Brain Metastases from Primary Tumors, Volume 2: Epidemiology, Biology, and Therapy
By M. A. Hayat
()
About this ebook
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 fills that gap, serving as the first two-part 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
- Provides 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
- The only comprehensive reference detailing the link between primary cancers and brain metastases
Related to Brain Metastases from Primary Tumors, Volume 2
Related ebooks
Brain Metastases from Primary Tumors, Volume 3: Epidemiology, Biology, and Therapy of Melanoma and Other Cancers Rating: 0 out of 5 stars0 ratingsClinical PET/MRI Rating: 0 out of 5 stars0 ratingsThe American Cancer Society's Principles of Oncology: Prevention to Survivorship Rating: 0 out of 5 stars0 ratingsOligodendroglioma: Clinical Presentation, Pathology, Molecular Biology, Imaging, and Treatment Rating: 0 out of 5 stars0 ratingsNanotechnology Methods for Neurological Diseases and Brain Tumors: Drug Delivery across the Blood–Brain Barrier Rating: 0 out of 5 stars0 ratingsCell Press Reviews: Stem Cells to Model and Treat Disease Rating: 0 out of 5 stars0 ratingsNeuroprotection in Alzheimer's Disease Rating: 0 out of 5 stars0 ratingsInflammation in Heart Failure Rating: 2 out of 5 stars2/5Cell Press Reviews: Cancer Therapeutics Rating: 0 out of 5 stars0 ratingsTeleStroke Rating: 0 out of 5 stars0 ratingsEpigenetics in Organ Specific Disorders Rating: 0 out of 5 stars0 ratingsInterventional Neuroradiology A Complete Guide - 2020 Edition Rating: 0 out of 5 stars0 ratingsHandbook of Neuroemergency Clinical Trials Rating: 0 out of 5 stars0 ratingsNoonan Syndrome: Characteristics and Interventions Rating: 0 out of 5 stars0 ratingsClinical Cases in Neurology Rating: 0 out of 5 stars0 ratingsInborn Errors of Metabolism - Early Detection, Key Symptoms and Therapeutic Options Rating: 0 out of 5 stars0 ratingsRecent Advances in iPSCs for Therapy Rating: 0 out of 5 stars0 ratingsPrecision Medicine Oncology: A Primer Rating: 0 out of 5 stars0 ratingsLiquid Biopsy in Urogenital Cancers and its Clinical Utility Rating: 0 out of 5 stars0 ratingsTuberculous Meningitis: Manual of Diagnosis and Therapy Rating: 0 out of 5 stars0 ratingsUICC Manual of Clinical Oncology Rating: 0 out of 5 stars0 ratingsHuman Brain in Standard MNI Space: A Comprehensive Pocket Atlas Rating: 0 out of 5 stars0 ratingsComprehensive Overview of Modern Surgical Approaches to Intrinsic Brain Tumors Rating: 0 out of 5 stars0 ratingsFrontiers in Clinical Drug Research - Anti-Cancer Agents: Volume 3 Rating: 0 out of 5 stars0 ratingsCentral Nervous System Depressant Drug Abuse And Addiction:: Implications for Counseling Rating: 0 out of 5 stars0 ratingsStructural Biology in Immunology: Structure/Function of Novel Molecules of Immunologic Importance Rating: 0 out of 5 stars0 ratingsNeuromonitoring Techniques: Quick Guide for Clinicians and Residents Rating: 0 out of 5 stars0 ratingsIntracranial Aneurysms Rating: 0 out of 5 stars0 ratingsNanomedicine-Based Approaches for the Treatment of Dementia Rating: 5 out of 5 stars5/5
Medical For You
The Lost Book of Simple Herbal Remedies: Discover over 100 herbal Medicine for all kinds of Ailment Inspired By Barbara O'Neill Rating: 0 out of 5 stars0 ratingsThe Vagina Bible: The Vulva and the Vagina: Separating the Myth from the Medicine Rating: 5 out of 5 stars5/5Mediterranean Diet Meal Prep Cookbook: Easy And Healthy Recipes You Can Meal Prep For The Week Rating: 5 out of 5 stars5/5The 40 Day Dopamine Fast Rating: 4 out of 5 stars4/5What Happened to You?: Conversations on Trauma, Resilience, and Healing Rating: 4 out of 5 stars4/5The Diabetes Code: Prevent and Reverse Type 2 Diabetes Naturally Rating: 4 out of 5 stars4/5Period Power: Harness Your Hormones and Get Your Cycle Working For You Rating: 4 out of 5 stars4/5Peptide Protocols: Volume One Rating: 4 out of 5 stars4/5The Hormone Reset Diet: Heal Your Metabolism to Lose Up to 15 Pounds in 21 Days Rating: 4 out of 5 stars4/5Living Daily With Adult ADD or ADHD: 365 Tips o the Day Rating: 5 out of 5 stars5/5The White Coat Investor: A Doctor's Guide to Personal Finance and Investing Rating: 4 out of 5 stars4/5Holistic Herbal: A Safe and Practical Guide to Making and Using Herbal Remedies Rating: 4 out of 5 stars4/5ATOMIC HABITS:: How to Disagree With Your Brain so You Can Break Bad Habits and End Negative Thinking Rating: 5 out of 5 stars5/5Adult ADHD: How to Succeed as a Hunter in a Farmer's World Rating: 4 out of 5 stars4/5Herbal Healing for Women Rating: 4 out of 5 stars4/5ketoCONTINUUM Consistently Keto For Life Rating: 5 out of 5 stars5/5Gut: The Inside Story of Our Body's Most Underrated Organ (Revised Edition) Rating: 4 out of 5 stars4/5Tight Hip Twisted Core: The Key To Unresolved Pain Rating: 4 out of 5 stars4/5Healing the Thyroid with Ayurveda: Natural Treatments for Hashimoto's, Hypothyroidism, and Hyperthyroidism Rating: 4 out of 5 stars4/5Women With Attention Deficit Disorder: Embrace Your Differences and Transform Your Life Rating: 5 out of 5 stars5/5The Emperor of All Maladies: A Biography of Cancer Rating: 5 out of 5 stars5/5Healthy Gut, Healthy You: The Personalized Plan to Transform Your Health from the Inside Out Rating: 4 out of 5 stars4/5The Big Fat Surprise: Why Butter, Meat and Cheese Belong in a Healthy Diet Rating: 4 out of 5 stars4/5As Nature Made Him: The Boy Who Was Raised as a Girl Rating: 4 out of 5 stars4/5
Reviews for Brain Metastases from Primary Tumors, Volume 2
0 ratings0 reviews
Book preview
Brain Metastases from Primary Tumors, Volume 2 - M. A. Hayat
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
Academic Press is an imprint of Elsevier
32 Jamestown Road, London NW1 7BY, UK
525 B Street, Suite 1800, San Diego, CA 92101-4495, USA
225 Wyman Street, Waltham, MA 02451, USA
The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, UK
Copyright © 2015 Elsevier Inc. All rights reserved
No part of this publication may be reproduced, stored in a retrieval system or transmitted in any form or by any means electronic, mechanical, photocopying, recording or otherwise without the prior written permission of the publisher
Permissions may be sought directly from Elsevier’s Science & Technology Rights
Department in Oxford, UK: phone (+44) (0) 1865 843830; fax (+44) (0) 1865 853333;
email: permissions@elsevier.com. Alternatively, visit the Science and Technology Books website at www.elsevierdirect.com/rights for further information
Notice
No responsibility is assumed by the publisher for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions or ideas contained in the material herein. Because of rapid advances in the medical sciences, in particular, independent verification of diagnoses and drug dosages should be made
British Library Cataloguing-in-Publication Data
A catalogue record for this book is available from the British Library
Library of Congress Cataloging-in-Publication Data
A catalog record for this book is available from the Library of Congress
ISBN: 978-0-12-801419-6
For information on all Academic Press publications visit our website at http://store.elsevier.com/
Typeset by Thomson Digital
Printed and bound in United States of America
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