2 Status for Targeted Therapy

Abstract

Introduction

Targeted therapy of NSCLC

EGFR deregulation

HER2 deregulation

Brain metastases in NSCLC

The question of the possibility of discordance in EGFR and HER2 status between primary tumor and metastases

Future perspective

Chapter 6: Brain Metastases from Non-Small Cell Lung Cancer: Current Evidence in Management Using Tyrosine Kinase Inhibitor and Whole-Brain Radiation Therapy

Abstract

Introduction

Brain metastases in EGFR-mutated NSCLC

TKI monotherapy in brain metastases NSCLC

Concurrent use of TKI and WBRT in brain metastases from NSCLC

Toxicities of combination of TKI and WBRT

Discussion

Chapter 7: Brain Metastasis in Patients with Non-Small Cell Lung Cancer: Immunohistochemical Markers

Abstract

Introduction

Markers with potential role in predicting NSCLC metastases to the brain Ki-67

Caspase-3

VEGF and VEGFR

E-cadherin/β-catenin complex

Epidermal growth factor receptor

Discussion

III: Breast cancer

Chapter 8: Brain Metastasis from Breast Cancer: Molecular Mechanisms

Abstract

Introduction

The seed and soil hypothesis

Molecular breast cancer subtypes and the patterns of metastatic dissemination

The blood–brain barrier is protective against BM and yet a challenge for BM therapeutics

Genes implicated in BM development

Future directions: What should we expect from omics studies on brain metastases?

Conclusions

Chapter 9: New Targeted Therapies for Brain Metastases from Breast and Lung Cancer and Melanoma

Abstract

Introduction

Targeted therapies for BM from breast cancer

Targeted therapies for BM from lung cancer

Targeted therapies for BM from melanoma patients

Chapter 10: Breast Cancers with Brain Metastases

Abstract

Introduction

Histopathology, grading, and molecular classification

Breast cancers with brain metastases

Molecular mechanisms

Treatment and prognosis

IV: Melanoma

Chapter 11: Brain Metastases in Melanoma Patients: Treatment with Adjuvant Postoperative Whole-Brain Radiotherapy

Abstract

Introduction

Therapies for melanoma BMs

Whole-brain radiotherapy

Current controversies in adjuvant WBRT

Future development and conclusion

Acknowledgments

Chapter 12: Melanoma Progression in the Brain: Role of Pericytes, the Basal Lamina, and Endothelial Cells in Tumor Vascularization

Abstract

Introduction

Role of pericytes in melanoma vascularization in the brain

Role of the basal lamina in melanoma vascularization in the brain

Role of endothelial cells in melanoma vascularization in the brain

Discussion

Acknowledgments

V: Esophageal cancer

Chapter 13: Brain Metastases from Esophageal Cancer in the Presence of HER-2 Overexpression

Abstract

Introduction

Brain metastases in esophageal cancer

HER-2 overexpression

Discussion

VI: Renal carcinoma

Chapter 14: Brain Metastasis from Renal Carcinoma: Locoregional and Systemic Treatments

Abstract

Introduction

Locoregional approach

Systemic approach: targeted therapies

Discussion

VII: Gastrointestinal cancer

Chapter 15: Gastrointestinal Cancer and Brain Metastasis Outcomes and Management

Abstract

Introduction

Esophageal cancer

Gastric cancer

Gallbladder cancer

Pancreatic cancer

Small bowel cancer

Colorectal cancer

Discussion

VIII: Colorectal cancer

Chapter 16: Brain Metastasis of Colorectal Cancer: Microenvironment and Molecular Mechanism

Abstract

Introduction

Molecules associated with metastatic potential

Role of BBB in brain metastasis

Brain microenvironment and tumor metastasis

Site-specific metastatic factors

Models for metastatic brain tumors

Conclusion

Acknowledgments

IX: Nasopharyngeal carcinoma

Chapter 17: Brain Metastasis from Nasopharyngeal Carcinoma

Abstract

Introduction

Brain metastasis from NPC

Summary

Index

Copyright

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Preface

Brain metastases are the most common intracranial neoplasms in adults, and occur in 20–40% of cancers. It is estimated that 100 000–170 000 persons are inflicted by metastatic brain cancer/year in the United States. Brain metastases occur 5–10 times more frequently than primary tumors of the brain. Approximately 10–20% of all brain metastases are single tumors, and the remaining are multiple tumors. Lung, breast, colon, and kidney cancers and melanoma commonly spread to the brain. Breast and kidney cancers often cause single brain tumors, whereas lung cancer and melanoma tend to cause multiple brain tumors. Approximately 85% of metastatic lesions are located in the cerebrum, and the remaining are located in the cerebellum. Autopsy analyses have shown that the incidence of brain metastases is as high as 30% in patients with breast cancer, 40% in those with lung cancer, 75% in those with melanoma, and 6% with those with kidney or bladder cancer. Brain metastases are among the most devastating and debilitating complications of lung cancer, breast cancer, and melanoma. Patients with brain metastases often develop serious deterioration in neurologic and neurocognitive functions. Intracranial bleeding is one of the fatal complications encountered in the patients. The role of novel targeted agents in the treatment of brain metastases from the following cancer types is explained in this volume: lung cancer, breast cancer, renal cancer, esophageal cancer, gastrointestinal cancer, and melanoma.

Currently, magnetic resonance imaging is the diagnostic test of choice for detecting intracranial lesions. The treatment of brain metastases is usually carried out using surgical resection, stereotactic radiosurgery, and whole-brain radiation therapy (WBRT). Adjuvant WBRT is given following localized treatment (e.g., surgery). However, WBRT is controversial, which is explained in this volume. Nevertheless, WBRT is beneficial in symptomatic patients for palliative relief.

Surgery plays an indispensable role in relieving increased intracranial pressure. Hemorrhagic and resistant lesions can also be treated with surgical interventions. Current guidelines and controversies regarding the use of surgery are discussed in this volume. Chemotherapy alone is largely ineffective and may result in impaired cognitive functions in patients. However, the importance of developing chemotherapeutic agents that are able to traverse the blood–brain barrier (BBB) is included in this volume. The advantages and limitations of these therapeutic methods are included.

It is emphasized that the effective therapy for brain metastases should be based on the elucidation of genetic events related to metastases and/or primary tumors. Targeted therapies based on genetic alterations are becoming standard treatments; a few examples are included in this volume. An attempt is made in this volume for unraveling the mechanisms responsible for the effectiveness of anticancer drugs.

Epidermal growth factor receptor (EGFR), a transmembrane tyrosine, is associated with cell proliferation, differentiation, migration, and adhesion. This receptor is overexpressed in a number of carcinomas including non-small cell lung cancer (NSCLC) and a proportion of gastrointestinal tumors. The presence of this receptor is associated with poor prognosis. The use of EGFR tyrosine kinase inhibitors (gefitinib, erlotinib) results in tumor response in patients even with advanced NSCLC. When erlotinib treatment follows previous chemotherapy, some increase in patient survival is achieved. Deletion of EGFR exon 19 using erlotinib tends to regress multiple intracranial brain metastases from NSCLC. In other words, this drug is site specific for intracranial metastases harboring EGFR exon 19. The efficacy of this inhibitor on EGFR-mutated NSCLC is pointed out in this volume. Patients with mutated NSCLC brain metastases present usually the same mutations as those in the primary tumor, but this is not true in some other cases. Furthermore, a treatment effective in the primary tumor may or may not be beneficial in the brain metastasis even though both tumor types have similar mutations; the primary reason seems to be the differences in the micro- and macro-environments between the two regions. Brain metastases from NSCLC is explained in detail in this volume. Many patients with NSCLS metastatic to the brain either harbor or develop multiple lesions.

Tyrosine kinase inhibitors used as monotherapy for brain metastases from lung adenocarcinoma has shown intracranial response rates of ∼80% and are safe to use. The use of these inhibitors in combination with WBRT for treating brain metastases from lung adenocarcinoma is another treatment option. However, the uses of such combination therapies invite caution because of their potential toxicity. Brain metastases of melanoma are associated with a poor prognosis and can impact on the quality of life. Adjuvant WBRT is given following localized treatment (e.g., surgery). However, the WBRT is beneficial in symptomatic patients for palliative relief. In fact, WBRT is the standard care for patients with multiple brain lesions.

Identification of molecular markers in primary tumors is important to predict the increased risk of developing brain metastases. Therefore, it is pointed out in this volume that patients with NSCLC who have high Ki-67 expression, low caspase-3 expression, high VEGF-C expression, and low E-cadherin expression in their primary tumors are at an increased risk of developing brain metastases. Potential association between brain metastases from esophageal carcinoma and HER-2 overexpression has also been found. This association has significant clinical impact of staging procedures and therapeutical choices for brain metastases. The importance of understanding the role played by angiogenesis in tumor growth is explained in this volume. The specific efficacy of antiangiogenic drugs in primary or secondary cancer is discussed. An attempt also has been made to discuss novel techniques involving the use of radiolabeled glucose and amino acids for better evaluation of intracranial metastases.

The prevention and palliation of neurologic problems due to metastatic progression are important goals of treatment. There is controversy regarding the ideal management of this disease. An improvement in survival, however, might not be an ideal measure of the benefit of a local therapy because overall survival is commonly determined by extracranial disease. Tumor stage, size, number, and location, commodities, sterol use, previous therapies, age, ethnicity, and gender of the patient complicate the evaluation of clinical benefits. The contents of this volume are divided into General Applications, Non-Small Cell Lung Cancer, Breast Cancer, Melanoma, Esophageal Cancer, Renal Carcinoma, Gastrointestinal Cancer, Colorectal Cancer, and Nasopharyngeal Carcinoma for the convenience of the readers.

By bringing together a large number of experts (oncologists, neurosurgeons, physicians, medical research scientists, and pathologists) in the field of brain metastases from primary cancer, it is my hope that substantial progress will be made against this devastating disease inflicting humans. It is difficult for a single author to discuss effectively and comprehensively various aspects of an exceedingly complex process such as brain metastasis. Another advantage of involving more than one author is to present different points of view on specific controversial aspects of the advantages and limitations of various treatments. I hope the information presented in this and other volumes will result in a better understanding of the molecular mechanisms underlying brain metastases and their cure and hopefully their prevention.

This volume was written by 52 contributors representing 7 countries. I am grateful to them for their promptness in accepting my suggestions. Their thoughtful, practical experience highlights the very high quality of their writings, which should build and further the endeavors of the readers in this important medical field. I respect and appreciate the time-consuming hard work invested by the contributors. There exists a tremendous urgent demand by the public and the medical community to address the treatment of this complex disease. In the light of existing disease calamities, government funding must give priority to eradicating deadly malignancies over global military superiority.

I am grateful to Dr. Dawood Farahi and Mr. Phil Connelly for recognizing the importance of medical research and publishing through an institution of higher education. I am thankful to my students for their contribution to the final preparation of this volume.

M.A. Hayat

    June 2014

Contributors

Sami I. Bashour,     Department of Internal Medicine, The American University of Beirut Medical Center, Beirut, Lebanon

Yazid Belkacemi,     GH Henri Mondor University Hospital and University Paris-Est Creteil (UPEC), France

Paul D. Brown,     Department of Radiation Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA

Jacques Cadranel,     Sorbonne Universités, UPMC Université Paris, Theranoscan; Service de pneumologie, centre expert en oncologie thoracique et maladies pulmonaires rares, hôpital Tenon, Paris, France

Ronald S. Chamberlain,     Saint Barnabas Medical Center, Livingston, New Jersey, USA

Abhinav B. Chandra,     Division of Hematology and Oncology, Department of Internal Medicine, Maiminides Medical Center, Brooklyn, New York, USA

Zong-You Chen,     Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China

Gerald Clamon,     Division of Hematology, Oncology and Marrow Transplantation, Department of Internal Medicine, University of Iowa Hospitals and Clinics, Iowa City, Iowa, USA

Charles Conrad,     Department of Neuro-oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA

Perrine Crequit,     Sorbonne Universités, UPMC Université Paris, Theranoscan; Service de pneumologie, centre expert en oncologie thoracique et maladies pulmonaires rares, hôpital Tenon, Paris, France

Leonard Medeiros Da Silva,     SalomaoZoppi Laboratory, Sao Paulo, Brazil

Jeremy M. Deutsch,     Division of Hematology, Oncology and Marrow Transplantation, Department of Internal Medicine, University of Iowa Hospitals and Clinics, Iowa City, Iowa, USA

Nicholas B. Dye,     University of Maryland School of Medicine, Baltimore, Maryland, USA

Réza Elaidi,     Association ARTIC, Service d’Oncologie Médicale Hôpital Européen Georges Pompidou, Paris, France

Gerald Fogarty,     Radiation Oncology, St Vincent’s and Mater Hospitals, Sydney, Australia

Emmanouil Fokas,     Gray Institute for Radiation Oncology and Biology, Department of Oncology, University of Oxford, Headington Oxford, United Kingdom

Philippe Giraud,     Association ARTIC, Service d’Oncologie Médicale Hôpital Européen Georges Pompidou, Paris, France

Vinai Gondi,     Cadence Brain Tumor Center; CDH Proton Center, Warrenville, Illinois, USA

Valérie Gounant,     Sorbonne Universités, UPMC Université Paris, Theranoscan; Service de pneumologie, centre expert en oncologie thoracique et maladies pulmonaires rares, hôpital Tenon, AP—HP; Service de chirurgie thoracique, hôpital Tenon, AP—HP, Paris, France

Xiao-Dong Gu,     Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China

Nandita Guha-Thakurta,     Department of Radiology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA

Taher Abu Hejleh,     Division of Hematology, Oncology and Marrow Transplantation, Department of Internal Medicine, University of Iowa Hospitals and Clinics, Iowa City, Iowa, USA

Angela Hong,     Melanoma Institute Australia, North Sydney; The University of Sydney, Central Clinical School, New South Wales, Australia

Nuhad K. Ibrahim,     Department of Breast Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA

Orit Kaidar-Person,     Division of Oncology, Rambam Health Care Campus, and Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel

Steven N. Kalkanis,     Department of Neurosurgery, Henry Ford Medical Health System, Detroit, Michigan, USA

Se Hoon Kim,     Department of Pathology, Yonsei University College of Medicine, Severance Hospital, Seoul, South Korea

Ja Seung Koo,     Department of Pathology, Yonsei University College of Medicine, Severance Hospital, Seoul, South Korea

Abraham Kuten,     Italian Hospital, Haifa, Israel

Jonathan Kuten,     Division of Oncology, Rambam Health Care Campus, and Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel

Maribel D. Lacambra,     Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, SAR

Armelle Lavole,     Sorbonne Universités, UPMC Université Paris, Theranoscan; Service de pneumologie, centre expert en oncologie thoracique et maladies pulmonaires rares, hôpital Tenon, Paris, France

Mary Frances McAleer,     Department of Radiation Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA

Minesh P. Mehta,     University of Maryland School of Medicine, Baltimore, Maryland, USA

Carl Nyberg,     Department of Surgery, Saint Barnabas Medical Center, Livingston, NJ Saint George’s University School of Medicine, Grenada, West Indies

Stéphane Oudard,     Association ARTIC, Service d’Oncologie Médicale Hôpital Européen Georges Pompidou, Paris, France

Aqueel Pabaney,     Department of Neurosurgery, Henry Ford Medical Health System, Detroit, Michigan, USA

Sapna Patel,     Department of Melanoma, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA

Ganesh Rao,     Department of Neurosurgery, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA

Anne-Marie Ruppert,     Sorbonne Universités, UPMC Université Paris, Theranoscan; Service de pneumologie, centre expert en oncologie thoracique et maladies pulmonaires rares, hôpital Tenon, Paris, France

Ali G. Saad,     Royal University Hospital, Saskatoon, Saskatchewan, Canada

Hyo Sup Shim,     Department of Pathology, Yonsei University College of Medicine, Severance Hospital, Seoul, South Korea

Sneha Shrestha,     Department of Surgery, Saint Barnabas Medical Center, Livingston, New Jersey, USA

William B. Stallcup,     Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla, California, USA

Eric Strom,     Department of Radiation Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA

Corine Takouchop Teghom,     Association ARTIC, Service d’Oncologie Médicale Hôpital Européen Georges Pompidou, Paris, France

Gary M. Tse,     Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, SAR

William N. William,     Department of Thoracic Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA

Marie Wislez,     Sorbonne Universités, UPMC Université Paris, Theranoscan; Service de pneumologie, centre expert en oncologie thoracique et maladies pulmonaires rares, hôpital Tenon, Paris, France

Yiqing Xu,     Division of Hematology and Oncology, Department of Internal Medicine, Maiminides Medical Center, Brooklyn, New York, USA

Weon-Kyoo You,     Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla, California, USA

Yi-Wen Zang,     Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China

Volume 1– Contributions

1. Brain Metastases

2. Epidemiology of Central Nervous System Metastases

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

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

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

6. Second Malignancies in Children Following Treatment for Neuroblastoma

7. The Role of Chemotherapy in Metastatic Brain Tumors

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

9. Synovial Sarcoma Metastasized to the Brain

10. Multiple Small Brain Metastases with Limited Focal Brain Edema from Non-Small Cell Lung Cancer with Epidermal Growth Factor Receptor Mutations

11. Brain Metastases of Patients with Lung Adenocarcinoma: Epidermal Growth Factor Receptor Mutations and Response to Whole-Brain Radiation Therapy

12. Metastatic Spread of Lung Cancer to Brain and Liver: Role of Cx3cr1

13. Solitary Brain Metastasis from Non-Small Cell Lung Cancer: Treatment with Linac-Based Stereotactic Radiosurgery

14. Brain Metastases from Non-Small Cell Lung Cancer: Clinical Benefits of Erlotinib and Gefitinib

15. Bispecific Targeted Toxin Dtategf Against Metastatic NsclC Brain Tumors

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

17. Radiation Management of Synchronous Brain Metastases from Non-Small Cell Lung Cancer

18. Brain Metastasis after Prophylactic Cranial Irradiation in Patients with Small Cell Lung Cancer

19. Brain Metastasis from Small-Cell Lung Cancer with High Levels of Placental Growth Factor

20. Brain Metastases from Lung Cancer

21. Lambert–Eaton Myesthenic Syndrome and Brain Metastasis from Occult Small Cell Lung Carcinoma: A Clinician’s Perspective

I

General applications

Chapter 1: Brain Metastasis from Solid Tumors

Chapter 2: The Role of Surgical Resection for Metastatic Brain Tumors

Chapter 3: Whole-Brain Radiotherapy for Brain Metastases: Is the Therapeutic Window Enlarging?

Chapter 1

Brain Metastasis from Solid Tumors

Sami I. Bashour

William N. William

Sapna Patel

Ganesh Rao

Eric Strom

Mary Frances McAleer

Nandita Guha-Thakurta

Charles Conrad

Nuhad K. Ibrahim

Abstract

Brain metastases occur in roughly 15% of all cancer patients, although autopsy analyses have shown that the incidence is as high as 30% in patients with breast cancer, 40% in those with lung cancer, and 75% in those with melanoma. Moreover, the incidence of brain metastasis has increased as imaging techniques have improved to allow smaller, subclinical lesions to be detected and extracranial systemic therapy has become effective enough that only the central nervous system (CNS) is left as a potential site for distant spread.

Of great importance is the role of the blood–brain barrier (BBB), which protects the CNS from toxic substances, foreign pathogens, and metastatic cells. However, research has shown that certain primary neoplasms can damage the BBB, thus allowing the neoplasm to spread to the CNS. Once these metastatic CNS deposits have crossed the BBB, they are protected from chemotherapy because the BBB repairs itself.

Currently, magnetic resonance imaging is the diagnostic test of choice for detecting intracranial lesions, although computed tomographic scans are used in the acute setting to rule out life-threatening complications. In addition, novel techniques involving the use of radiolabeled glucose and amino acids are gaining popularity for better evaluation of intracranial metastases.

Prognostic factors differ among various types of primary tumors, but classification systems exist to guide clinical decision making. The retrospective recursive partitioning analysis, score index for radiosurgery, and basic score for brain metastasis measures are used to inform clinicians of patients’ long-term prognosis and to identify which patients should receive aggressive treatment and which should receive palliative care.

Numerous treatment options exist for patients with brain metastasis, although side effects are common. Isolated chemotherapy has been shown to be largely ineffective, and recent research has documented impaired cognitive function in patients who undergo this treatment. Similarly, risks and long-term effects associated with more invasive therapy, such as surgery, whole-brain radiotherapy, stereotactic radiosurgery, and the combination of multiple treatment modalities, have been extensively studied. Still, the standard of care for patients with brain metastasis is a combination of chemotherapy and radiotherapy to provide the best treatment for symptoms and chances of long-term survival.

Prophylactic cranial irradiation is now being used to reduce the incidence of brain metastasis, especially in patients with breast or lung cancer or melanoma, which are known to spread to the CNS early. Extensive research is underway to develop chemotherapeutic agents that are better able to traverse the BBB.

Keywords

blood–brain barrier

central nervous system

solid tumors

breast cancer

melanoma

lung cancers

radiation treatment

surgical treatment

Outline

Introduction 3

Pathophysiology 4

Clinical Presentation 7

Diagnosis 7

Prognostic Factors 9

Breast Cancer 11

Lung Cancer 12

Melanoma 13

Treatment Options 14

Surgery 14

Whole-Brain Radiotherapy 15

WBRT Following Surgical Resection 15

Stereotactic Radiosurgery 16

WBRT and SRS 16

Chemotherapy and WBRT 17

Chemotherapy Alone 18

Chemotherapeutic Agents in Breast Cancer Metastatic to the Brain 19

Chemotherapeutic Agents in Lung Cancer Metastatic to the Brain 20

Chemotherapeutic Agents in Melanoma Metastatic to the Brain 21

Future Prospects and Research Approaches 23

Prophylactic Cranial Irradiation 23

Preventive Approach 24

Future Research Avenues 25

References 26

Introduction

Brain metastasis is common in patients with advanced solid tumors, occurring in roughly 15% of all cancer patients. According to autopsy analyses, the incidence of brain metastasis is as high as 30% in patients with breast cancer, 40% in patients with lung cancer, and 75% in patients with melanoma (Schuette, 2004). With 170 000 new cases diagnosed annually in the United Sates alone, brain metastases are 10 times more common than primary intracranial tumors and can be associated with substantial morbidity and mortality.

Although central nervous system (CNS) metastases can develop from any primary cancer, the predilection for distant spread varies by cancer type. Roughly 50% of all CNS metastases arise from primary lung cancer, 20% from breast cancer, 15% from melanoma, and 5–10% from unknown primary cancers; CNS metastases from renal cell carcinoma, colorectal cancer, gynecologic cancers, and other miscellaneous cancers account for an additional 5–10% (Wilhelm et al., 2013). Interestingly, prostate, oropharyngeal, and non-melanoma skin cancers rarely spread to the CNS (Sneed et al., 2008).

Although new, more effective anticancer therapies have been developed over the past several decades, multiple studies report that the incidence of brain metastasis is rising. One hypothesized reason for this rise is that brain metastases are sequelae of newly developed highly efficacious selective therapies for systemic extracranial metastases. Because patients receiving these therapies live longer, they may have more time (and thus are more likely) to develop brain metastases: the CNS is considered a sanctuary site, protecting tumor cells from exposure to full-dose systemic agents. In addition, technologic advances in diagnostic imaging have likely helped increase detection of brain metastasis.

Although brain metastases are typically a late manifestation of disease, primary cancers can spread to the brain at various times in the course of the illness; some studies have shown that synchronous brain metastases (those found within 1 month of the primary cancer diagnosis) occur in almost one-third of patients (Sneed et al., 2008). More commonly, however, brain metastases are diagnosed after a primary cancer is known to have spread to other systemic organs first. The average time between primary diagnosis and detection of brain metastasis is less than 1 year in patients with lung cancer and 2–3 years in patients with breast cancer, melanoma, or renal cell carcinoma. Overall, the average time between primary cancer diagnosis and diagnosis of metastatic brain disease is approximately 12 months.

This chapter focuses on brain metastases from primary lung cancer, breast cancer, and melanoma, which are by far the most common malignancies associated with brain metastases. Additional information about other solid organ tumors will be included as appropriate, for comparison.

Pathophysiology

The blood–brain barrier (BBB) is located at the level of the cerebral capillaries. It is instrumental in protecting the CNS by restricting the movement of solutes and cellular elements between the systemic circulation and neuronal tissue. The endothelial cells, astrocytes, and pericytes that form the neurovascular unit are critical to the function of the BBB. Endothelial cells are thin, flat cells that course along the cerebral capillaries. They are interconnected by a continuous line of tight junctions and thereby limit the movement of particles. Pericytes are contractile cells that synthesize biologically active substances and lie close to endothelial cells. They have been shown to contribute to the regulation of blood flow, endothelial cell proliferation, angiogenesis, and inflammatory processes. Researchers have found that, without pericytes, endothelial cells undergo hyperplasia, and abnormal vasculogenesis then occurs, allowing the BBB to become more permeable (Armulik et al., 2010). Astrocytes ensheath the capillary walls, almost fully covering endothelial cells and pericytes. Where this coverage is not complete, nerve endings have direct contact with the basement membrane. Astrocytes are known to maintain the homeostasis of the brain’s microenvironment and protect metastatic tumor cells from cytotoxicity induced by chemotherapy via mechanisms that upregulate survival genes in tumor cells.

As such, transport across the BBB is highly regulated. Molecules must penetrate a fourfold defense mechanism consisting of a paracellular barrier (maintained by the interendothelial tight junctions), a transcellular barrier (assured by the presence of endothelial cells, pericytes, and astrocytes), an enzymatic barrier that degrades numerous neurotransmitters, and a multitude of efflux transporters that expel chemicals from the CNS (Table 1.1). Small gaseous molecules, such as oxygen and carbon dioxide, along with lipophilic agents, such as barbiturates, nicotine, and ethanol, can freely diffuse through the BBB, but specific influx transporters are required for nutrients such as glucose and amino acids to enter the CNS.

Table 1.1

Structural Components of the Blood–Brain Barrier

Tight junctures

Intercellular pathways: water-soluble molecules

Transcellular lipophilic pathways: lipid-soluble molecules

Basement membrane

Endothelium (low pinocytic activity)

Receptor-mediated transcytosis: insulin, transferrin

Absorptive transcytosis: albumin

Astrocytes

Pericytes

Microglia (tumor-associated macrophages)

High IL-10 and low IL-2

TNFα → phosphorylation of JNK and NFκB

Wnt gene

Fibroblasts

Drug transporters

Influx: LRP1

Efflux: MRP, PgP, ABCG2

Markers