The Neuropsychology of Cancer and Oncology -

The Neuropsychology of

Cancer and Oncology

EDITORS

Chad A. NoggleRaymond S. Dean

ASSOCIATE EDITORS

Gary Alan Johnson

Thomas H. Tarter

Rhonda L. Johnson

• • • • • • • • • • • • • • • • • • • • • CONTEMPORARY NEUROPSYCHOLOGY SERIES

The Neuropsychology

of Cancer and Oncology

Noggle

Dean

11 W. 42nd StreetNew York, NY 10036-8002 www.springerpub.com 9 780826 108173

ISBN 978-0-8261-0817-3

Interest in the neurocognitive and sensory impairments resulting from many cancers and their interventions has grown considerably over the past decades as an important aspect of quality of life issues for cancer patients and survivors. The Neuropsychology of Cancer and Oncology features current findings on the neuropsychological effects of these cancers and their treatments along with the most promising neuropsychological and behavioral health interventions available to mitigate these deficits. This edited volume, part of the Contemporary Neuropsychology series, bridges the gap between the knowledge of neuropsychologists, who are grounded in the biological and physiological bases of cognition and behavior but not in pathology, and that of oncologists, who often lack expertise in the neuropsychological aspects of cancer.

This text first addresses the biological components and medical care of these cancers, and issues relating to bioimaging. It then discusses the neurological impact of these cancers as they affect different functions, such as memory, learning, and sensory-motor ability, as well as discusses the effects of childhood cancers on neurological development. State-of-the-art neuropsychological and behavioral health interventions are considered, including neuropsychological/cognitive rehabilitation and habituation, pharmacological interventions, and collaborative medical practices. This text is a unique and timely resource for clinical neuropsychologists, clinical psychologists, neurologists, oncologists, oncology nurses, and neurorehabilitation professionals.

Key Features:

◗ Bridges the gap of knowledge between neuropsychologists and oncologists

◗ Explores the most current research on the neuropsychological effects of various cancers and their treatments

◗ Provides state-of-the-art information on promising neuropsychological and behavioral–health interventions for impairments created by cancers and their treatments

◗ Represents a collaboration between some of the foremost scholars and practitioners in neuropsychology and oncology

The Neuropsychology of Cancer and OncologyEditors

Chad A. Noggle, PhD

Raymond S. Dean, PhD, ABPP, ABN

Associate Editors

Gary Johnson, MD

Thomas Tarter, MD

Rhonda Johnson, PhD

The

Neuropsychology of

Cancer and Oncology

Noogle_PTR_CH00_21-11_12_i-xvi.indd iNoogle_PTR_CH00_21-11_12_i-xvi.indd i 11/22/2012 4:05:19 PM11/22/2012 4:05:19 PM

About the Editors

Chad A. Noggle, PhD, ABN, is an Assistant Professor of Clinical Psychiatry and Chief of the Division of Behavioral and Psychosocial Oncology at Southern Illinois University–School of Medicine. He previously served as an Assistant Professor at both Ball State University and Middle Tennessee State University. Dr. Noggle holds a BA in Psychology from the University of Illinois at Springfi eld and completed his MA and PhD at Ball State University with special-ization in Clinical Neuropsychology. He completed a two-year postdoctoral residency at the Indiana Neuroscience Institute at St. Vincent’s Hospital with specialization in Pediatric and Adult/Geriatric Neuropsychology. To date, Dr. Noggle has published more than 300 articles, book chapters, encyclopedia entries, and research abstracts and has made over 100 presenta-tions at national and international conferences in neuropsychology. He served as the lead Editor of The Encyclopedia of Neuropsychological Disorders and The Neuropsychology of Psychopathology. He currently serves as a reviewer for a number of neuropsychology journals and is a member of the Editorial Board for Applied Neuropsychology-Adult and Applied Neuropsychology-Child. Dr. Noggle is a Diplomate of the American Board of Professional Neuropsychology. He is a professional member of the American Psychological Association (APA; Divisions 5, 22, 38, 40), the National Academy of Neuropsychology, and the International Neuropsychological Society. He is a licensed psychologist in both Illinois and Indiana. His research interests focus on both adult and pediatric populations, spanning psychiatric illnesses, dementia, PDDs, and neuromedical disorders.

Raymond S. Dean, PhD, ABPP, ABN, holds a BA degree in Psychology (magna cum laude) and an MS degree in Research and Psychometrics from the State University of New York at Albany. As a Parachek-Frazier Research Fellow, he completed a PhD in School/Child Clinical Psychology at Arizona State University in 1978. Dr. Dean completed an internship focused on neuropsychology at the Arizona Neurophychiatric Hospital and postdoctoral work at the University of Wisconsin at Madison. Since his doctoral degree he has served in a num-ber of positions and has been recognized for his work. From 1978–1980, Dr. Dean was an Assistant Professor and Director of the Child Clinic at the University of Wisconsin at Madison. During this time, he was awarded the Lightner Witmer Award by the School Psychology Division of the American Psychological Association. From 1980–1981, he served as Assistant Professor of Psychological Services at the University of North Carolina at Chapel Hill. From 1981–1984, Dr. Dean served as Assistant Professor of Medical Psychology and Director of the Neuropsychology Internship at Washington University School of Medicine in St. Louis. During this same time, Dr. Dean received both the Outstanding Contribution Award from the National Academy of Neuropsychology and the Early Contribution Award by Division 15 of the APA. He was named the George and Frances Ball Distinguished Professor of Neuropsychology and Director of the Neuropsychology Laboratory at Ball State University and has served in this position since 1984. In addition, Dr. Dean served as Distinguished Visiting Faculty at the Staff College of the NIMH. Dr. Dean is a Diplomate of the American Board of Professional Psychology, the American Board of Professional Neuropsychology, and the American Board of Pediatric Neuropsychology. He is a Fellow of the APA (Divisions: Clinical, Educational, and School and Clinical Neuropsychology), the National Academy of Neuropsychology, and the American Psychopathological Association. Dr. Dean is a Past President of the Clinical Neuropsychology Division of the APA and the National Academy of Neuropsychology. He also served as Editor of the Archives of Clinical Neuropsychology, Journal of School Psychology and the Bulletin of the National Academy of Neuropsychology. Dr. Dean has published some 600 research articles, books, chapters, and tests. For his work he has been recognized by awards from the National Academy of Neuropsychology, the Journal of School Psychology, and the Clinical Neuropsychology Division of APA.

Noogle_PTR_CH00_21-11_12_i-xvi.indd iiNoogle_PTR_CH00_21-11_12_i-xvi.indd ii 11/22/2012 4:05:20 PM11/22/2012 4:05:20 PM

About the Associate Editors

Thomas Tarter, PhD, MD, is Urologic Oncologist with the Cancer Care Specialists of Central Illinois (CCSCI). Dr. Tarter is a national leader in the treatment of urologic cancer and he is also recognized by his peers as an expert in urologic cancer surgery, including robotic surgery. Dr. Tarter received a PhD in Anatomy from Oregon Health Sciences University College of Medicine in 1983 and completed a fellowship in Reproductive Immunology at the Population Council Center for Biomedical Research at the prestigious Rockefeller University in 1986. Dr. Tarter received his MD degree from Albany Medical College in Albany, New York, in 1990. He also completed an internship and residency in General Surgery (1992) and a residency in Urology (1996) at Los Angeles County Hospital University of Southern California Medical Center in Los Angeles. He is a Diplomate of the American Board of Urology and the National Board of Medical Examiners. Before joining CCSCI, Dr. Tarter served as an Associate Professor for the Southern Illinois University–School of Medicine, where he also served as Director of Urologic Oncology. He has received numerous awards including election to Alpha Omega Alpha, eta chapter, and “Teacher of the Year” in 2005 and 2006 for residents and medical students, respec-tively. He holds membership with the American Urological Association and American College of Surgeons Oncology Group. In 2007, he was elected to the Society of Urologic Oncology in recognition for outstanding contributions and acknowledged concentration of study in the fi eld of urologic cancer. Dr. Tarter has authored more than 40 articles and abstracts and is renowned for giving numerous presentations on various aspects of Urologic Oncology throughout the country. He also serves as an active National Cancer Institute (NCI) investigator.

Gary Johnson, MD, is a specialist in Gynecological Oncology and minimally invasive cancer surgery at the University of Kansas Medical Center where he holds rank as Professor in the Department of Obstetrics and Gynecology within the Division of Gynecologic Oncology. Dr. Gary Johnson is a national leader in the treatment of gynecologic cancer including minimally invasive techniques. He completed his medical education at the University of Kansas School of Medicine followed by his Obstetrics and Gynecology residency at the University of Wisconsin in Madison, Wisconsin. After his residency, Dr. Johnson joined the University of California–Irvine where he completed a fellowship in Gynecological Oncology. He rose to the rank of Professor at the University of Oklahoma College of Medicine. He was also previously the Director of the Gynecological Oncology Division at Southern Illinois University–School of Medicine.

Rhonda Johnson, PhD, is an Associate Professor within the Departments of Psychiatry and Behavioral Sciences and Medical Oncology at the University of Kansas Medical Center. She pre-viously was Chief of the Division of Psycho-Oncology at Southern Illinois University–School of Medicine with the Department of Psychiatry and Assistant Professor of Psychiatry. She received her doctorate degree in Counseling Psychology at Oklahoma State University and has internship and postdoctoral experience in Health Psychology at the University of Oklahoma. Dr. Johnson is also a Certifi ed Sex Therapist and Sex Educator (American Association of Sex Educators, Counselors and Therapists). She serves on the Quality of Life Committee for the Gynecologic Oncology Group (GOG). Dr. Johnson has over 10 years experience in Psychological Oncology focused on wellness for cancer patients and cancer survivors. She has published in several peer-reviewed journals related to her research interest in quality of life and survivorship for cancer survivors and has served as a reviewer for several scholarly journals.

Noogle_PTR_CH00_21-11_12_i-xvi.indd iiiNoogle_PTR_CH00_21-11_12_i-xvi.indd iii 11/22/2012 4:05:20 PM11/22/2012 4:05:20 PM

Noogle_PTR_CH00_21-11_12_i-xvi.indd ivNoogle_PTR_CH00_21-11_12_i-xvi.indd iv 11/22/2012 4:05:20 PM11/22/2012 4:05:20 PM

CHAPTER ICHAPTER ICHAPTER ICONTEMPORARY NEUROPSYCHOLOGY SERIES

The

Neuropsychology of

Cancer and Oncology

EDITORS

Chad A. Noggle, PhD, ABN, and

Raymond S. Dean, PhD, ABPP, ABN

ASSOCIATE EDITORS

Thomas Tarter, PhD, MD, Gary Johnson, MD,

and Rhonda Johnson, PhD


Noogle_PTR_CH00_21-11_12_i-xvi.indd vNoogle_PTR_CH00_21-11_12_i-xvi.indd v 11/22/2012 4:05:20 PM11/22/2012 4:05:20 PM

Copyright © 2013 Springer Publishing Company, LLC

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 permission of Springer Publishing Company, LLC, or authorization through payment of the appropriate fees to the Copyright Clearance Center, Inc., 222 Rosewood Drive, Danvers, MA 01923, 978–750-8400, fax 978–646-8600, [email protected] or on the Web at www.copyright.com.

Springer Publishing Company, LLC11 West 42nd StreetNew York, NY 10036www.springerpub.com

Acquisitions Editor: Nancy S. HaleProduction Editor: Joseph StubenrauchComposition: Newgen Imaging

ISBN: 978–0-8261–0817-3e-book ISBN: 978–0-8261–0694-0

12 13 14 15 / 5 4 3 2 1

The author and the publisher of this Work have made every effort to use sources believed to be reliable to provide information that is accurate and compatible with the standards generally accepted at the time of publication. The author and publisher shall not be liable for any special, consequential, or exemplary damages resulting, in whole or in part, from the readers’ use of, or reliance on, the information contained in this book. The publisher has no responsibility for the persistence or accuracy of URLs for external or third-party Internet websites referred to in this publication and does not guarantee that any content on such websites is, or will remain, accurate or appropriate.

Library of Congress Cataloging-in-Publication Data

The neuropsychology of cancer and oncology / editors, Chad A. Noggle & Raymond S. Dean; associate editors, Thomas Tarter, Gary Johnson, and Rhonda Johnson. p. ; cm. — (Contemporary neuropsychology series) Includes bibliographical references and index. ISBN 978-0-8261-0817-3 — ISBN 978-0-8261-0694-0 (e-book) I. Noggle, Chad A. II. Dean, Raymond S. III. Series: Contemporary neuropsychology series. [DNLM: 1. Neoplasms—complications. 2. Neoplasms—psychology. 3. Mental Disorders—etiology. 4. Mental Disorders—therapy. 5. Nervous System Diseases—psychology. 6. Nervous System Diseases—therapy. 7. Social Support. QZ 200]

616.99’4—dc23 2012037336

Special discounts on bulk quantities of our books are available to corporations, professional associations, pharmaceutical companies, health care organizations, and other qualifying groups. If you are interested in a custom book, including chapters from more than one of our titles, we can provide that service as well.For details, please contact:Special Sales Department, Springer Publishing Company, LLC11 West 42nd Street, 15th Floor, New York, NY 10036–8002Phone: 877–687-7476 or 212–431-4370; Fax: 212–941-7842E-mail: [email protected]

Printed in the United States of America by Bang Printing.

Noogle_PTR_CH00_21-11_12_i-xvi.indd viNoogle_PTR_CH00_21-11_12_i-xvi.indd vi 11/22/2012 4:05:20 PM11/22/2012 4:05:20 PM

I dedicate this to my uncle, Gail LeCount, who passed away during the preparation of this book, following a long battle with cancer. I also dedicate this book to my grandpar-

ents, Walter “Papa” Burress, who passed away due to cancer, and Francis “Mama” Burress who was a survivor of cancer—CAN

To my children with all my heart—RSD

Noogle_PTR_CH00_21-11_12_i-xvi.indd viiNoogle_PTR_CH00_21-11_12_i-xvi.indd vii 11/22/2012 4:05:20 PM11/22/2012 4:05:20 PM

Noogle_PTR_CH00_21-11_12_i-xvi.indd viiiNoogle_PTR_CH00_21-11_12_i-xvi.indd viii 11/22/2012 4:05:20 PM11/22/2012 4:05:20 PM

Contents

Contributors xiPreface xvAcknowledgments xvii

Section I: Biological Components, Medical Care, and Special Considerations

Chapter 1: Neuropsychology and Cancer: An Emerging Focus 3Chad A. Noggle and Raymond S. Dean

Chapter 2: Urological Cancers 41Thomas Frye, Joe Miller, and Thomas Tarter

Chapter 3: Neuropsychological Sequelae of Breast Cancer and Its Treatment 65Elizabeth A. Peralta

Chapter 4: Neurocognitive Impact of Gynecologic Cancers and Their Treatment 83Lisa M. Hess and Jeanne M. Schilder

Chapter 5: Colorectal Cancers 99Imran Hassan, Vriti Advani, and Asha M. Alex

Chapter 6: The Neuropsychological Aspects of Head and Neck Cancer 111Sandra Ettema, Sheryl Reminger, and K. Thomas Robbins

Chapter 7: Neuropsychological Correlates of Lung Cancer 123Chad A. Noggle and Christopher M. McCormick

Chapter 8: Neuropsychological Implications of Skin Cancer 151Daniel Combs and Lee D. Cranmer

Chapter 9: Hematological Malignancies 175Christopher M. McCormick and Chad A. Noggle

Chapter 10: Cancers of Childhood: Biology and Forms 205Neelam Jain, Lana Harder, Brian Potter, and Kevin R. Krull

Noogle_PTR_CH00_21-11_12_i-xvi.indd ixNoogle_PTR_CH00_21-11_12_i-xvi.indd ix 11/22/2012 4:05:20 PM11/22/2012 4:05:20 PM

x CONTENTS

Chapter 11: Brain Metastases and Tumors 225Joachim Baehring

Chapter 12: Neuroimaging in Cancer and Oncology 235Susan K. Conroy, Brenna C. McDonald, Darren P. O’Neill, and Andrew J. Saykin

Section II: Neuropsychological Impact

Chapter 13: Attention and Executive Functions in Cancer and Cancer Treatment 263Amy L. Swier-Vosnos

Chapter 14: Effects of Cancer and Cancer Treatment on Learning and Memory in Adults 273Martin Klein

Chapter 15: Language Functioning and Cancer 293Michelle R. Pagoria

Chapter 16: Impact of Cancer and Oncology on Visuospatial and Visuoperceptual Functioning 303Amy R. Steiner, Chad A. Noggle, and Amanda R. W. Steiner

Chapter 17: Sensory–Motor Functioning in Cancer and Oncology 321Raymond S. Dean and Chad A. Noggle

Chapter 18: Psychosocial Functioning 343Joel Marcus

Chapter 19: Childhood Cancers: Neurological Development and Integrity 363Deborah G. Dwelle, Corey D. Anderson, and Robert W. Butler

Section III: Neuropsychological and Behavioral Health Interventions

Chapter 20: Neuropsychological Rehabilitation 381Susan Walsh and Margaret Primeau

Chapter 21: Pharmacological Interventions: Addressing Residuals and Outcomes 399Linda M. Sutton and Ivy Altomare

Chapter 22: Complementary Practices: Fatigue, Stress, Exercise, and Diet 413Sandra Vicari and Phil Anton

Chapter 23: Survivorship and Quality of Life 425Rhonda Johnson and Gary Johnson

Chapter 24: Psycho-Oncology: A Specialty Practice 441Teresa Deshields, Shannon Nanna, and Karl Chiang

Index 451

Noogle_PTR_CH00_21-11_12_i-xvi.indd xNoogle_PTR_CH00_21-11_12_i-xvi.indd x 11/22/2012 4:05:20 PM11/22/2012 4:05:20 PM

xi

CHAPTER ICHAPTER I

Contributors

Vriti Advani, MD Department of SurgerySouthern Illinois University–School of

MedicineSpringfi eld, IL

Asha M. Alex, MDDepartment of Internal Medicine Southern Illinois University–School of

MedicineSpringfield, IL

Ivy Altomare, MDAssistant Professor of MedicineDepartment of OncologyDuke University School of MedicineDurham, NC

Corey D. Anderson, MSPacifi c UniversitySchool of Professional PsychologyHillsboro, OR

Phil Anton, PhDAssistant Professor of Exercise PhysiologyExercise Program DirectorSIH-SIUC Strong Survivors Exercise

and Nutrition Program for Cancer Survivors and Caregivers

Department of KinesiologySouthern Illinois University Carbondale Carbondale, IL

Joachim Baehring, MDAssociate Professor of Neurology, of

Medicine (Medical Oncology), and of Neurosurgery

Clinical Program Leader, Brain Tumor Program

Smilow Cancer HospitalYale University School of MedicineNew Haven, CT

Robert W. Butler, PhD, ABPP-CNDepartment of PsychiatryOregon Health & Science UniversityPortland, OR

Karl Chiang, PhDAssistant Professor of PsychiatryUniversity of Massachusetts Medical

School UMass Memorial Medical CenterWorcester, MA

Daniel Combs, MDDepartment of PediatricsUniversity of ArizonaTucson, AZ

Susan K. Conroy, PhDMedical Scientist, Training Program Department of Radiology and Imaging

SciencesIndiana University School of MedicineIndianapolis, IN

Noogle_PTR_CH00_21-11_12_i-xvi.indd xiNoogle_PTR_CH00_21-11_12_i-xvi.indd xi 11/22/2012 4:05:21 PM11/22/2012 4:05:21 PM

xii CONTRIBUTORS

Lee D. Cranmer, PhD, MDAssociate Professor Section of Hematology and OncologyUniversity of Arizona Cancer CenterTucson, AZ

Raymond S. Dean, PhD, ABPP, ABNGeorge & Frances Ball Distinguished

Professor of Neuropsychology Director, BSU Neuropsychology

LaboratoryProfessor of PsychologyDirector of Educational PsychologyDepartmant of Educational PsychologyBall State UniversityMuncie, IN

Teresa Deshields, PhDManager, Siteman Counseling ServiceSiteman Cancer CenterBarnes-Jewish HospitalSt. Louis, MO

Deborah G. Dwelle, MSPacifi c UniversitySchool of Professional PsychologyHillsboro, OR

Sandra Ettema, PhD, MDAssociate ProfessorDepartment of SurgerySouthern Illinois University–School of


Thomas Frye, MDUrology Resident Southern Illinois University–School of


Lana Harder, PhD, ABPP Neuropsychologist Department of Psychiatry Children’s Medical Center DallasDallas, TX

Imran Hassan, MDAssistant Professor of SurgeryDivision of General SurgerySouthern Illinois University–School of


Lisa M. Hess, PhDDepartment of Public HealthDepartment of Obstetrics and GynecologyIndiana University School of MedicineIndianapolis, IN

Neelam Jain, PhDClinical NeuropsychologistGermantown Psychological Associates Germantown, TN

Gary Johnson, MDProfessor Gynecologic OncologyDepartment of Obstetrics and GynecologyUniversity of Kansas Medical Center Kansas City, KS

Rhonda Johnson, PhDAssociate ProfessorDepartment of PsychiatryUniversity of Kansas Medical Center Kansas City, KS

Martin Klein, PhDAssociate Professor of Medical

NeuropsychologyDepartment of Medical PsychologyVU University Medical CenterAmsterdam, The Netherlands

Kevin R. Krull, PhDAssociate MemberDepartment of Epidemiology and Cancer

ControlDepartment of PsychologySt. Jude Children’s Research HospitalMemphis, TN

Joel Marcus, PsyDNevada Cancer InstituteLas Vegas, NV

Noogle_PTR_CH00_21-11_12_i-xvi.indd xiiNoogle_PTR_CH00_21-11_12_i-xvi.indd xii 11/22/2012 4:05:21 PM11/22/2012 4:05:21 PM

CONTRIBUTORS xiii

Christopher M. McCormick, MADoctoral StudentDepartment of Educational PsychologyBall State UniversityMuncie, IN

Brenna C. McDonald, PsyD, MBAAssistant Professor of Radiology and

Imaging Sciences and of NeurologyIndiana University School of MedicineIndianapolis, IN

Joe Miller, MDSouthern Illinois University–School

of MedicineSpringfi eld, IL

Shannon Nanna, PsyDStaff PsychologistSiteman Counseling CenterSiteman Cancer CenterBarnes-Jewish HospitalWashington UniversitySt. Louis, MO

Chad A. Noggle, PhD, ABNClinical NeuropsychologistAssistant Professor of PsychiatryChief, Division of Behavioral &

Psychosocial Oncology Department of PsychiatrySouthern Illinois University–School of


Darren P. O’Neill, MDAssistant Professor of Radiology and

Imaging SciencesSection ChiefNeuroradiologyIndiana University School of MedicineIndianapolis, IN

Michelle R. Pagoria, PsyDClinical NeuropsychologistFounder and Clinical DirectorAdult Neuropsychology ServiceThe Neurobehavioral Group, P.C.Naperville, IL

Elizabeth A. Peralta, MD, FACS Breast Surgeon Department of Surgery Sutter Pacifi c Medical Foundation Santa Rosa, CA

Brian Potter, PsyDPediatric NeuropsychologistDepartment of Psychology/

Neuropsychology Nationwide Children’s HospitalColumbus, OH

Margaret Primeau, PhD, ABPPProfessorDepartment of Psychiatry and Behavioral

NeurosciencesLoyola University Chicago Stritch School

of MedicineMaywood, IL

Sheryl Reminger, PhDAssociate ProfessorDepartment of PsychologyUniversity of Illinois–Springfi eldSpringfi eld, IL

K. Thomas Robbins, MDExecutive DirectorSimmons Cancer InstituteSouthern Illinois University–School of


Andrew J. Saykin, PsyD, ABCNRaymond C. Beeler Professor of Radiology

and Imaging SciencesDirectorCenter for NeuroimagingIndiana University School of MedicineIndianapolis, IN

Jeanne M. Schilder, MDAssociate ProfessorDepartment of Obstetrics and GynecologyDivision of Gynecologic OncologyIndiana University School of Medicine Indianapolis, IN

Noogle_PTR_CH00_21-11_12_i-xvi.indd xiiiNoogle_PTR_CH00_21-11_12_i-xvi.indd xiii 11/22/2012 4:05:21 PM11/22/2012 4:05:21 PM

xiv CONTRIBUTORS

Amanda R. W. Steiner, PhDPost-Doctoral FellowVA San Diego Healthcare SystemSan Diego, CA

Amy R. Steiner, PsyD, ABPPBoard Certifi ed Clinical

NeuropsychologistHealthPartners NeurologyMinneapolis, MN

Linda M. Sutton, MDDuke University Medical CenterDuke Cancer InstituteDurham, NC

Amy L. Swier-Vosnos, PsyDDepartment of Behavioral SciencesRush University Medical CenterChicago, IL

Thomas Tarter, PhD, MDDirector, Urological OncologyCancer Care Specialists of Central IllinoisDecatur, IL

Sandra Vicari, PhDAssociate Professor of PsychiatryDepartment of PsychiatrySouthern Illinois University–School of


Susan Walsh, PsyDAssistant ProfessorDepartment of Psychiatry and Behavioral

NeurosciencesLoyola University Chicago Stritch School

of MedicineMaywood, IL

Noogle_PTR_CH00_21-11_12_i-xvi.indd xivNoogle_PTR_CH00_21-11_12_i-xvi.indd xiv 11/22/2012 4:05:21 PM11/22/2012 4:05:21 PM

xv

CHAPTER ICHAPTER ICHAPTER I

Preface

Whether due to the effects of the disease process itself or the negative outcomes associated with various treatment methods from the time of diagnosis and even beforehand, cancer patients frequently experience a number of adverse symptoms. Fatigue, sleep disturbances, and emotional problems such as depression and anxiety are often reported. In addition, cognitive defi cits are being recognized with increasing frequency as possible negative outcomes related to cancer and its treatment. Cognitive dysfunction occurs in both patients with central nervous system (CNS) tumors and those with non-CNS disease types. In addition, a majority of patients during active treatment will experience cognitive problems. While these defi cits are not consistently identifi ed on objective assessment, their impact on a patient’s daily life can be quite signifi cant. Patients may struggle returning to school or work. They may fi nd themselves unable to handle the same amount and type of work as they did before. Normal tasks are more trying and may take more time to complete.

Neuropsychology, a fi eld that represents the study of brain–behavior relationships, is being utilized more frequently within the cancer population to assess cognitive functioning prior to, during, and after treatment. Advances in functional and structural neuroimaging, as well as other biological tests have provided further insight into the pathological roots of cognitive defi cits in the cancer population. Still, the majority of practicing neuropsychologists are not well versed in their knowledge of cancer, oncology, and their potential infl uence on cognitive functioning. At the same time, professionals within oncology and surrounding domains have minimal exposure to neuropsychological practice or the literature on the neuropsychological impact of cancer and antineoplastic care.

The Neuropsychology of Cancer and Oncology is a unique text in that it discusses the integration of neuroscience, neuropsychology, and cancer and oncology to outline how both the disease (i.e., CNS and non-CNS cancers) and its treatment (i.e., surgery, radiation, chemotherapy, hormonal therapies, etc.) may negatively impact cognition. In lieu of simply discussing brain tumors or therapies that specifi cally target the CNS, we have chosen to cover both these issues while also discussing the means by which non-CNS cancers and their treatments affect cognition. Because defi cits may be indirect manifestations of treatment (e.g., poor memory due to fatigue that itself is due to treatment), an understanding of current methods of treatment is important as is an understanding of the disease processes themselves. The chapters included herein discuss many of the different forms of cancer, including current methods of treatment and the potential for neurocognitive defi cits related to the disease process and therapies employed. Potential neurocognitive defi cits are discussed from a domain perspective as well. Finally, supplementary services and resources are discussed. We hope that this volume will serve professionals in two diverse areas of practice—clinical neuropsychology, clinical psychology, and psychiatry on the one hand, and oncology on the other—in order to provide the highest quality of care to the patients in their care and to ensure a better quality of life for these patients overall.

Noogle_PTR_CH00_21-11_12_i-xvi.indd xvNoogle_PTR_CH00_21-11_12_i-xvi.indd xv 11/22/2012 4:05:21 PM11/22/2012 4:05:21 PM

Noogle_PTR_CH00_21-11_12_i-xvi.indd xviNoogle_PTR_CH00_21-11_12_i-xvi.indd xvi 11/22/2012 4:05:21 PM11/22/2012 4:05:21 PM

CHAPTER ICHAPTER ICHAPTER I

xvii

Acknowledgments

We would like to thank our associate editors for their contributions to this project. We want to also acknowledge the work put forth by the assistant editors for this book including Dr. Michelle Pagoria who served as lead assistant editor on this book, Dr. Amy R. Steiner, Dr. Javan Horwitz, and Dr. John Joshua Hall.

A book such as this is only made possible through the contribution of various authors. We want to acknowledge their willingness to volunteer their time and knowledge to this work. As always, we must acknowledge the support of our colleagues and associated institutions; SIU School of Medicine and Ball State University, without whom this project would not be possible. Finally, we would like to express our sincerest gratitude to our publisher and those with whom we have worked with very closely to complete this book, especially Nancy S. Hale and Joseph Stubenrauch.

Noogle_PTR_CH00_21-11_12_i-xvi.indd xviiNoogle_PTR_CH00_21-11_12_i-xvi.indd xvii 11/22/2012 4:05:21 PM11/22/2012 4:05:21 PM

Noogle_PTR_CH00_21-11_12_i-xvi.indd xviiiNoogle_PTR_CH00_21-11_12_i-xvi.indd xviii 11/22/2012 4:05:21 PM11/22/2012 4:05:21 PM

SERIES EDITORS Chad A. Noggle, PhD, ABNRaymond S. Dean, PhD, ABPP, ABN

The Neuropsychology of Psychopathology

The Neuropsychology of Cancer and Oncology

Neuropsychological Rehabilitation

The Neuropsychology of Cortical Dementias

The Neuropsychology of Pervasive Developmental Disorders

The Neuropsychology of Psychopharmacology


Noogle_PTR_CH00_21-11_12_i-xvi.indd xixNoogle_PTR_CH00_21-11_12_i-xvi.indd xix 11/22/2012 4:05:21 PM11/22/2012 4:05:21 PM

Noogle_PTR_CH00_21-11_12_i-xvi.indd xxNoogle_PTR_CH00_21-11_12_i-xvi.indd xx 11/22/2012 4:05:21 PM11/22/2012 4:05:21 PM

Biological Components, Medical Care, and Special Considerations

SECTION I

Noogle_PTR_CH01_21-11-12_1-40.indd 1Noogle_PTR_CH01_21-11-12_1-40.indd 1 11/21/2012 4:13:37 PM11/21/2012 4:13:37 PM

3

Neuropsychology and Cancer: An Emerging Focus

Chad A. Noggle and Raymond S. Dean

Annually, nearly 1.5 million people in the United States are diagnosed with cancer. While in previous decades the 5-year survival rate was far lower, continued advances in early diag-nosis and treatment options has led to improved morbidity and mortality rates. In the past, treatment mainly took on an antineoplastic approach, with the intention of treating the dis-ease and increasing quantity of life. Yet, increased survival rates have simultaneously led to an increase in the number of reported long-term complications of the disease and its treatment. Consequently, as the population of cancer survivors has grown, we too have grown in our focus on issues pertaining to and ensuring a quality of life (QOL).

QOL can be described in many ways. We conceptualize it as an individual’s self-appraisal of how their life is currently compared to where they would like it to be. However, this global QOL is merely the by-product of various domain-specifi c appraisals and quali-ties of life. As depicted in Figure 1.1, we conceptualize QOL as a multifactorial entity with contributions and infl uences from various aspects of one’s life. Hyperfocus on one or only a few domains can still lead to poor quality of life, due to the infl uence of negative self-appraisals within the neglected domains. The classic approach to cancer care is a good example of this approach. Focus was primarily placed on the individual’s health and anti-neoplastic treatment. However, factors such as emotional well-being, cognitive well-being, and so on, were neglected and, thus, patients could demonstrate a positive response to treatment but still have a poor net QOL. In reality, within the cancer population, from initial diagnosis through treatment and on into survivorship, all of these domains are sus-ceptible to negative infl uence and, consequently, diminished or poor QOL.

In the past two decades, one area that has received increased attention within this pop-ulation is cognition. More specifi cally, cognitive dysfunction associated with cancer and its treatment has grown in interest over the past few decades. Though changes in cognition may not be as noticeable as external features, such as an individual losing his or her hair due to chemotherapy, patients often struggle to cope with and overcome such cognitive defi cits. Patients may report things like “I don’t feel like the same person,” “My mind just does not work the same,” “I cannot remember anything anymore,” and “My short-term memory is horrible.” All of these statements have been made to the lead author of this chapter by actual patients, either through clinical encounters or as part of research studies. Such cognitive com-plaints are signifi cant as they may excert an infl uence over multiple other domains of one’s

CHAPTER 1

Portions of this chapter were adapted with permission from Noggle & Dean (2011a,b).


4 THE NEUROPSYCHOLOGY OF CANCER AND ONCOLOGY

life. Individuals may struggle in returning to school or work. As they perceive diffi culties within these settings, individuals may develop strong emotional reactions such as depression or anxiety in response to their self-awareness of these cognitive defi cits. This is in addition to the risk of depression and anxiety related to having cancer. Emotionality (e.g., depression or anxiety) may then serve to exacerbate the cognitive defi cits, thus creating a cyclical exchange between cognition and emotions.

Though cognitive complaints within the cancer population are discussed more fre-quently today than 20 years ago, there remains considerable limitation in the knowledge of the subject matter by those in and around the fi elds of neuropsychology, oncology, and other neuroscience and medical fi elds. Although previous conceptualizations primarily iso-late neurocognitive defi cits to cancer or treatment directly affecting the CNS (e.g., primary or metastatic brain tumors, neurosurgical intervention), research has demonstrated this is an inaccurate conclusion. The reality is that neurocognitive dysfunction arises from both direct and indirect infl uences of the disease and its forms of treatment. Furthermore, these infl u-ences are not limited to CNS foci, as systemic disease and systemic treatment have also been related to persistent cognitive complaints within the cancer population. We would argue that neuropsychology as a fi eld is best suited to address these cognitive issues. Oftentimes, when cognitive defi cits present, they stem from a mixture of physiological, medical, or psychologi-cal factors. Neuropsychologists, through their training within multiple domains, tend to have a great appreciation for the potential infl uence of these various factors. The robustness of neuropsychological assessments also provides a means for fully appreciating ones individual strengths and weaknesses. Screening measures such as the Mini Mental Status Examination, with its low ceiling, is often insensitive to the effects of cancer and its treatment on cognition. Consequently, a comprehensive, standardized, and objective measure of cognition, as is pur-sued as part of a neuropsychological assessment, remains the most appropriate way of assess-ing cognitive defi cits related to cancer and its treatment.

In this chapter, we provide a brief overview of the fi eld of neuropsychology, including the fi eld’s historical roots and principles of clinical practice. From there we discuss cognitive defi cits as they present in cancer and its treatment. This includes a general introduction to the potential etiologies of these defi cits, which will be expanded upon in later chapters through disease specifi c and domain specifi c discussions.

HISTORY OF NEUROPSYCHOLOGY

Historically, the fi eld of clinical neuropsychology grew out of a need to localize cerebral lesions and determine the extent of neurological impairment through nonintrusive meth-ods. Regarding working with the medical fi elds and assisting in rehabilitation 30 years

FIGURE 1.1 Enmeshment of functionality.

Physical & Neurological Health

Psychological/ EmotionalWell-Being

Behavioral Control & Regulation

Cognitive Integrity

Academic/OccupationalAchievement

Socialization/Family Life

OptimalQuality of Life


NEUROPSYCHOLOGY AND CANCER: AN EMERGING FOCUS 5

ago, neuropsychologists were primarily responsible for localizing lesions and determining the lateralization of impairment. Early neuropsychologists utilized both direct and indirect observation. Indirect observation included observing visible neurological impairment and extrapolating to observable behaviors (e.g., the case of Phineus Gage) or using neuropsycho-logical test instruments that measure behavior as supposedly correlated to specifi c process-ing areas. Direct measurement was not possible until autopsy, such as the case of Paul Broca examining the brain of his famous patient with expressive aphasia after death. Despite the success of neuropsychologists using indirect measurement, it is diffi cult to argue that direct measurement of functions is the future of the fi eld, as well as the far superior technique. Indirect measurement and estimation of localization of impairment suffers from the fact that neuropsychologists are not really measuring a neurological region, they are measuring behav-ior that they believe is related to a specifi c neural processing area based on research or anec-dotal evidence.

Humans have long been aware of the brain–behavior relationship, with the search for information and treatment extending back thousands of years. Archeologists have dis-covered several thousand skulls that show evidence of humans having survived trephina-tion (Zillmer & Spiers, 2001). Trephination is the ancient practice of removing pieces of the skull, designed to relieve swelling of the brain. The ancient Greeks produced the fi rst written records of brain–behavior relationships. They tended to regard cognitive functioning from a divine nature. The fi rst recorded observation that the brain is the center of human reason-ing was produced by Pythagoras (580–500 BCE). Pythagoras and other scholars developed the idea of the brain hypothesis, which stipulated that the brain is the source of all behavior (Zillmer & Spiers, 2001).

Hippocrates, largely credited with founding modern medicine, held that the brain was the center of sensations, wisdom, consciousness, emotions, and movement. He also postu-lated that psychological disorders were caused by brain pathology and head trauma. This was in opposition to the commonly held belief that brain disorders, especially seizures, were the work of gods. In discussing head trauma, he correctly noted that paralysis occurred con-tralaterally to the hemisphere of the injury. Plato (420–347 BCE) wrote that the soul, respon-sible for rational thought, was located in the brain and noted that head trauma will result in impairment in reasoning (Robinson, 1970). Aristotle (384–322 BCE), a student of Plato, pos-tulated that the heart is the seat of all mental processes. He argued that as the heart is warm and active, it was the seat of emotions such as love and anger. The brain worked to cool the hot blood that rises from the heart. This viewpoint was called the cardiac hypothesis (Zillmer & Spiers, 2001). Although he made numerous contributions to ethics, psychology, poetry, and politics, his erroneous viewpoint of the location of the soul may be responsible for the large gap that existed before the next major contribution was made to the brain–behavior relationship. The ideas of the Greek philosophers, although anatomically wrong in many counts, provided the foundation upon which the study of neuropsychology was built, and future philosophers and physiologists may not have made their contributions without the advances of the Greeks.

Galen (130–201 AD), a Roman anatomist and physician, is a key fi gure in the history of neuropsychology. His observations of the human body came from his work as a surgeon who was appointed to gladiators (Finger, 1994a). Galen believed that the functioning of the body and brain resulted from the combination of the four elements, qualities, and humors (May, 1968). Galen’s view of humors became so ingrained that physicians barely elaborated on the role of the brain for the next thousand years. During the 16th century, Galen’s anatomic mis-takes began to be corrected. Rene Descartes (1596–1650), a French philosopher and mathema-tician, is an important fi gure in the history of neuropsychology, in that he proposed a division between mental and physical processes. He viewed the human body as a material entity that functioned like a machine, where the mind was free to carry out the functions of conscious-ness. This idea is now referred to as interactive dualism (Benjamin, 1997).

As the 18th century approached, more accurate representations of the brain and its functions were occurring. This may have been related to the conviction that all things could be conceptualized as machines (Zillmer & Spiers, 2001). Emanual Swedenborg (1688–1772) was likely the fi rst to generate a theory of cortical localization of behavioral functions.



Swedenborg wrote that separate areas of the brain were necessary to prevent psychologi-cal chaos, and charted his ideas of discrete areas for vision and hearing based on his studies of pathology and anatomy (Finger, 1994b). Although ahead of his time, his ideas were not published until the end of the 19th century, when localization theory was broadly accepted. It was with the idea of brain localization in mind that Franz Gall (1758–1828) developed the science of phrenology. Phrenologists believed that the brain consists of a number of separate organs that are independently responsible for some aspect of behavior or personality. They stipulated that variations in brain functions among individuals led to variations in the shape or size of that organ of the brain. Hence, it was possible to detect variations in brain func-tions by looking for differences along the shape of the skull. Although today phrenology is referred to with contempt and humor, the advocates of phrenology made many important contributions to the study of the brain and how it affects behavior. Gall was among the fi rst to propose that the cerebral cortex is not merely the outer area of the brain with no specifi c functions. Although the anatomical deductions of phrenology are erroneous, the determina-tion to objectively study the mind without metaphysical conceptions is a landmark in the history of neuropsychology.

Paul Broca (1824–1880), a French surgeon-anthropologist, was able to identify specifi c functional areas within the cerebrum. He is best remembered for identifying an area that is related to expressive speech that produces a speech disorder we now commonly call Broca’s area. Damage to this area is called Broca’s aphasia, usually resulting from a lesion to the left hemisphere of the brain in either the frontal operculum, or the corticocortical association path-ways in the white matter of the temporal, parietal, and frontal lobes that relate to the motor speech areas. Broca is also responsible for starting a decades-long trend that the left hemi-sphere was regarded as the dominant hemisphere. After performing an autopsy on his famous patient, Leborgne (also called Tan), who was suffering from a degenerative ability to produce speech, Broca was able to identify the area of the cerebrum, which bears his name, responsible for the damage. On an autopsy, Broca was able to identify several areas of the brain that were destroyed, which led him to conclude that the area of the brain which bears his name was responsible for causing the expressive language problem.

Another 19th century researcher, Carl Wernicke (1848–1904), was also to have an area of the brain named after him in honor of his fi ndings. Wernicke postulated that the ability to understand spoken language had a specifi c localization site in the brain, in the posterior half of the left superior temporal gyrus. The disorder now known as Wernicke’s aphasia is characterized by defective comprehension of spoken words, and fl uent yet incoherent speech. Wernicke was also responsible for casting light on a disorder that may have been previously referred to as madness in earlier centuries, which was actually a problem of the left hemisphere (Harris, 1999). Wernicke’s fi ndings are important in brain localization theory, as, along with Broca, he was able to demonstrate that language is located in at least two different cortical areas. Wernicke’s fi ndings cast a realistic shadow on 19th-century proponents of brain local-ization theory, who hypothesized functions had one specifi c location. In the case of speech, there were at least two areas of the cortex operating, Broca’s and Wernicke’s areas, as well as association pathways.

Early neuropsychologists were interested in studying other aspects of the brain aside from motor and sensory areas. The frontal lobes received a lot of attention, as many 19th century philosophers held that the frontal lobes are what separate man from the lower order species. Phineus Gage, a railroad worker suffered a traumatic brain injury when an explosion forced a large piece of metal into the front of his brain. Although he recovered with his lower order functions (respiration, heart rate) intact, he suffered a noticeable change in personality and behavior. This and other cases of people surviving injuries, led to speculation that ele-ments of personality could be localized in the frontal lobes.

Hughlings Jackson (1835–1911) was an English neurologist who hypothesized that higher mental functions are not discrete actions unto themselves, but are combinations of a series of simpler mental processes. He disagreed with localization theorists who proposed that the brain has a single speech center. For example, he viewed speech as a sequence of simple mental abilities, such as hearing, fi ne motor movements, and kinesthetic control of the



mouth. Thus, if there is an injury to the brain that results in loss of speech, it does not neces-sarily occur in Broca’s or Wernicke’s area since the injury could disrupt any one of the many processes that are necessary to create speech. Jackson was not interested in answering the question, “Where is language located?”; he wanted to know “What is each region’s contribu-tion to language?” (Harris, 1999).

Alexander Luria (1902–1977), a Russian neuropsychologist, built on Jackson’s theories to become one of the most prominent neuropsychologists of the 20th century. Luria did not view any complex higher cortical functions as products of a particular tissue or organ, but as the coordination of several different brain areas. Luria combined elements of localization, equipotentiality theory, and the work of Hughlings Jackson to create a conceptualization of a normally functioning brain as three units. The fi rst unit regulates activation, muscle tone, and vigilance and consists of the reticular formation, limbic system, and mesial basal frontal lobes. Injuries to the fi rst unit can result in lethargy and apathy, which will impair higher cortical systems, even though the areas related to higher cortical functions, may remain intact. The second unit is responsible for registration, analysis, and the storage of sensory information, and is comprised of the temporal, parietal, and occipital lobes. The third unit regulates complex mental activity, such as planning, abstract thought, and organization. This unit is dependent upon the integrity of the frontal lobes. All activities depend upon the cooperation of all three units. Luria’s theory hypothesizes that when a functional system ceases to operate correctly as a result of an injury, it is not obvious which cerebral structure in the brain is impaired. For example, a brain-injured patient may not be attending (Unit 1), he may not be able to analyze relevant stimuli (Unit 2), or he may not be actively trying to use the information; all three of these possibilities will have similar functional presentations (Gouvier et. al., 1997). No single unit or area of the brain is solely responsible for the execu-tion of any activity. In order to assess which system is impaired, Luria proposed testing a series of hypotheses that call upon each unit to sequentially demonstrate its integrity. Luria’s idea of harmonious processing remains very relevant today, decades after he fi rst published his ideas. His ideas have directly infl uenced modern neuropsychological tests such as the Luria-Nebraska Neuropsychological Test Battery (Golden, Purisch, & Hammeke, 1985) and the NEPSY: A Developmental Neuropsychological Assessment (NEPSY; Korkman, Kirk, & Kemp, 1998). More importantly, Luria’s idea of harmonious processing demonstrates some of the weaknesses regarding modern neuroimaging. Although functional neuroimaging is adept at showing regional processing, more widely used measures of static functioning (e.g., MRI, CT) only identify a lesion site and do not provide evidence of functional impairment. Thus, while the fi eld of neuropsychology is likely to undergo signifi cant changes in the next sev-eral years, the identifi cation of functional implications and the interaction of the neuro-logical impairment, behavior, and the environment are likely to remain the domain of the neuropsychologist.

Through modern neuroimaging analyses, we have been able to confi rm the ideas pro-posed by Luria and Jackson regarding the overlapping of functional systems in producing behavior. As suggested by Luria (1964, 1966) the brain is best characterized as having har-monious functional systems that interact with one another to varying degrees to carry out all behavior and function. Clinically, a patient may present with dysnomia (i.e., diffi culty in naming); however, this manifestation may originate from at least eight different sites of neuro-anatomical impact (e.g., Broca’s area, Wernicke’s area, arcuate fasciculous, Perisylvian region, anterior borderzone, posterior borderzone, angular gyrus, anterior, and posterior borderzone; Filley, 2001). Truly, assessment of additional domains of language functioning (e.g., sponta-neous speech, auditory comprehension, repetition) may better establish regional differentia-tion; however, imaging can more accurately achieve this same differentiation when a lesion is viewable via imaging, which, in turn, the neuropsychologist may then use to guide their understanding of the individuals functional presentation. This understanding is of particu-larly great importance, as although the functional aftermath of two very different lesions may be similar, their responsiveness to methods of intervention will differ according to regional origin (see Crosson, Bacon-Moore, Gopinath, White, Wierenga, et al., 2005). Given this, it stresses the importance of utilizing neuroimaging fi ndings in neuropsychological practice.



The following section will explain the mechanical and scientifi c underpinnings of modern neuroimaging techniques.

NEUROPSYCHOLOGICAL PRACTICE

Neuropsychology is best conceptualized as a mixture between behavioral neurology, clini-cal and experimental psychology, and objective measurement of human behavior. This is evident in many of the procedures that currently make up available neuropsychological test batteries. With few exceptions, current assessment procedures are either standardized versions of preexisting clinical procedures or adaptations of neuropsychological laboratory procedures for clinical use. Often seen as an expansion of the neurologic examination, neu-ropsychological assessment emphasizes standardized behavioral observations and interpre-tations that rely on normative standards and critical value cutting scores. This approach has been shown to be of value in diagnosing neurologic disorders and defi ning the behavioral effects of brain damage. In retrospect, one can criticize 19th and early 20th century meth-ods that based conclusions about normal brain functioning on case studies of patients with diseased brains. Nevertheless, these early reports led to our present understanding of the relationship between clinically expressed behaviors and cerebral functions. The notion of a direct correspondence between behavior and localized microstructures of the brain seems naive by present standards. We now recognize that the magnitude, site, and chronicity of a brain lesion, developmental history, and individual differences in brain structure and chem-istry all interact to make highly specifi c localization tenuous. The infl exible notions of a one-to-one correspondence between observable behavior and structures of the brain have been rejected by most neuroscientists. However, a quantitative-actuarial approach remains, which concentrates on the differential diagnosis of neurologically related conditions and their behavioral correlates. The emphasis on differential diagnosis in neuropsychologi-cal assessment is relatively recent in the history of the fi eld, and grows out of a need to describe more objectively the behavioral effects of neurological and psychiatric presenta-tions. Although the neurologist or radiologist may be able to document and localize lesions, rarely is it possible to make specifi c predictions about a patient’s behavioral functioning in their premorbid environment. Thus, neuropsychological assessment provides information useful in aftercare planning and following progressive disorders.

The scientifi c approach to indentifying individual differences of the late 19th and early 20th centuries continues to infl uence psychometric theory in general and neuropsychological assessment specifi cally. From this perspective, various aspects of human behavior (e.g., mem-ory) are viewed on a continuum rather than as a normal–abnormal dichotomy, with the major-ity of individuals clustering around a midpoint on a given ability spectrum. This approach to neuropsychological assessment has resulted in the scaling of functions and the interpretation of individual behaviors relative to normal cohorts.

Neuropsychological assessment comprises tasks examining a comprehensive array of behaviors that are compared with normative standards and those occurring in known neu-rologic conditions. Such information permits recognition of “minor” behavioral/cognitive impairment, often the early sign of neurologic disorders, which the cumulative literature over the past few decades has clearly linked with neurological substrates. Of use in differential diagnosis, these data also provide the clinician information concerning the extent of a patient’s behavioral impairment. Neuropsychological assessment provides the objectivity necessary in following the course of progressive or chronic disorders or presentations and offers the clini-cian a monitoring capability not available with other procedures. It also offers the opportunity for reassessment, which may be necessary in relation to (a) questionable validity on previ-ous testing related to poor attention or motivation; (b) decline or improvement in cognition, (c) functional decline, (d) effects of a neurological event, (e) effects of substance abuse, (f) effects of cognitive interventions, (g) medication effects, and (h) test–retest for research pur-poses (Marcopulos et al., 2008). Within the cancer population, this is useful both within the experimental/scientifi c and clinical realms as it permits for the assessment of change over time in relation to an intervention (e.g., serial assessment), allows for pre- and postresection



assessments for brain tumor patients, and allows for the monitoring of change in relation to cognitive rehabilitation endeavors.

Neuropsychological examinations involve measures of cognitive, sensorimotor, and emotional functioning. Some of the tests are the same as those routinely administered in clinical evaluation. For example, the Minnesota Multiphasic Personality Inventory II (MMPI) and the Wechsler Intelligence Scales have been included as part of most neuropsy-chological evaluations after extensive research concerning the neurologic correspondence of these measures. These tests have allowed a more comprehensive view of the patient’s level of functioning. The tests used may vary somewhat with the individual laboratory or practitioner.

Neuropsychological Practice in Oncology

Within the domain of cancer and oncology, neuropsychological assessment may be pursued for both clinical and research purposes. In both instances, clinicians must be mindful of those areas most susceptible to the effects of treatment (e.g., attention, processing speed, executive functioning, memory, etc.). While measures such as the Mini Mental Status Examination may be a helpful initial screening tool for other presentations, it is unlikely to capture the functional defi cits related to cancer and its treatment, aside from a few exceptions. This further empha-sizes the importance of neuropsychological assessment as it provides a means of objectively identifying potential brain dysfunction, including mild or subtle cognitive disturbances such as those described in relation to cancer and oncology. Consequently, measures used should be sensitive to subtle changes across specifi ed functional domains. The assessment must also be comprehensive as neuropsychological profi les related to cancer and its treatment can result in various impairments.

In general, assessments should (a) measure premorbid functioning, (b) assess a wide range of cognitive domains, (c) evaluate for potential malingering, (d) be mindful of examinee burden, and (e) be at the functional level of the client (Marcopulos et al., 2008). Within the cancer population, while particular domains may be focused on more than oth-ers because of the case presentation, we recommend that assessments include measures of intelligence, attention and processing speed, language, memory and learning, visuospatial/visuoperceptual skills, academic functioning, executive functioning, sensory-motor func-tioning, and mood. Inclusion of both objective measures and subjective report measures are essential as patients may often report greater impairments in everyday functioning than is revealed on objective assessment. For example, objective measures of executive func-tioning should be utilized while also including self-report measures such as the Behavior Rating Inventory of Executive Functioning (Roth et al., 2005) to obtain a quantifi cation of the patient’s potential for daily problems in this domain. Inclusion of academic functioning measures is particularly important for children, adolescents, or others who may be in school or returning to school. However, academic functioning measures are also important from a functional standpoint given the potential for neurological features presenting in these domains (e.g., alexia, agraphia). Within the clinical setting, this comprehensiveness is more essential; within the parameters of a clinical study, the desired end points may direct assess-ment toward a more focused direction.

Interpretation must not simply focus on quantitative outcomes but also on the qualita-tive input and output, as task failure can stem from various cognitive processes and not nec-essarily a unitary function.

Table 1.1 includes a potential battery for a comprehensive neuropsychological assess-ment as well as a neuropsychological screening battery. An in-depth review of neuropsycho-logical assessment can be found in other sources (e.g., Lezak et al., 2004).

Competing or Infl uential Factors in Assessment and Interpretation

Premorbid and Neurodevelopmental History. The impact of neurocognitive defi cits within the cancer setting is dependent on the individual’s life stage, both in terms of chronological age and environmental demands of “normal” neurocognitive functioning. The timing of disease



onset and treatment initiation should be taken into account when considering neuropsy-chological defi cits. Discrepancies between children and adults should be anticipated as this refl ects differences in exposing a developing brain to such insults compared to exposing a developed brain. A detailed developmental and premorbid history is critical to fully appreci-ate and conceptualize the potential impact of the cancer itself and the impact of the treatment delivered, and to understanding the interrelationship between cognitive, behavioral, biologi-cal, and environmental factors.

As is true in other clinical medical sciences, a patient’s presenting symptoms must be interpreted relative to their medical, social, and family history. Although it is often diffi cult to examine the effect of education, socioeconomic status, and occupation for the individual, each has been shown to be related to the performance on psychological measures in general, and on measures of neuropsychological functioning specifi cally, and may modify their inter-pretation. Prigatano and Parsons report a considerable relationship between the results on measures of neuropsychological functioning and the level of education for patients from a general medical service.

TABLE 1.1 Brief and Comprehensive Neuropsychological Assessment

TYPE OF EVALUATION TESTS

Neuropsychological Screen Wechsler Abbreviated Scale of Intelligence (WASI)• Wechsler Test of Adult Reading (WTAR)• Repeatable Battery of Neuropsychological Status (RBANS)• Trails A and B• or Comprehensive Trail Making Test (CTMT)Stroop• Wisconsin Card Sorting Test• Grooved Pegboard• Beck Depression Inventory-2• Beck Anxiety Inventory•

Comprehensive Neuropsychological Evaluation

Wechsler Adult Intelligence Scale-IV (WAIS-IV) • or Woodcock-Johnson-III-Tests of Cognitive Abilities (WJ-III-COG)Wechsler Test of Adult Reading (WTAR)• California Verbal Learning Test-II (CVLT-II)• Wechsler Memory Scale-IV (WMS-IV) • or Wide Range Assessment of Memory and Learning-2 (WRAML-2)Rey Complex Figure Test• Trails A and B • or Comprehensive Trail Making Test (CTMT)Stroop• Wisconsin Card Sorting Test• MAE Token Test• Boston Naming Test• Verbal Fluencies (e.g., COWAT & animals)• Continuous Performance Test-II• Wechsler Individual Achievement Test-III (WIAT-III) • or Woodcock-Johnson-III-Tests of Achievement-III (WJ-III-ACH) or Kaufman Functional Academic Skills Test (K-FAST)Test of Memory Malingering (TOMM) • and/or Word Memory TestHalstead-Reitan Sensory–Motor Battery• or Dean-Woodcock Sensory-Motor BatteryGrooved Pegboard• Behavior Rating Inventory of Executive Functioning (BRIEF)• / Minnesota Multiphasic Personality Inventory-II—Restructured Format (MMPI-2-RF)Beck Depression Inventory-2• Beck Anxiety Inventory•



Dean has argued that the adult patient’s premorbid occupation and the concomitant opportunity to refi ne academic skills may be a potent predictor of neuropsychological func-tioning. Indeed, there seems to be a substantial relationship between socioeconomic status, when measured by occupation, and normal individuals’ general cognitive abilities. The effect of race on neuropsychological functioning is not as clear. Although some have hypothesized a genetic component for race on such measures, the interaction of socioeconomic differences and aspects of cultural transmission make interpretation of these data for the individual patient tenuous.

As one would expect, the effects of age on neuropsychological performance are clearest at the two extremes with batteries developed exclusively for adults and exclusively for chil-dren. Although diminution in neuropsychological functions is known to exist with advancing years, the extent to which these results are dependent on past learning and experience is not clear. In one early study, Reed and Reitan reported a moderate negative correlation between age and scores on the neuropsychological battery. However, this summary statistic obscures the more interesting result that little dependable change in neuropsychological functioning was observed for abilities that depended most directly on past learning. This replicated fi nd-ing was as clear as the decline with advancing years of performance on tasks requiring mental fl exibility, new learning, and memory when not based on old associations.

Finally, in taking a patient’s developmental and premorbid history it is important to assess for preexisting and comorbid conditions. Histories of ADHD, learning disabilities, exernalizing disorders, pervasive developmental disorders, or more general intellectual dis-abilities must be taken into account clinically and not ignored simply because these traits may not be the basis for the referral per se. Clearly, the patient’s developmental and medical his-tory provides insight into their neuropsychological performance. Thus, the patient’s present functioning level must be evaluated in light of seemingly unrelated factors.

Timing of Assessment(s). Within the cancer population, the timing of assessments is a critical issue for clinicians. Differing opinions could likely be found within the profession. IN reality, this decision is largely based on the purpose of the assessment. Within the research setting, with most studies focusing on either the impact of the disease itself or the treatment, we would argue that pretreatment assessment is always critical. If there is interest purely on the impact of the disease, assessment should be carried out prior to any treatment being deliv-ered which itself could carry some degree of neuropsychological burden. Depending on the additional research interests, further assessments may be utilized. This could involve assess-ment during treatment, immediately following the completion of active treatment, and at key time points following treatment. This may even include assessments out to a year or more after treatment as latency effects have been reported. Due to the potential of practice effects across some measures, assessment timing and choice of measures may be modifi ed. Emerging computer-based assessments, which report a greater control for practice effects may offer the best potential for minimizing these issues. In addition, given the potential impact of factors such as fatigue and sleep disturbance, mood, medicinal changes, anemia, and so on, these factors should be examined at the same time as the various assessments to offer some control over their potential confounding effects.

When the purpose of the assessment is purely clinical, one may argue that pretreatment assessment is not strongly warranted. However, we would argue, depending on the specifi cs of the case, that pretreatment assessment can be critical in many ways. Neuropsychological assessment has proven effective in the monitoring of disease status. Like in the case of CNS tumors, neuropsychological assessment has demonstrated the capacity to identify progres-sion before MRI (Armstrong et al., 2003; Meyers, 2000; Meyers & Hess, 2003; Meyers et al., 2004). Consequently, this form of clinical tracking relies critically on baseline assessment. At the same time, with evidence demonstrating the potential of non-CNS cancers contributing to cognitive problems, pretreatment assessment remains critical. By having such data for com-parison, one may better determine the potential toxicity of treatment if such concerns were raised by patients or providers. In the absence of such baseline data, one may view cognitive problems as potential evidence of toxicity of the treatment when, in reality, compared whit baseline data, they may be improving. This has played out already, in some ways, within



the lung cancer population, where individuals have argued against the use of prophylactic cranial irradiation (PCI), stating the potential benefi ts did not outweigh the potential nega-tive outcomes in neuropsychological functioning. These arguments were based on research where patients were just assessed following PCI. However, later studies, which included base-line assessments, revealed cognitive problems even prior to treatment that, in some instances, never worsened as a result of treatment. This is discussed in greater depth in the chapter on lung cancer within this text.

When assessment is carried out during treatment, just as in research, professionals should be mindful of fatigue, mood, medicinal changes, and anemia, as well as other factors, as they may have a direct infl uence on performance.

Following treatment, assessment can be carried out at different time points and is largely dictated by when the referral is received, unless pretreatment assessment has been utilized, which permits greater control on the part of the neuropsychologist as to when assessment would be appropriate. Given some patients experience a latency effect when it comes to the development of neuropsychological defi cits (e.g., following radiation treatment), an assess-ment in closer proximity to the end of treatment and then one carried out months down the road may carry some utility. Whenever comparing repeated assessments to one another, uti-lizing a reliable change index calculation (e.g., Jacobsen & Traux, 1991) is essential to deter-mine if change, whether positive or negative, is meaningful.

Motivation. Practicing neuropsychologists must always be mindful of potential con-founds to assessment results. Exaggeration and malingering has been well discussed in the literature when it comes to forensic proceedings. These same issues can arise within the gen-eral clinical arena. While debate can be found in the literature, it is our professional belief that measures of symptom validity should be used in most every assessment scenario, as motivation toward assessment and specifi c assessment outcomes can vary for many reasons. In reality, before clear judgments can be made about objective data, one must be able to rea-sonably judge the reliability of that data and the likelihood that it represents the patient’s true abilities.

Neuropsychological assessment is an interactive process and the results are depen-dent on the patient’s motivation. The interpretation of neuropsychological functioning is predicated on the assumption that the patient has tried to cooperate. Although the patient’s motivation is continuously monitored during the examination and reinforcement is pro-vided, secondary gains may infl uence the patient’s performance. Measures such as the Word Memory Test, Test of Memory Malingering, and even the validity scales of the MMPI are designed to predict purposeful aberrations in performance. At the same time, a deliberate effort to infl uence neuropsychological test results in any consistent manner is diffi cult for the patient. Malingering and factitious disorders can be detected with considerable accuracy. Even if there is not a forensic application to the assessment, patients within various settings can have a tendency toward exaggerating cognitive defi cits as a means of demonstrating the degree of affl iction they are experiencing related to their reported complaints. In the cancer population this may be seen in instances where patients are applying for disability or seeking particular medications (e.g., psychostimulants). Further, mental fl uctuations related to their physical state can manifest as poor outcomes on measures of effort and thus call assessment outcomes into question.

Mood. Another issue within the cancer and oncology setting is the impact of mood on test performance and assessment outcomes. This is outlined in greater detail below, but must be noted within the context of this discussion. Neuropsychological examination requires the patient’s cooperation and concentration. Emotional disturbance may be important to consider in measuring neuropsychological function. Most research here has examined the relation-ship between measures of emotional disturbance and the results of neuropsychological tests. Emotional features such as depression, anxiety, as well as others commonly present within the cancer population and, as discussed below, may negatively impact test performance. Consequently, objective measures of mood should be included in assessments within the can-cer population. This will not only assist in determining the possibility that neuropsychological problems are related to these mood disturbances, but also evaluate the severity of features that may themselves require clinical intervention.



Interpretation and Intervention Following Neuropsychological Assessment

Neuropsychological practice within any setting must go beyond descriptions and formula-tions of phenomenology. The relative importance of neuropsychology within the oncology setting is seen when the data obtained through assessment is used to develop appropriate cognitive remediation strategies. When done, the combination of neuropsychological assess-ment and functional intervention is amongst the most impactful services

The intervention process starts with interpretation of the assessment results, as is the case with any neuropsychological evaluation. This should include a discussion of not only the cognitive strengths and weaknesses but also the functional implications of any impairments and recommendations to circumvent those diffi culties to maximize functioning (Marcopulos et al., 2008). As previously noted, interpretation not only can focus on the quantitative results but must also take into account the qualitative input and output. This is best done through behavioral observation throughout the course of the assessment. This can help explain/understand variations in specifi c tests in the case of environmental distracters as well as offer qualitative judgment of the individual’s capacity for sustained effort.

Recent research has evaluated the utility and effectiveness of neuropsychological reha-bilitation for neuropsychological impairments. Readers are directed to Chapter 20, which offers a thorough discussion of these principles and techniques.

NEUROPSYCHOLOGICAL IMPACT OF CANCER AND ONCOLOGY

Cognitive defi cits are common within the cancer population and remain one of the most salient concerns of cancer survivors after treatment (Hewitt et al., 2006). Though cognitive dysfunc-tion is most commonly reported during active treatment, defi cits have been noted at all phases of the disease and treatment. That is, cognitive defi cits have been noted prior to, during, and following treatment. The nature of these defi cits may arise from both direct and indirect infl u-ences of both the disease itself and the various forms of treatment. Various causes have been discussed including the effects of CNS and non-CNS cancers, infl ammatory and autoimmune responses, and the effects of treatment including surgery, chemotherapy, hormonal treatment, and radiation. These causes are discussed below.

While the cognitive defi cits arising from these various sources may vary, defi cits in attention, processing speed, and working memory, are the most common defi cits. Individuals may report a wider variety of defi cits in day-to-day life, such as executive dysfunction, which may come out on self-report measures, but are not necessarily identifi ed on objective assess-ment. Furthermore, the impact of cognitive dysfunction on cancer patients depends on their developmental stage of life, the type of work they do, where they are at in school, and their preillness lifestyle. Those defi cits that are found on standardized assessment are oftentimes mild in nature. Nevertheless, they commonly impede individuals functioning atme, at work, or in school.

Disease-Related Defi cits

Cognitive defi cits may arise prior to or in the absence of treatment. These disease-related defi cits include the effects of primary and metastatic tumors of the CNS, the development of paraneoplastic syndromes, and infl ammatory and autoimmune responses.

Primary and Metastatic CNS Lesions

A tumor is a mass of new tissue that persists and grows independently of its surround-ing structures and has no physiological use. They vary in pathological origin as discussed below. The rate of the tumor’s growth varies greatly depending on the type of cell from which it grows. They are distinguished as being primary or secondary, or benign or malig-nant. Furthermore, malignancy is divided into low-grade and high-grade. A primary tumor is defi ned as a tumor that arises from substances within the brain itself. A secondary or metastatic tumor is carried through the blood to the nervous system from a primary tumor elsewhere (e.g., lungs or breasts). Brain metastasis actually represents the most common



intracranial tumor (Mehta & Tremont-Lucas, 2004). In reality, with improvements in treat-ment and increased length of survival after diagnosis increases, the risk of metastases to the brain also increases (Carney et al., 1999; Chidel et al., 2000).

When taken together, both primary and secondary tumors, the brain is the second most common site of tumors with the uterus being the fi rst. Brain tumors are most common in early to middle adulthood. The overall incidence is nearly equal for males and females. Benign tumors may be as serious as malignant tumors because the site of the tumor may be inacces-sible to the surgeon without risk to life.

As suggested, an initial means of classifi cation is whether the tumor is primary or sec-ondary, which coincides with its pathological origin. In addition, the area or tissue of invasion suggests underlying physiology. The combination of these factors results in various tumor classes including those discussed below. Tumor locality can be divided into (a) skull, (b) meninges, (c) cranial nerves, (d) supporting tissue, (e) pituitary or pineal body, and (e) con-genital origin. The various tumors are discussed individually for clarity sake.

A tumor may develop as a distinct entity in the brain (encapsulated tumor) and put pressure on the rest of the brain. These are known as cystic tumors because they produce a fl uid-fi lled cavity in the brain, usually lined with the tumor cells. The additional space occu-pied by these tumors compresses the brain, resulting in dysfunction. A second type of tumor is the infi ltrating tumor. These tumors are not clearly marked off from the surrounding tissue. They may destroy normal cells and occupy their place or they may surround existing cells and interfere with normal functioning.

The gliomas are likely the most discussed tumors, as they constitute the greatest portion of primary tumors. They arise from glial cells and are classifi ed as low-grade or high-grade. They are further divided as specifi c tumor types. These include astrocytomas, glioblastomas, oligodedrogliomas, medulloblastomas, and ependymomas.

Beyond the gliomas, multitudes of other tumors are important to mention. These include meningiomas, schwannomas, pituitary adenomas, primary CNS lymphoma, and metastatic tumors. Table 1.2 outlines the pathological features associated with these various tumors.

Emerging literature has suggested the potential role of genetics in the manifestation of primary CNS tumors, particularly malignant gliomas. Janus and Yung (2007) reported, to date, the most common alterations along these lines include deletions in chromosome 17p, 9p, 10q, and multiple copies of chromosome 7 across all types; 1p, 9p, 10p, 10q, 11p, 13q, and 17p in relation to astrocytomas; 19q in oligodendrocytes; and 22q in meningiomas.

Functionally, variability is seen in neuropsychological presentation and outcome based on the locality of the tumor(s) (Meyers, 2000, Meyers et al., 2000; Scheibel et al., 1996). While there is a tendency to conceptualize malignant tumors as most devastating from this perspec-tive as well as from a mortality standpoint, benign tumors may be as serious as malignant tumors because the site of the tumor may be inaccessible to the surgeon without risk to life. As noted by Anderson and Ryken (2008), clinical presentation is consistent with a patterning consistent with expanding mass lesioning As the authors note, progressive neurologic defi cit (68%), motor defi cits or weakness (45%), headache (54%), and seizures (36%) are all common features across tumor types. In addition to the sequelae associated the tumor itself, there may be defi cits arise from treatment, including surgical approach and chemotherapeutic and/or radiation therapy in cases of malignancy.

There is no unitary profi le for intracranial brain tumors. Consequently, neuropsycholog-ical features vary. Anderson and Ryken (2008) said it best in noting that such tumors involve the potential for “virtually any neurological or neuropsychological sign.” However, as shown in Table 1.3, there are certain characteristics most commonly seen based on the locality of the tumor. While these features largely adhere to regional activation/localization theory, this is not always the case (Anderson, Damasio, & Tranel, 1990). Sometimes tumors do not produce the symptoms one would expect given their localities (e.g., a left frontal tumor may have only subtle effects on language based on the subtleties in its regional infi ltrate). For example, tumors arising in the third ventricle tend to cause defi cits in manual dexterity, memory, and executive functioning (Friedman et al., 2003). Oftentimes, sensory and motor features can be the fi rst clinical symptoms seen and may serve as the most effective means of localization from



TUMOR TYPE NEUROPATHOLOGY/PATHOPHYSIOLOGY ADDITIONAL DESCRIPTION

Astrocytomas Infi ltrate and invade vital neural systems• Characterized by increased cell number and • nuclear pleomorphism without necrosisMitotic fi gures should not be present• Uniformity of cells closely resembling mature • resting or reactive, nonanaplastic astrocytes

Usually develop slowly• Account for about 40% of• gliomasMost common in adults over 30 • years of ageAt times all the timorous infi ltrates • can be removed which can coin-cide with prognosis

Anaplastic Astrocytoma

Increased cellular and nuclear pleomorphism• Increased cell density• Increased mitoses• Vascular endothelial proliferation•

Pilocytic Astrocytoma

Most commonly found in the cerebellum, • brain stem, thalamus, and optic nerveGelatinous appearance, often well circum-• scribed and can be fully removed if in an acceptable surgical planeHistologically marked by fi brillary astrocytes • and stellate cells, and often Rosenthal fi bers and microsystic changes

Glioblastomas Presents with all of the same features of • astrocytomas and anaplastic astrocytomasGrow far more rapidly• Demonstrates foci of coagulative necrosis• Infi ltrate and migrate along white matter • pathways

Rapidly growing gliomas• They are highly malignant• Represent about 30% of gliomas• Most common in men over 35 • years of ageSometimes considered a malig-• nant form of astrocytomasPrognosis is poor, life expectancy • is short, usually less than one year after surgery

Oligodedroglioma Arise from oligodendrocytes and thus • develop in the white matter of the cerebrumMost commonly present in frontotemporal • regions simply due to the prominence of white matter and thus oligodendrocytes in these areasDemonstrate signifi cant overlap with astrocy-• tomas making differentiation diffi cult at times. When differentiation cannot be made it is termed a oligoastrocytomaTumor cell infi ltration in the cortex is seen in • most casesMany tumors show an artifactual halo around • the nucleusVascular channels are common•

Generally slow growing hemi-• spheric tumorsThe grade may vary from 1 • to 4 with grade 4 being rare. Survival may extend to 15 years Oligodendrogliomas represent about 5% of gliomas

Medulloblastoma The cerebellum is the most common site of • originAppears on macroscopic exam as friable • tumor with central necrosisProposed as arising from the germinal neu-• roepithelium during embrogenesis permitting differentiation into tumor cells with neuronal, glial, or ependymal characteristicsSmall blue cell tumors with little cytoplasm • and pseudorosettas

Highly malignant tumor• Most commonly found in children • and is the most common form of brain tumor in childrenApproximately 80% of all cases • occur during the fi rst 15 years of life and mainly during the fi rst decadeBoys are affected more than girls• They account for about 10% of • gliomas. Survival beyond fi ve years of age ranges between 18% to 38%

TABLE 1.2 Brain Tumor Types

(continued)




Ependymomas Associated with and arise in the cerebral • ventricles from ependymal cells, particularly from the fourth ventricleMarked by pseduorosettas, often located in • the perivascular regionBlepharoplasts are present•

Anaplastic EpendymomasHave increasing features of nuclear atypia, • necrosis, and mitotic fi gures

Myxopapillary EpendymomasUsually confi ned to the fi lum terminale and • have a distinctive fi brillary pattern with mucin secretion

Represent about 10% of gliomas• Slow growing and tend to block • the fourth ventricle, thus prevent-ing the fl ow of CSF resulting in hydrocephalusSuch tumors are usually benign• Ependymomas constitute about • 10% of all intracranial tumors in children with a peak incidence during the fi rst decadeThe 5-year survival rate in chil-• dren with postoperative treatment is about 40%–50%

Meningiomas These are extrinsic tumors which grow from • the arachnoid matterThey irritate the surface and compress the brain• Have a fi rm off-white appearance and are • well demarcated from surrounding tissue as they are extra-axial in positioningDemonstrates a whorled pattern with • calcifi cationsBrain invasion and mitotic activity can be • seen in aggressive tumorsClassifi ed as fi broblastic, syncytial, transi-• tional, and angioblastic

They are the most benign of all • brain tumorsMeningiomas can occur between • the hemispheresWhen surgically removed they • generally will not recur

Schwannomas Sex hormone infl uence has been suggested • due to predominance in femalesMost commonly involve cranial nerves VIII, • V, VII

Tend to be slow growing• Benign• Intervention is not always needed • beyond sequential monitoring of the tumor if individuals are not overly troubled by symptomsOften found incidentally•

Pituitary Adenomas

These are neuroepithelial tumors of the • pituitary regionAppear acophilic, basophilic, or chromopho-• bic on stainingVary in whether they secrete hormones•

A variety of problems arise with • respect to growth characteristics of these tumors, including obe-sity, hairiness of the face, and amenorrhoeaIf they develop before puberty, the • child may demonstrate gigantisismThey can also cause acromegaly • after pubertyThese tumors are treatable and • can be removedDevelop in a stepwise fashion•

Primary CNS Lymphomas

Mass lesion presenting in the periventricular • white matterDiffuse histological activity, even in tissues • appearing normal macroscopicallyMechanisms of transformation largely unknown • given there are no lymphatics in the CNSConsidered a non-Hodgkins Lymphoma, of B • cell origin, which is perplexing as these cells are not usually present in the CNSAggregate near blood vessels• Stain positive for appropriate immunohisto-• logical B cell or T cell markers

Commonly associated with • immunocompromise or immunosuppression

TABLE 1.2 Brain Tumor Types (continued)

(continued)



pure functional assessment (not that this is needed per se given imaging techniques). It should be noted that the neurological and neuropsychogical impairment resulting from metastatic lesions is similar to those arising from primary brain tumors (Hirsch et al., 1982).

Symptoms result from regional infi ltration of the tumor, mass effect, and increased intrac-ranial pressure caused by growth of the tumor and blockage of the fl ow of CSF through the ventricles. In some cases, the tumor presses upon or destroys parts of the brain, which produces effects which become gradually worse as the tumor grows. Consequently, common symptoms of intracranial tumors include headaches, especially after lying fl at, increased by coughing or stooping; vomiting, this usually occurs at the peak of the headache; diplopia; blurred vision when moving the head; slowing of the pulse; increased drowsiness which progresses to coma; dilation of the pupils which fail to react to light; and papilledema. Convulsive seizures, focal or general-ized, occur with cerebral hemisphere tumors and may precede other symptoms by months or years. They are most common with meningiomas and the slow growing astrocytomas.

In many instances, cognitive features are seen later as unrecognized tumors continue to grow and become more infi ltrating, potentially causing mass effect. Yet, interestingly, subtle changes in cognition can be predictive of recurrence and/or tumor growth prior to it even being recognized on imaging (Armstrong et al., 2003; Meyers & Hess, 2003).

Cognitive issues have likely been historically underreported as neurologists and neuro-surgeons who primarily serve these patients do not regularly seek neuropsychological consul-tation, relying on traditional mental status checks such as the MMSE. Emerging literature has demonstrated the relative insensitivity of such measures and practices to identifying cognitive defi cits in tumors due to a low ceiling effect (Pahlson, Elk, Ahlstronm & Smits, 2003). Newer data suggests that nonspecifi c neurocognitive defi cits present in upward of 90% of patients (Tucha et al., 2000) with nondominant hemisphere lesions constituting the majority of cases that do not present with cognitive defi cits (Hahn et al., 2003). Approximately 91% of patients with primary brain tumors will present with at least one area of cognitive dysfunction at baseline and roughly 70% will present with at least three areas of dysfunction (Tucha et al., 2000). The frequency of cognitive defi cits emphasizes the role of neuropsychological assessment in the care of patients. In fact, neuropsychological assessment in some ways is more powerful then neuroimaging. Meyers and Hess (2003) performed a baseline neuropsychological assessment on 80 patients with recurrent glioblastoma or anaplastic astrocytoma prior to beginning a clini-cal trial for recurrence. They found that 61% of patients who demonstrated measurable change in neurocognition on assessment prior to imaging could demonstrate signifi cant change. In fact, neuropsychological assessment has demonstrated the ability to predict MRI evidence of tumor progression in both low-grade (Armstrong et al., 2003) and high-grade (Meyers, 2000; Meyers & Hess, 2003) gliomas and patients with brain metastases (Meyers et al., 2004).

Beyond defi cits associated with tumors themselves, negative neuropsychological out-comes have also been linked with treatment modalities. In general, those clinical features apparently related to the hemispheric origin of the tumor oftentimes remain even following resection, but sometimes to a lesser extent. Where improvement is seen is in the reduction of mass effect and those residuals related to it (Duffau, 2006). This is in comparison to focal


Metastases Can present throughout the CNS• Associated with cancerous presentations • of different organ sites with breast and lung cancers being the most common preceding cancer presentationsAlso can occur in relation to skin, colorectal, • and renal cancers

The most common intracranial • tumor

Source: Reproduced with Permission from Noggle & Dean (2011); Adapted from Janus & Yung (2007) and Anderson & Ryken (2008).

TABLE 1.2 Brain Tumor Types (continued)



TABLE 1.3 Common Symptoms Based on Tumor Location

TUMOR LOCATION SYMPTOMS

Cerebral hemispheres—frontal lobes Hemiplegia, focal or generalized seizures, and mental • changesExpressive aphasia may be present with tumors present in • the dominate hemispherePrecipitate urination may be associated with a tumor on the • medial surfaceInattention, loss of motivation, and ataxic gait may be • exhibited as the tumor spreads to both lobes

Cerebral hemispheres—parietal lobes Astereognosis and sensory impairment contralaterally• Seizures may be either generalized or focal• Anosognosia, apraxia, and denial of illness may be • presentSpeech disturbances may be associated with a tumor in the • dominant hemisphere

Cerebral hemispheres—temporal lobes Usually show few indications except for seizures• Tumors involving the dominant hemisphere may produce • mixed expressive and receptive aphasia or more pure receptive aphasiaMemory defi cits can occur•

Cerebral hemispheres—occipital lobes Result in contralateral quadrant defect in the visual fi eld• Convulsion may have an aura of fl ashing lights•

Cerebral hemispheres—subcortical Commonly contralateral hemiparesis is present—tumors • which invade the thalamus produce contralateral cutaneous sensory impairmentWith basal ganglia involvement there is sometimes atheto-• sis, bizarre tremors, or dystonic posturing

Pituitary and suprasellar region Headache and visual fi eld defects, usually bitemporal hemi-• anopia, are commonOther endocrinopathies resulting from tumors of this region • were mentioned under pituitary adenomas above

Pineal area Precocious puberty may result, more common in boys• Hydrocephalus and papilledema result from compression of • the aqueduct of SylviusParalysis of upward gaze, ptosis, and loss of pupillary light • and accommodation refl exes result from compression of the pretectumThere may be unilateral or bilateral paralysis of the 5th, 6th, • 7th, and 10th cranial nerves and of lateral gazeHemiplegia, hemianesthesia, ataxia, nystagmus, or intention • tremor may be present

Cranial fossas Symptoms of increased intracranial pressure appear • earlyPosterior fossa tumor has primary signs of ataxia and inten-• tion tremorAnterior fossa can have more cognitive issues similar to • executive dysfunction and poor attentionHemiparesis, language defi cits, and personality changes • may be present

Cerebellopontine fossa Produce tinnitus, unilateral hearing impairment, • and vertigoThere will be loss of corneal refl ex, facial palsy, anathesia, • and signs of cerebellar dysfunction

Source: Reproduced with Permission from Noggle & Dean (2011).



defi cits that present immediately following surgery and recover gradually over the course of 3 to 6 months (Duffau et al., 2003).

Whereas surgery contributes to focal defi cits that are not necessarily new features, but likely a continuation of defi cits owning to the locality of the tumor, radiation and chemo-therapy coincide with more diffuse and potentially new defi cits. Radiation of the brain has been associated with demyelination and small vessel damage, which coincide with a diffuse subcortical pattern of cognitive dysfunction. The most common features include slowed reac-tion time, diminished processing speed, retrieval-based memory defi cits, diminished working memory capacity, slowed or impeded problem solving skills, diminished reading comprehen-sion, reduced initial learning capacity, and varied executive defi cits. Of interest, while some of these features present early on related to the demyelinating effects, some defi cits do not come to light until months after treatment and are related to a diffuse encephalopathy (Armstrong et al., 2002). When it comes to chemotherapy, a similar diffuse pattern may be seen. This has included changes in working memory, executive functions, processing speed, and memory (Ahles & Saykin, 2002; Anderson-Hanley et al., 2003; Ferguson & Ahles, 2003; Tannock et al., 2004). While such defi cits are most commonly noted acutely during chemotherapy (Ahles & Saykin, 2002; Ferguson & Ahles, 2003), some may persist at lesser levels following treatment discontinuation. Research in this area has however been plagued by fl aws in methodology in addition to diffi culties in controlling for confounds. There needs to be recognition that the idea of “chemo-brain” is not necessarily restricted to direct effect. Indirect effects due to fatigue, metabolic changes, and so forth must also be considered.

Paraneoplastic Syndromes and Cytokines

The role of an infl ammatory response has been described in the literature (Lee et al., 2004; Meyers et al., 2005) as has an autoimmune response (Dropcho, 2005). Studies have revealed that even prior to chemotherapy, a greater than expected number of patients present with cog-nitive dysfunction (Meyers et al., 2005; Wagner et al., 2006; Wefel et al., 2004). These responses correspond with the manifestation of paraneoplastic syndromes and the impact of cytokines.

Paraneoplastic syndromes represent a group of disorders that are varied in their func-tional impact and clinical presentation. They may affect all levels of the central and peripheral nervous system. Paraneoplastic syndromes manifest as a result of the immune systems detec-tion and response to a tumor antigen that cross-reacts with similar antigens expressed by the nervous system (Baehering, Quant, & Hochberg, 2007).

It is estimated that paraneoplastic syndromes affect up to 8% of patients with cancer (Baijens &, Manni, 2006). Variability is seen based on the location of the uconerual antigen and thus impact on the system. Based on the clinical features that arise, paraneoplastic syndromes can be divided into four categories: Paraneoplastic Endocrine Syndrome, Paraneoplastic Hematologic Syndromes, Paraneoplastic Dermatologic and Rheumatologic Syndromes, and Paraneoplastic Neurologic Syndromes.

Individual discrepancies in physiology exist amongst the subtypes. As tumor cells invade the lymphatic system, this elicits the noted immune-detection. Baehring and colleagues (2007) note that onconeural antigens are classifi ed by their location, either on the cell surface or intracellular, in addition to their subcellular expression pattern. The underlying mechanism across presentations appears to be a serological immune response, targeting intracellular anti-gens that activate cytotoxic T-cells directed at peptide sequences arising from the intracellular antigen (Yu et al., 2001).

Pathologically, paraneoplastic syndromes can correspond with neuronal loss that is fairly extensive and irreversible in combination with reactive gliosis, perivascular cuffi ng by lymphocytes, and meningeal infi ltrates affecting the limbic system, brain stem, and spinal cord (Baehring et al., 2007). Again, variability is seen based on the syndrome type and its origin. Pelosof and Gerber (2010), in their review, offered a detailed synthesis of the literature in terms of the types of paraneoplastic syndromes that present, their features, pathology, diag-nostic fi ndings, and treatment options that have been adapted in Table 1.4. Paranaeoplastic disorders are discussed throughout the book as they relate to particular neoplastic presenta-tions or functional domains.

(text continues on page 27)



TABLE 1.4 Paraneoplastic Endocrine Syndrome

SYNDROMEPATHOLOGICAL CORRELATES

CLINICAL FEATURES

DIAGNOSTIC FINDINGS TREATMENT

SIADH Small cell lung cancer, mesothe-homa, bladder, ureteral, endo-metrial, prostate, oropharyngeal, thymoma, lym-phoma, Ewing sarcoma, brain, gastrointestinal, breast, adrenal

Gait distur-bance and falls, seizures, headache, nausea, fatigue, muscle cramps, anorexia, confu-sion, lethargy, respiratory depression, coma

Hyponatremia: mild, sodium: 130–134 mEq/L; moderate, sodium: 125–129 mEq/L; severe, sodium: <125 mEq/L

Increased urine osmo-lality (>100 mOsm/kg in the context of euv-olemic hyponatremia)

Restrict fl uids (usually <1,000 TíúJd) and encourage adequate salt and protein intake

Demeclocycline: 300–600 mg, orally twice daily

Conivaptan: 20–40 mg/d IV

Tolvaptan: 10–60 mg/d orally

Hypertonie (3%) saline at <l–2 mL/kg/h

Hypercalcemia Breast, multiple myeloma renal cell, squamous cell cancers (espe-cially lung), lym-phoma (including HTLV-associated lymphoma), ovar-ian endometrial

Altered mental status weak-ness, ataxia, lethargy, hyper-tonia, renal failure, nausea/vomiting, hypertension, bradycardia

Hypercalcemia: mild, calcium: 10.5–11.9 mg/dL; moderate,calcium: 12.0–13.9 mg/dL; severe, calcium: l4.0 mg/dL

Low to normal (<20 pg/mL)

PTH levelElevated PTHrP level

Normal saline: 200–500 mL/h

Furosemide: 20–40 mg IV(use with caution and

onlyafter adequate fl uidresuscitation)Pamidronate:

60–90 mg IVZoledronate: 4 mg IVPrednisone,

40–100 mg/d orally(for lymphoma, myeloma)Calcitonin: 4–8 IU/kg

SC or IMevery 12 hMithramycin: 25 ng/kg IV(often requires multiple

doses)Gallium nitrate:

100–200 mg/mVdIV continuous infusion

for 5 dHemodialysis

Cushing Syndrome

Small cell lung cancer, bronchial carcinoid (neu-roendocrine lung tumors account for 50%–60% of cases of paraneo-plastic Cushing syndrome), thy-moma, medullary thyroid cancer, GI, pancreatic, adrenal, ovarian

Muscle weak-ness, peripheral edema, hyper-tension, weight gain, centripetal fat distribution

Hypokalemia (usu-ally <3.0 mmol/L), elevated baseline serum cortisol (>29.0 ng/dL), normal to ele-vated midnight serum ACTH(>100ng/L) not suppressed with dexamethasone

Ketoconazole: 600–1200 mg/d orally

Octreoüde: 600–1500 mg/d SC

orOctreotide LAR: 20–30

mg IM monthlyAminoglutethimide:

0.5–2 g/d orallyMetyrapone: 1.0 g/d

orallyMitotane: 0.5–8 g/d

orallyEtomidate: 0.3 mg/

kg/h IVMifepristone: 10–20

mg/kg/d orallyAdrenalectomy

(continued)



TABLE 1.4 Paraneoplastic Endocrine Syndrome (continued)


CLINICAL FEATURES


Hypoglycemia Mesothelioma, sar-comas, lung, GI

Sweating, anxiety, tremors, palpitations, hunger, weak-ness, seizures, confusion, coma

For nonislet cell tumorhypoglycemia: low glu-cose, low insulin (often <1.44–3.60 nIU/mL), low C-peptide (often <0.3 ng/mL), elevated IGF-2;IGF-1 ratio (often >10:l) For insulinomas: low glucose, elevated insulin, elevated C-peptide, normal IGF-2:IGF-1 ratio

Glucose (oral and/or parenteral)Dexamethasone: 4 mg 2 or 3 times dailyPrednisone: 10–15 mg/dDiazoxide: 3–8 mg/kg/d orally, divided in 2 or 3 dosesGlucagon infusion: 0.06–0.3 mg/h IVOctreotide: 50–1500 ng/d SCorOctreotide LAR, 20–30 mg IM monthly (often with corticosteroids)Human growth hor-mone: 2 U/d SC (often with corticosteroids)

PARANEOPLASTIC HEMATOLOGIC SYNDROMES


CLINICAL FEATURES


Eosinophilia Hodgkin lymphoma, non-Hodgkin lymphoma (B- and T-cell), chronic myeloid leukemia, acute lymphocytic leukemia, lung, thyroid, GI (pancre-atic, colon, gastric, liver), renal, breast, gynecologic

Dyspnea, wheezing

Hypereosinophilia (>0.5 × lO’/L); elevated serum IL-5, IL-3, IL-2, and GM-CSF

Inhaled corticosteroidsPrednisone: 1 mg/kg/d

orally

Granulocytosis GI, lung, breast, gynecologic, GU, brain, Hodgkin lymphoma, sarcomas

Asymptomatic (no symptoms or signs of leu-kostasis such as neurologic defi cits or dyspnea)

Granulocyte (neutrophil) count >8 × lO’/L, typi-cally without a shift to immature neutro-phil forms; elevated LAP; elevated serum G-CSF

Specifi c treatment not indicated

Pure red cell aplasia

Thymoma, leuke-mia/lymphoma, myelodysplastic syndrome

Dyspnea, pal-lor, fatigue, syncope

Anemia (hematocrit, <20 not uncommon), low/absent reticulo-cytes, bone marrow with nearly absent erythroid precursors, platelet and white blood cell counts in normal ranges

Blood transfusionsPrednisone: 1 mg/kg/d

orally Antithymocyte globulin: 500 mg daily IV (with corti-costeroids and/or cyciophosphamide)

Cyclosporine A: 100 mg orally, twice daily

Cyciophosphamide: 1–3 mg/kg/d orally

(continued)





CLINICAL FEATURES


Rituximab: 375 mg/m IV per dose

Alemtuzumab, 30 mg IV per dose

Plasma exchangeSplenectomy

Thrombocytosis GI, lung, breast, gynecologic lym-phoma, renal cell, prostate mesothe-lioma, glioblastoma, head and neck

Asymptomatic (no bleed-ing or clotting abnormalities)

Elevated platelet count greater than -400 × lO’/L; elevated serumIL-6

Specifi c treatment not indicated

PARANEOPLASTIC DERMATOLOGIC AND RHEUMATOLOGIC SYNDROMES


CLINICAL FEATURES


Acanthosis nigricans

Adenocarcinoma of abdominal organs, especially gastric adenocarcinoma (90% of malignan-cies in patients with acanthosis nigricans are abdominal); gynecologic

Velvety, hyper-pigmented skin (usually on fl exural regions); papillomatous changes involv-ing mucous membranes and mucocutane-ous junctions; rugose changes on palms and dorsal surface of large joints (e.g., tripe palms)

Skin biopsy: histology shows hyperkeratosis and papillomatosis

Topical corticosteroids

Dermatomyositis Ovarian, breast, prostate, lung, colorectal non-Hodgkin lymphoma, nasopharyngeal

Heliotrope rash (violaceous edematous rash on upper eyelids); Gottron papules (scaly papules on bony surfaces); ery-thematous rash on face, neck, chest, back, or shoulders (the last of which is known as shawl sign); rash may be photosen-sitive; proximal muscle weak-ness; swallowing diffi culty; respi-ratory diffi culty; muscle pain

Laboratory fi ndings:elevated serum CK,

AST, ALT, LDH, and aldolase;

EMG: increased spon-taneous activity with fi brillations, complex repetitive discharges, and positive sharp waves;

Muscle biopsy: perivascular

or interfascicularseptal infl ammation andperifascicular atrophy

Prednisone: 80–100 mg/d orally

Methylprednisolone: up to 1 g/d IV

Azathioprine: up to 2.5 mg/kg/d orally

Methotrexate: up to 25 mg/wk orally

Cyclosporine A:100–150 mg orally twice daily

Mycophenolate mofetil: 2 g/d orally

Cyclophosphamide: 0.5–1.0 g/mMV

IVIG, 400–1000 mg/d to total 2–3 g

(continued)





CLINICAL FEATURES


Erythroderma Chronic lympho-cytic leukemia, cutaneous T-cell lymphoma (includ-ing mycosis fungoides), GI (colorectal, gastric esophageai, gallbladder), adult T-cell leukemia/lymphoma,

myeloproliferative disorders

Erythematous, exfoliating, dif-fuse rash (often pruritic)

Skin biopsy: histology shows dense perivas-cular lymphocytic infi ltrate

Topical corticosteroidsNarrow-band UVB

phototherapy

Hypertrophic osteoarthropa-thy

Intrathoracic tumors,

metastases to lung,métastases to bone,nasopharyngeal

carcinoma,rhabdomyosarcoma

Subperiosteal new bone formation on phalangeal shafts (“club-bing”), synovial effusions (mainly large joints), pain, swelling along affected bones and joints

Plain radiography: periosteal reaction along long bones

Nuclear bone scan: intense and symmetric uptake in

long bones

NSAIDsOpiate analgesicsPamidronate: 90 mg IVZoledronate: 4 mg IVLocalized radiation

therapy

Leukocytoclastic vasculitis

Leukemia/lym-phoma, myelodys-plastic syndromes, colon, lung, urologie, multiple myeloma, rhab-domyosarcoma

Ulcération, cyanosis, and pain over affected regions (especially digits); palpable purpura, often over lower extremities; renal impair-ment; peripheral neuropathy

Skin biopsy: histol-ogy shows fi brinoid necrosis, endothelial swelling, leukocy-toclasis, and RBC extravasation

Methylprednisolone: up to 1 g/d IV

Prednisone: 1.0—1.5 mg/kg/d orally

Dapsone: -25–50 mg/d orally

Colchicine: 0.5 mg orally, two or three times daily

Methotrexate: 5–20 mg/wk orally

Azathioprine: 0.5–2.5 mg/kg/d orally

IVIG: 400–1000 mg/d to total 2–3 g

Paraneoplastic pemphigus

Non-Hodgkin lym-phoma, chronic lymphocytic leuke-mia, thymoma,

Castleman disease,follicular dendritic

cell sarcoma

Severe cutane-ous blisters and and erosions (predominantly on trunk, soles, palms); severe mucosal ero-sions including stomatitis

Serum antibodies to epithelia (against plakin proteins and desmogleins)

Skin biopsy: histology shows keratinocyte necrosis, epidermal acantholysis, and IgG and complement deposition in epider-mal and basement membrane zones

orally dailyAzathioprine: -1.5 mg/

kg/d orallyCyclophosphamide:

100–150 mg/d orallyCyclosporine A (target

plasmalevels 100–150 ng/L)IVIG: 400–1000 mg/d

to total 2–3 gMycophenolate mofetil:

1–2 g/d orallyPlasma exchangeRituximab: 375 mg/m’

IV per dose

(continued)





CLINICAL FEATURES


Polymyalgia rheumatic

Leukemia/lym-phoma, myelodys-plastic syndromes, colon, lung, renal, prostate, breast

Limb girdle pain and stiffness

Laboratory fi ndings:elevated serum ESR

(often not as high as in nonparaneoplastic PMR) and CRP

Prednisone: 15 mg/d orally

Methotrexate: 10 mg/wk orally

Sweet syndrome Leukemia (espe-cially AML), non-Hodgkin lymphoma, myelodysplastic syndromes, genito-urinary, breast, GI, multiple myeloma, gynecologic, tes-ticular melanoma

Acute onset of tender erythema-tous nodules, papules, plaques, or pustules on extremities, face, or upper trunk, neutrophilia, fever, malaise

Skin biopsy: histology shows a polymorpho-nuclear cell dermal infi ltrate

Clobetasol propionate: 0.05% topicalTriamcinolone acetonide: 3–10 mg/mL intralesional injection(s)Methylprednisolone: up to 1 g/d IVPrednisone: 30–60 mg/d orallyPotassium iodide: 300 mg orally, 3 times daily (tablets) or 1,050–1,500 mg/d orally of saturatedsolution (Lugol solution)Colchicine: 0.5 mg orally 3 times daily

PARANEOPLASTIC NEUROLOGIC SYNDROMES


CLINICAL FEATURES


Limbic Encephalitis

SCLC (~40%–50% of LE patients), testicular germ-cell (20% of LE patients), breast (8% of LE patients), thy-moma, teratoma,

Hodgkin lymphomaAssociated

antibodies:anti-Hu (typicallywith small celllung cancer),anti-Ma2(typicallytesticular cancer),anti-CRMP5(anü-CV2)anti-amphiphysin

Mood changes,hallucinations,memory loss,seizures, and lesscommonly

hypothalamicsymptoms(hyperthermia,somnolence,

endocrinedysfunction);onset over days

tomonths

EEG: epileptic foci intemporal lobe(s); focalor generalized slowactivityFDG-PET; increasedmetabolism in temporallobe(ss)MRI: hyperintensity inmedial temporal lobe(s)CSF analysis;

pleocytosis,elevated protein,

elevatedIgG, oligoclonal bands

IVIG, 400–1,000 mg/dto total 2–3 gMethylprednisolone,up to 1 g/d IVPrednisone, 1 mg/kgper day orallyPlasma exchangeCyclophosphamide,-2 mg/kg/d orallyRituximab, 375 mg/mIV per dose

(continued)





CLINICAL FEATURES


Paraneoplastic cerebellar degeneration

SCLC,gynecologic.Hodgkin lymphoma.BreastAssociated

antibodies:anti-Yoanti-Huanü-CRMP5(anti-CV2)anti-Maanti-Tranti-Rianü-VGCCanti-mGluRl

Ataxia, diplopia,dysphagia,

dysarthria,prodrome ofdizziness,

nausea,vomiting

FDG-PET, increasedmetabolism (early stage)and then decreasedmetabolism (late stage)in cerebellumMRI. cerebellar atrophy(late stage)

IVIG, 400–1,000 mg/dto total 2–3 gMethylprednisolone:up to 1 g/d IVPlasma exchangeCyclophosphamide:~2 mg/kg/d orallyRituximab: 375 mg/

m^ IVper dose

Lambert-Eaton Syndrome

SCLC (-3% ofpatients have

LEMS),prostate, cervical,lymphomas,adenocarcinomasAssociated

antibodies:anü-VGCC(P/Q type)

Lower extremityproximal muscleweakness,

fatigue,diaphragmaticweakness, bulbarsymptoms

(usuallymilder than in

MG)later in course,autonomie

symptoms(ptosis,

impotence,dry mouth) in mostpatients

EMG; low compoundmuscle action potentialamplitude; décrémentairesponse with low-ratestimulation butincremental responsewith high-ratestimulation

3,4-DAP: maximum of80 mg/d orallyGuanidine: -575 mg/dorally (withpyridostigmine)Pyridostigmine:-240–360 mg/d orally(with guanidine)Prednisolone: 60–100

mgorally every other dayAzathioprine: up to2.5 mg/kg/d orallyIVIG: 400–1,000 mg/dto total 2–3 gPlasma exchange

Myasthenia Gravis

Thymoma(in -15% ofMG patients)Associated

antibodies:anti-AchR

Eatigable weakness

of voluntary muscles

(ocular-bulbar and

limbs), diaphragmatic

weakness

EMG; décrémentairesponse torepetitive nervestimulation

ThymectomyPyridostigmine,-600 mg/d orallyin divided dosesPrednisone,-1 mg/kg/d orallyAzathioprine, up to2.5 mg/kg/d orally(with corticosteroids)Cyclosporine A,-3 mg/kg/d orallyTacrolimus, 3–4 mg/dorallyMycophenolate mofetil,1–3 g/d orallyRituximab, 375 mg/m^IV per doseCyclophosphamide,50 mg/kg/d IV for 4 dPlasma exchangeIVIG, 400–1000 mg/dto total 2–3 g

(continued)





CLINICAL FEATURES


Autonomic neuropathy

SCLC,ThymomaAssociated

antibodies:anti-Huanti-CRMP5(anti-CV2)anti-nAchRanti-amphiphysin

Panautonomic neuropathy:

often subacute onset

(weeks), involvingsympathetic,

parasympa-thetic,

and entericsystems;

orthostatic hypotension;

GI dysfunction;dry eyes/mouth;

bowel/bladder dysfunc-

tion; alteredpupillary light

refl exes; lossof sinus

arrhythmiaCGP:

constipation.nausea/vomiting.dysphagia,

weight loss.abdominal

distention

Abdominal radiography/barium studies/CT: GI dilatation butno mechanicalobstruction (for CGP)Esophagealmanometry:achalasia orspasms (for CGP)

For orthostatiehypotension:Water, salt intakeFludrocortisone:0.1–1.0 mg/d orallyMidodrine: 2.5–10 mgorally 3 times dailyCaffeine: -200 mg/d

orallyFor pseduo-

obstruction:Neostigmine: 2 mg IV

Subacute sensory neuropathy

Lung (-70%-80%), usuallySCLC, breast,ovarian,sarcomasHodgkinLymphomaAssociated

antibodies:anti-Huanti-CRMP5(anti-CV2)anti-amphiphysin

Parasthesias/pain (typically

upper extremities before

lower), followed by ataxia;

multifocal/asymmetric

distribution; all sensory

modalities decreased but

especially deep sensation/

pseudoathetosis of hands;

deep tendon refl exes

decreased/absent; onset

over weeks to months

NCS: reduced/absentsensory nerveaction potentialsCSF analysis:pleocytosis, highIgG, oligoclonalbands

Methylprednisolone:up to 1 g/d IVCyciophosphamide:-3 mg/kg/d orallyIVIG: 400–1,000 mg/d.to total 2–3 gPlasma exchange

Opsoclonus-myoclonus syndrome

Source: Adapted with Permission from Pelosof & Gerber (2010).



As suggested, evidence across cancer types now supports the idea that neurocognitive defi cits may present without direct CNS involvement and prior to any treatment. Findings have been most commonly reported in relation to lung cancer, breast cancer, and hematologi-cal cancer patients (Meyers, Albitar, & Estey, 2005; Meyers, Byrne, & Komaki, 1995; Wefel et al., 2004). This has been associated with the infl uence of cytokines on the system and cognition and the infl uence on cytokines by systemic cancer.

Cytokines represent small proteins released by cells to mediate the interaction between cells and the behavior of cells. They are most commonly associated with the CNS as they have been shown to (a) infl uence synaptic transmission of serotonin and dopamine, (b) modify N-methyl-daspartate, glutamatergic, and c-amino butyric acid ion channels, and (c) activate and maintain infl ammatory cytokine cascades secondary to the infl uence of norepinephrine (Hama et al., 1991; Ransohoff & Benveniste, 1996; Viviani, Gardoni, & Marinovich, 2007; Zalcman et al., 1994). B-cells have also been linked with proinfl amma-tory cytokine secretion, including IL-6, TNF-a (Dalakas, 2006), and IL-12 (Stern, Magram, & Presky, 1996). This cytokine cascade occurs in response to the detection of the cancerous cells. Increases in cytokines, amongst other things, can cause an inhibition of cognitive functioning. Cytokine increases have been associated with problems in defi cits in memory, processing speed, and executive functioning (Meyers et al., 2005; Rachal, Pugh, Fleshner, Watkins, Maier, & Rudy, 2001; Suarez-Krabbe et al., 2005). The impact of cytokines is dis-cussed further throughout this text.

Treatment-Related Defi cits

Advances in the successful treatment of cancer have been achieved largely by an increased aggressiveness of therapy, which now generally combines surgery, radiation, cytotoxic drugs, and immunotherapy. Unfortunately, cancer treatments are not highly specifi c and place normal tissues and organs at risk. The CNS is vulnerable to many types of cancer treat-ments, both systemic and those directed against CNS tumors. In addition, many adjuvant medications necessary for the treatment of medical complications also affect CNS function (e.g., steroids, antiepileptics, immunosuppressive agents, and drugs used for pain, nausea, and infection).

Surgery

Surgical intervention is most often associated with neuropsychological defi cits when the sur-gical approach is directed at the CNS. In this case, the surgical effects largely extend those defi -cits experienced by the patient in relation to the brain tumor itself in a focal manner (Archibald et al., 1994; Levins et al., 2002). As previously noted, those clinical features apparently related to the hemispheric origin of the tumor oftentimes remain even following resection, but are sometimes to a lesser extent. However, tumors arising in areas with a diffi cult surgical approach, or tumors in ‘eloquent cortex’ not amenable to surgery, run increased risk of the surgery, damaging healthy tissue (Laws et al., 2003; Packer et al., 1998). In some instances, sur-gical intervention does improve symptoms, particularly when such intervention reduces mass effect (Duffau, 2006). Much of the impact of tumors on surrounding areas can correspond with the rate of tumor growth, such that slowly growing tumors may present with lesser impair-ments compared with more rapidly growing tumors due to the greater potential for functional displacement associated with the latter (Anderson et al., 1990). This is in comparison to focal defi cits that present immediately following surgery and recover gradually over the course of 3 to 6 months (Duffau et al., 2003). Chapter 11 discusses this in further depth.

Radiation

Radiation has been regularly associated with neurocognitive defi cits and structural changes on imaging, presenting in a dose dependent fashion. In general, effects are minimized if dos-ing does not exceed 2GY. Total dose, does per fraction, total time, volume, host factors, radia-tion quality and adjunctive therapies all infl uence CNS tolerability of radiation. Even when considering these factors, acute and chronic impairments are commonly reported, with some defi cits developing in a latent fashion. Individuals older than 60 years of age are at additional



risk of the neurotoxic effects of cranial irradiation. Defi cits may develop over the course of a few weeks to several years following cranial radiation.

Meyers and colleagues (2000) revealed neurocognitive dysfunction in relation to direct or indirect cranial irradiation. Radiation induced progressive neurocognitive dys-function, dementia, ataxia, and death have all been reported in the literature (DeAngelis, 1994; DeAngelis et al., 1989; Sheline et al., 1980; Sundaresan et al., 1981). In fact, defi cits in attention, memory, information processing, executive functioning, and motor coordination have all been linked with cranial radiation (Archibald et al., 1994; Helfre & Pierga, 1999; Hochberg & Slotnick, 1980; Imperato et al., 1990; Lang et al., 2000; Lieberman et al., 1982; Salander et al., 1995; Scheibel et al., 1996; Surma-Aho et al., Taphoorn et al., 1994). Many of these defi cits have been noted in both pediatric and adult populations (Abayomi et al., 1996; Anderson et al., 2000).

In general, defi cits are most commonly associated with white matter reductions (Roman et al., 1993). The basis for these structural changes however remains debated, with several reported contributors. Research suggests brain radiation leads to increased apoptosis and neu-ronal loss (Nakaya et al., 2005) along with decreased cell proliferation, and a decreased stem/precursor cell differentiation into neurons within the neurogenic region of the hippocampus (Monje et al., 2002; Snyder et al., 2003). Robbins and Zhao (2004) suggest radiation-induced CNS damage results from a combination of acute cell death and an induced intrinsic recov-ery/repair response in the form of specifi c cytokines, and may initiate secondary reactive processes that result in the generation of a persistent oxidative stress and/or chronic infl am-mation. Constine and colleagues (1988) suggested white matter changes were seen in 40% to 50% of patients postcranial irradiation.

Originally, a vascular basis was proposed. Admittedly, along with demyelination, vas-cular abnormalities are the most predominant biological change seen in radiation-induced CNS injury. Radiation-induced vascular changes including blood vessel wall thickening, ves-sel dilation, and endothelial cell nuclear enlargement have all been described (Reinhold et al., 1990; Schultheiss & Stephens, 1992). However, the vascular hypothesis has not bore fruit as white matter necrosis has been reported in the absence of vascular changes (Schultheiss & Stephens, 1992). Rather, a multidimensional model suggests many contributing factors, including the role of and impact on oligodendrocytes, endothelial cells, astrocytes, microglial, and neurogenesis.

Reduced numbers of oligodendrocytes and endothelial cells have been reported as a result of radiation-induced CNS injury (Van der Maazen et al., 1993; Calvo et al., 1988). These reductions have been found to precede necrosis. Reductions of oligodendrocytes may itself be a secondary manifestation as radiation has been found to diminish the reproductive capacity of the O-2A progenitor cells (van der Maazen et al., 1991a, b), which would, in turn, lead to a lack of replacement of oligodendrocytes resulting in demyelination.

While these previous factors may explain acute injury, they do not explain the late radi-ation-induced CNS injury per se. In this case, impeded neurogenesis may serve as a potential explanation. Radiation corresponds with an increased number of microglial, which has an inhibitory effect on neurogenesis (Nakagawa et al., 1996; Rola et al., 2004). This is particularly relevant to the hippocampus. Consequently, radiation induced changes in hippocampal cellu-lar activity, synaptic effi ciency, spike generation, and neuronal gene expression have all been reported (Pellmar & Lepinski, 1993; Surma-aho et al., 2001).

Findings of radiation-induced dysfunction are discussed throughout many of the addi-tional chapters.

Chemotherapy and Biological Modifi ers

Cross-sectional and longitudinal studies of cancer survivors have suggested detrimental effects of chemotherapy on cognitive performance (Ahles et al., 2002; Brezden et al., 2000; Castellon et al., 2004; Shilling et al., 2005). Chemotherapy-related cognitive dysfunction is reported in 15% to 70% of patients (Bender et al., 2006; Shilling et al., 2005; Wefel et al., 2004). These changes are usually subtle with patients often showing mildly reduced functioning in comparison to controls across an array of neurocognitive domains. The general pattern of chemotherapy-induced cognitive defi cits is suggestive of preferential



dysfunction of frontal subcortical networks (Kayl et al., 2006). This has included changes in working memory, executive functions, and processing speed amongst others (Ahles & Saykin, 2002; Ferguson & Ahles, 2003; Tannock et al., 2004). Anderson-Hanley et al. (2003), in their meta-analysis, reported statistically signifi cant defi cits in memory, executive func-tioning, and motor functioning in cancer survivors, post-chemotherapy, when compared to normal controls. While such defi cits are most commonly noted acutely during chemo-therapy, long-term residuals have been reported in 17% to 34% of patients (Ahles & Saykin, 2002; Ferguson & Ahles, 2003). We place emphasis on these studies in particular, as con-founding factors, including psychological status (e.g., depression and anxiety) and physi-cal well-being (e.g., fatigue), were taken into account and controlled for.

Within the pediatric population, similar defi cits have been reported. In addition, Mulhern and Butler (2005) found that pediatric patients who received chemotherapy for ALL presented with defi cits in nonverbal memory, visual-motor integration, visual spatial reasoning, and visual perceptual abilities. Findings of nonverbal memory defi cits had been previously noted by Moleski (2000), who also reported defi cits in attention as a key feature. Defi cits in process-ing speed, working memory, vigilance, and cognitive fl exibility have been reported in ALL survivors (Butler & Copeland, 2002; Langer et al., 2002; Schatz et al., 2000).

Certain factors have been associated with increased risk of chemotherapy-induced neu-rotoxicity. This includes but is not limited to (a) additive or synergistic effects of multimodality therapy that includes administration of chemotherapy either concurrently with or subsequent to cerebral radiation (Sul & DeAngelis, 2006), (b) additive or synergistic effects of multiagent chemotherapy, (c) exposure to higher dosing either due to planned use of high-dose regimens or higher concentrations of the parent drug and/or its metabolite secondary to disrupted systemic clearance and/or pharmacogenetic modulation of drug pharmacokinetics (Shah, 2005), (d) intra-arterial administration with blood–brain barrier disruption, and (e) intrathecal administration (Sul & DeAngelis, 2006; Taphoorn & Klein, 2004).

When defi cits manifest, they have been associated with both direct and indirect causes of chemotherapy. We conceptualize direct causes as actual neurotoxic effects of the chemo-therapeutic agents. In recent years, these effects have been visualized through advanced neu-roimaging. We conceptualize indirect causes as secondary manifestations of chemotherapy, which themselves contribute to neuropsychological dysfunction. This includes but is not lim-ited to fatigue, metabolic changes/abnormalities, anemia, and elevated cytokines related to a pro-infl ammatory response.

Metabolic abnormalities have been associated with the use of chemotherapeutic agents and have also been linked with cognitive defi cits. For example, methotrexate has been asso-ciated with hyperhomocysteinemia, which itself can lead to mineralizing microangiopathy in the white matter and alterations of monoamines such as norepinephrine, amongst other changes, which may contribute to neurocognitive changes and psychiatric manifestations (Haykin et al., 2006; Madhyastha et al., 2002).

Anemia is a very common side effect of chemotherapy, occurring in approximately 80% of patients (Cunningham, 2003). Anemia has been tied directly to cognitive dysfunction and also indirectly as it is strongly associated with fatigue, which also contributes to cognitive defi cits (O’Shaughnessy et al., 2005; Wagner et al., 2005). Anemia also raises the risk for cere-bral hypoxia, which overtime, at sub-threshold levels, can contribute to a slow deterioration of white matter.

Finally, just as increases in cytokines related to a proinfl ammatory response have been observed prior to treatment, as discussed previously, chemotherapeutic agents have also been linked with increases in various cytokines. Carboplatin, etoposide, paclitaxel, and docetaxel have all been associated with such a proinfl ammatory response that is associated with neu-rocognitive defi cits, including defi cits in memory and attention amongst other possible traits (Penson et al., 2000; Pusztai et al., 2004; Tsavaris et al., 2002).

When it comes to the direct physiological impact of chemotherapy, advances in neu-roimaging and other neurodiagnostic technologies have allowed for the neurotoxic effects of chemotherapy to be visualized. The sum of these fi ndings has demonstrated both structural and functional changes in the brain in relation to chemotherapy (Saykin et al., 2003b), with white matter abnormalities representing the most commonly reported trait (e.g., Hook et al.,



1992; Inagaki et al., 2007; Lien et al., 1991; Saykin et al., 2003a,b; Stemmer et al., 1994). Most commonly, this is generalized as reductions in prefrontal regions and adjacent to lateral ven-tricles, though, specifi c abnormalities have been noted in the centrum semiovale and corpus collaosum (Lien et al., 1991), as well as the parahippocampal, cingulated gyrus, and precu-neus regions (Inagaki et al., 2007). To date, studies have been most commonly done within the pediatric and breast cancer populations, though other studies have been undertaken.

Ciesielski and colleagues (1999) found signifi cant volumetric reductions in both the mammillary bodies and prefrontal cortices in a sample of children receiving chemotherapy without radiation therapy, for ALL using MRI morphometry, when compared with healthy controls. This sample was previously evaluated by Lesnik and colleagues (1998) whom at that time, noted smaller volumes in the PFC and cerebellar lobuli VI-VII. In this earlier study, structural changes were associated with defi cits in short-term memory, visuospatial attention, visuomotor integration, and coordination corresponding with this cerebellar-frontal circuitry. Additional studies have also noted MRI abnormalities in relation to chemotherapy for ALL in pediatric samples (e.g., Harila-Saari et al., 1998; Kingma et al., 2001; Reddick et al., 2007). Across these additional studies, not surprisingly, it was demonstrated that combined cerebral radiation greatly increases the neurotoxic effects. Additionally, researchers found that changes related to chemotherapy, and even radiation, are not noted in all children (Harila-Saari et al., 1998; Kingma et al., 2001). This is an idea being increasingly discussed in the adult literature as well, with some suggesting that genetic polymorphisms may explain the susceptibility of some patients compared with others to the neurotoxic effects of chemotherapy (Largillier et al., 2006). Harila-Saari and colleagues (1998) specifi ed that the two children, out of 15, who demonstrated structural changes after receiving chemotherapy alone were born prematurely and that this may be seen as an increased host risk factor.

An interesting fi nding noted by Kingma and colleagues (2001) was that while volumet-ric decreases in white matter and atrophy were observed in select patients, these structural abnormalities were not related to cognitive or academic defi cits. Fliessbach and colleagues (2003) have also reported that while white matter pathology occurs in relation to chemother-apy, it does not necessarily manifest as neurocognitive dysfunction. Again, one might propose that just as one has a genetic susceptibility to displaying structural changes as a result of chemotherapy, there may too be a genetic predisposition for manifesting those changes as cognitive sequelae. However, some have demonstrated a link between structural changes and cognitive defi cits (e.g., Reddick et al., 2006).

Reddick and colleagues (2006) offered good insights into the differential risk for neu-rotoxicity in chemotherapy alone compared with chemotherapy with cerebral radiation. In their study, Reddick and colleagues (2006) examined a large cohort of children treated with chemotherapy alone or combined chemotherapy and radiation for ALL, comparing them to healthy siblings. The researchers found both those with chemotherapy alone and those treated with both chemotherapy and radiation exhibited defi cits on neuropsychological assessment. Comparatively, those receiving radiation in addition to chemotherapy presented with greater impairments. Those receiving chemotherapy alone demonstrated defi cits in attentional func-tioning compared with healthy controls. This group also demonstrated signifi cant volumetric reductions in white matter compared with healthy controls. Those receiving additive radia-tion therapy presented with signifi cantly greater white matter reductions.

Within the adult population, structural abnormalities have still been observed. For example, Saykin et al. (2003a,b), using voxel-based morphometry (VBM) found volumetric reductions of local bilateral neocortical grey matter and cortical and subcotical white matter in several regions. This was noted in a sample of patients who had received chemotherapy for either lymphoma or breast cancer compared with healthy controls. In a later study, Saykin and colleagues (2007) also found reduced brain activation in frontal areas on fMRI during a work-ing memory task in patients who had previously received chemotherapy. Silverman and col-leagues (2007) have also demonstrated functional disruptions related to chemotherapy. Using PET, increased activation in the left inferior frontal gyrus and posterior cerebellum was noted in individuals who had underwent chemotherapy 5 to 10 years previously (Silverman et al., 2007). Related fi ndings were noted by Kreukels and colleagues (2006) using EEG, in which decreased P3 amplitude was noted in chemotherapy survivors compared with controls.



Findings of chemotherapy-related dysfunction are discussed throughout many of the chapters.

Endocrine/Hormone Therapy

Though not as commonly discussed or considered as radiation or chemotherapy, endo-crine/hormonal therapy is frequently used in both the breast cancer and prostate cancer populations. Wefel and colleagues (2004; Chapter 1) have discussed the potential infl uence of hormones and hormonal changes in the development of neurocognitive defi cits within the cancer population. This is due to the relative importance of reproductive hormones in cogni-tive functioning (Bender et al., 2001), with some suggesting their roles in organizing neural systems leading to gender-based, neurological strengths (Maki et al., 2002; Sanders et al., 2002). For example, higher levels of estrogen appear to be benefi cial to the performance on tasks such as verbal fl uency and verbal memory (Maki et al., 2002), whereas higher levels of testosterone appear benefi cial to performance on spatial perception and mental rotation tasks (Sanders et al., 2002). When the system, including the brain, is deprived of these hormones, defi cits arise.

Within the prostate cancer population, research has long demonstrated the role tes-tosterone plays in the development and growth of prostate cancer. Consequently, treatment success has been achieved with androgen deprivation therapy (ADT). While this is effective from an antineoplastic standpoint, negative consequences can be seen. Amongst the potential negative sequelae of ADT lies neurocognitive and psychiatric features. Both depression and anxiety have been associated with ADT (Di Blasio, Hammett, Malcolm, Judge, Womack, et al., 2008).Similarly, defi cits in verbal memory, spatial reasoning, and attention have been associ-ated with ADT (Beer, Bland, Bussiere, Neiss, Wersinger, et al., 2006; Cherrier, Rose, Higano, 2003; Green, Pakenham, Headley, et al., 2004; Herr, O’Sullivan, 2000; Holzbeierlein, Castle, Thrasher, 2004; Salminen, Portin, Koskinen, Helenius, & Nurmi, 2004; Thompson, Shanafelt, Loprinzi, 2003). This is discussed in greater depth in Chapter 2.

Regarding breast cancer population, tamoxifen, which is a selective estrogen receptor modulator, has shown signifi cant benefi t in reducing recurrence and mortality. However, it has also been linked with neurocognitive defi cits. Paganini-Hill and Clark (2000) reported signifi cantly more memory complaints on the part of women using tamoxifen compared with those who did not. In rodent models, memory defi cits have also been shown in relation to tamoxifen use (Chen et al., 2002a,b). This is not that surprising given previous research has demonstrated declines in verbal memory following surgically induced menopause (Verghese et al., 2000). Eberling and colleagues (2004) not only found naming defi cits in relation to the use of tamoxifen but also noted hypometabolism in the inferior and dorsolateral regions of the frontal lobes on PET related to tamoxifen. Chapter 3 discusses this in further depth.

Pharmacological Effects

In addition to the neurotoxic effects of primary cancer therapy, adjuvant medications such as steroids, anticonvulsants, and pain medications may also cause neurocognitive and neurobe-havioral symptoms. The use of glucocorticoids is ubiquitous and is associated with a 5% to 50% incidence of steroid-induced psychiatric syndromes including euphoria, mania, insom-nia, restlessness, and increased motor activity. Glucocorticoids have been implicated in the development of memory dysfunction across a variety of conditions including chronic stress and posttraumatic stress disorder. Certain anticonvulsants (e.g., topiramate, phenobarbital) are also known to have adverse neurocognitive effects. Both seizure frequency and the use of anticonvulsants have been demonstrated to adversely impact neurocognitive function in brain tumor patients. Pharmacologic intervention for symptoms of pain may cause sedation and associated diminution of cognitive function.

The assessment of cognitive dysfunction secondary to cancer treatment is complicated by the use of supportive medications (e.g., steroids, immunosuppressive agents, anticonvul-sants) that can alter cognitive function.

Pharmacologic intervention for symptoms of pain may cause sedation and associated diminution of neurocognitive function. Abnormalities in endocrinologic function secondary



to hypothalamic/pituitary injury are very common following radiotherapy. Thyroid dys-function, loss of libido, and erectile dysfunction are present in a large proportion of patients. Endocrinologic replacement therapy has the potential to improve neurocognitive and neu-robehavioral function in patients who have abnormal hormone levels. Anemia is a side effect of some chemotherapeutic agents/regimens that is associated with both fatigue and neurocognitive problems including decreased attention, processing speed, and memory.

Psychological Status

The word “cancer” itself elicits a cognitive and emotional reaction in many individuals. Within the clinical setting, once patients have a confirmed diagnosis, they may experi-ence a wide range of emotions that are constantly changing as they proceed through their treatment. Depression and anxiety are by far the two most common psychiatric symp-toms experienced within the cancer population, having been associated with the majority of disease sites and ages. As with other medical ailments, the experience of prominent psychological distress in cancer has been linked with poorer outcomes in terms of mortal-ity and morbidity (Litofsky et al., 2004; Spiegel, 1996). Functionally, the negative impact of depression, anxiety, as well as other such features has been extensively described, including within the cancer population (Scheibel et al., 2004). For example, Scheibel and colleagues (2004) not only discuss the relative frequency of depression during chemo-therapy but have also discussed depression’s role in the manifestation and maintenance of neurocognitive deficits. Airaksinen et al. (2004) found that depressed individuals and patients with mixed anxiety and depression demonstrated significant deficits in memory. Consequently, these factors must be considered in clinical evaluations and controlled for in empirical investigations. Chapter 18 discusses psychosocial functioning in cancer in greater depth.

Fatigue

When it comes to functional sequelae of cancer and the various forms of treatment, there is likely no symptom more common than fatigue. As previously suggested, fatigue is a primary residual of anemia and anemia presents in approximately 80% of patients. Hayes and colleagues (2003) have suggested that cancer-related fatigue (CRF) remains the most common and most debilitating side effect experienced by cancer survivors. In one study on older patients (>60 years), fatigue was nearly universal, significantly interfered with functional level, and was related to their level of reported depression (Respini et al., 2003).

McNeely and Courneya (2010) describes CRF as a multifactorial and multidimensional entity arising from biological, psychological, emotional, and/or behavioral factors. CRF is unique in that it is not responsive to increased sleep and can contribute to cognitive decline (Iop et al., 2004; Speck, et al. 2010; Tierney et al., 1991). Consequently, CRF can be quite debili-tating and signifi cantly affect an individual’s functional capacity and overall QOL. While CRF it is most often experienced during active treatment, many patients report CRF as a chronic and pervasive residual (Speck et al., 2010).

CRF has been regularly associated with neuropsychological defi cits across cancer pop-ulations, though it often does not explain such defi cits fully. Further, CRF is associated with most every treatment option for cancer, but is particularly relevant in certain therapeutic options. For example, Malik and colleagues (2001) reported 70% to 100% of patients receiv-ing interferon-alpha will present with marked fatigue. In fact, these authors noted that 10% to 40% of these patients will present with such prominent symptoms that dose reduction is required. When considering neuropsychological status, fatigue must be considered, both in experimental investigations and in clinical evaluations. Interestingly, treatments that have shown promise in improving fatigue have also shown promise in improving cognitive defi -cits and vice versa. In particular, psychostimulants have shown promise both in the treat-ment of CRF and neuropsychological defi cits related to treatment such as “chemo-brain.” CRF is discussed in greater depth in Chapter 22, and potential pharmacological interventions are discussed in Chapter 21.



SUMMARY

Over the past 20 years, antineoplastic treatments have grown by leaps and bounds. As a result, there has been a substantial growth in the number of cancer survivors. With advancements in medical therapies, we have seen an increased interest in the functional impact of cancer and its treatment on individual’s lives. Cognitive dysfunction is an area of growing interest as a majority of patients on active treatment and a fair portion of those posttreatment report cognitive problems. This is in addition to those defi cits experienced prior to treatment, related to either tumors of the CNS or the negative infl uence of infl ammatory/immune responses. Cognitive problems can thus be viewed as arising from direct and indirect features of both the cancer itself and its treatment. These defi cits may range from prominent, focal impairments, to mild yet diffuse problems. In both instances, the effects these symptoms may have on indi-viduals’ daily lives may be profound.

In this chapter, we discussed the common cognitive problems arising from cancer and its treatment and how neuropsychology, as a fi eld, may address these issues both clinically and scientifi cally. In the following chapters, neuropsychological problems are discussed in relation to specifi c cancer types and particular cancer therapies related to those cancer types. The idea is that for professionals to fully appreciate the neuropsychological problems reported or demonstrated by patients, they must have an appreciation and understanding of the road the patient has traveled. Differential risks of neuropsychological problems have been associated with lung cancer versus prostate cancer as an example. Similarly, their meth-ods of treatment vary and are also associated with different neuopsychological problems. One cannot adequately appreciate the subject matter clinically or scientifi cally if they simply lump all cancers and all treatments together. Discussion must be offered on both CNS and non-CNS cancers, and separation, as much as possible, amongst therapies must be offered. This book represents an attempt to discuss the effects of cancer and cancer treatment on cognition in this fashion. As the number of cancer survivors continues to grow, there will be continued growth in the need for services that address aspects of QOL. It is fairly clear that cognitive problems has been and will remain one of the main areas of concern for patients within this mindset.

REFERENCES

Abayomi, O. K. (1996). Pathogenesis of irradiation-induced cognitive dysfunction. Acta Oncologica, 35(6),

659–663.

Ahles, T. A., & Saykin, A. J. (2002). Breast cancer chemotherapy-related cognitive dysfunction. Clin Breast Cancer, 3(3), 84–90.

Ahles, T. A., Saykin, A. J., et al. (2002). Neuropsychological impact of standard-dose systemic chemo-

therapy in long-term survivors of breast cancer and lymphoma. J Clin Oncol, 20(2), 485–493.

Airaksinen, E., Larsson, M., Lundberg, I., et al. (2004). Cognitive functions in depressive disorders:

Evidence from a population-based study. Psychol Med, 34(1), 83–91.

Anderson, S. W., Damasio, H., & Tranel, D. (1990). Neuropsychological profi les associated with lesions

caused by tumor or stroke. Arch Neurol, 47, 397–405

Anderson, V. A., Godber, T., Smibert, E., Weiskop, S., & Ekert, H. (2000). Cognitive and academic outcome

following cranial irradiation and chemotherapy in children: a longitudinal study. British Journal of Cancer, 82(2), 255–262.

Anderson, S. W., & Ryken, T. C. (2008). Intracranial tumors. In J. E. Morgan & J. H. Ricker (Eds.) Textbook of clinical neuropsychology (pp. 578–587). New York, NY: Taylor & Francis.

Anderson-Hanley, C., Sherman, M. L., Riggs, R., et al. (2003). Neuropsychological effects of treatments for

adults with cancer: A meta-analysis and review of the literature. J Int Neuropsychol Soc, 9, 967–982.

Archibald, Y. M, Lunn, D., Ruttan, L. A., et al. (1994). Cognitive functioning in long-term survivors of

high grade glioma. J Neurosurg, 80, 247–253.

Armstrong, C. L., Goldstein, B., Shera, D., et al. (2003). The predictive value of longitudinal neuropsycho-

logic assessment in the early detection of brain tumor recurrence. Cancer, 97, 649–656.



Armstrong, C. L., Hunter, J. V., Ledakis, G. E., et al. (2002). Late cognitive and radiographic changes

related to radiotherapy: Initial prospective fi ndings. Neurology, 59, 40–48.

Baehring, J. M., Quant, E., & Hochberg, F. H. (2007). Metastatic neoplasms and paraneoplastic syndromes.

In C. Goetz (Ed.), Textbook of clinical neurology (3rd ed., pp. 1081–1102). Philadelphia, PA: Saunders

Elsevier.

Baijens, L. W., & Manni, J. J. (2006). Paraneoplastic syndromes in patients with primary malignancies of the

head and neck: Four cases and a review of the literature. Eur Arch Otorhinolaryngol, 263, 32–36.

Beer, T. M., Bland, L. B., Bussiere, J. R., Neiss, M. B., Wersinger, E. M., Garzotto, M., Ryan, C. W., Janowsky,

J. S. (2006). Testosterone loss and estradiol administration modify memory in men. The Journal of Urology, 175(1), 130–135.

Bender, C. M., Paraska, K. K., Sereika, S. M., Ryan, C. M., & Berga, S. L. (2001). Cognitive function and

reproductive hormones in adjuvant therapy for breast cancer: a critical review. Journal of Pain and Symptom Management, 21(5), 407–424.

Bender, C. M., Sereika, S. M., Berga, S. L., Vogel, V. G., Brufsky, A. M., Paraska, K. K., & Ryan, C. M. (2006).

Cognitive impairment associated with adjuvant therapy in breast cancer. Psycho-Oncology, 15(5),

422–430.

Benjamin, L. (1997). A history of psychology: Original sources and contemporary research (2nd ed.). New York,

NY: McGraw-Hill.

Brezden, C. B., Phillips, K. A., Abdolell M, et al. (2000). Cognitive function in breast cancer patients receiv-

ing adjuvant chemotherapy. J Clin Oncol, 18, 2695–2701.

Butler, R. W., & Copeland, D. R. (2002). Attentional processes and their remediation in children treated

for cancer: A literature review and the development of a therapeutic approach. J Int Neuropsychol Soc, 8, 115–124.

Calvo, W., Hopewell, J. W., Reinhold, H. S., & Yeung, T. K. (1988). Time- and dose-related changes in the

white matter of the rat brain after single doses of X rays. The British Journal of Radiology, 61(731),

1043–1052.

Carney, D. N. (1999). Prophylactic cranial irradiation and small-cell lung cancer [editorial; comment].

New Engl J Med, 341, 524–526.

Castellon, S. A., Ganz, P. A., Bower, J. E., Petersen, L., Abraham, L., & Greendale, G. A. (2004).

Neurocognitive performance in breast cancer survivors exposed to adjuvant chemotherapy and

tamoxifen. Journal of Clinical and Experimental Neuropsychology, 26(7), 955–969.

Chen, D., Wu, C. F., Shi, B., & Xu, Y. M. (2002a). Tamoxifen and toremifene cause impairment of learning

and memory function in mice. Pharmacology, Biochemistry, and Behavior, 71(1–2), 269–276.

Chen, D., Wu, C. F., Shi, B., & Xu, Y. M. (2002b). Tamoxifen and toremifene impair retrieval, but not acqui-

sition, of spatial information processing in mice. Pharmacology, Biochemistry, and Behavior, 72(1–2),

417–421.

Cherrier, M. M., Rose, A. L., Higano, C. (2003). The effects of combined androgen blockade on cogni-

tive function during the fi rst cycle of intermittent androgen suppression in patients with prostate

cancer. The Journal of Urology, 170(5), 1808–1811.

Chidel, M. A., Suh, J. H., Barnett, G. H. (2000). Brain metastases: presentation, evaluation, and manage-

ment. Clevel Clin J Med, 67, 120–127.

Ciesielski, K. T., Lesnik, P. G., Benzel, E. C., Hart, B. L., & Sanders, J. A. (1999). MRI morphometry of

mamillary bodies, caudate nuclei, and prefrontal cortices after chemotherapy for childhood leuke-

mia: multivariate models of early and late developing memory subsystems. Behavioral Neuroscience,

113(3), 439–450.

Constine, L. S., Konski, A., Ekholm, S., McDonald, S., & Rubin, P. (1988). Adverse effects of brain irra-

diation correlated with MR and CT imaging. International Journal of Radiation Oncology, Biology, Physics, 15(2), 319–330.

Crosson, B., Bacon Moore, A., Gopinath, K., White, K. D., Wierenga, C. E., Gaiefsky, M. E., (2005)

Cunningham, R. S. (2003). Anemia in the oncology patient: cognitive function and cancer. Cancer Nurs, 26, 38S-42S.

Dalakas, M. C. (2006). B cells in the pathophysiology of autoimmune neurological disorders: a credible

therapeutic target. Pharmacology & Therapeutics, 112(1), 57–70.



DeAngelis, L. M. (1994). Management of brain metastases. Cancer Invest, 12, 156–165.

DeAngelis, L. M., Delattre, J. Y., Posner, J. B. (1989). Radiation-induced dementia in patients cured of

brain metastases. Neurology, 39, 789–796.

DiBlasio, C. J., Hammett, J., Malcolm, J. B., Judge, B. A., Womack, J. H., Kincade, M. C., . . . Derweesh, I.

H. (2008). Prevalence and predictive factors for the development of de novo psychiatric illness

in patients receiving androgen deprivation therapy for prostate cancer. The Canadian Journal of Urology, 15(5), 4249–56; discussion 4256.

Dropcho, E. J. (2005). Immunotherapy for paraneoplastic neurological disorders. Expert Opinion on Biological Therapy, 5(10), 1339–1348.

Duffau, H. (2006). New concepts in surgery of WHO grade II glioma: Functional brain mapping, connec-

tionism and plasticity review. Journal of Neurooncology, 79, 77–115.

Duffau, H, H., Capelle, L., Denvil, D. et al., (2003). Functional recovery after surgical resection of low

grade gliomaa in eloquent brain: Hypothesis of brain compensation. Journal of Neurology,

Neurossurgery, and Psychiatry, 74(7), 901–907.

Eberling, J. L., Wu, C., Tong-Turnbeaugh, R., & Jagust, W. J. (2004). Estrogen- and tamoxifen-associated

effects on brain structure and function. NeuroImage, 21(1), 364–371.

Fabrizio, K. R., Peck, K. K., Soltysik, D., Milstead, C., Briggs, R. W., Conway, T. W., & Rothi, L. J. G. (2005).

Role of the right and left hemispheres in recovery of function during treatment of intention in

aphasia. Journal of Cognitive Neuroscience, 17, 392–406.

Ferguson, R. J. & Ahles, T. A. (2003). Low neuropsychologic performance among adult cancer survivors

treated with chemotherapy. Current Neurology and Neuroscience Reports, 3, 215–222.

Filley, C. M.(2001). Neurobehavioral Anatomy (2nd Edition). University Press: Boulder,CO.

Finger, S. (1994a). Origins of Neuroscience: A history of Explorations into Brain Function.Oxford University

Press: New York.

Finger, S. (1994b). History of Neuropsychology. In Zaidel, D. (Eds.) Neuropsychology.Academic Press: San

Diego.

Fliessbach K, Urbach H, Helmstaedter C, et al. (2003). Cognitive performance and magnetic resonance

imaging fi ndings after high-dose systemic and intraventricular chemotherapy for primary central

nervous system lymphoma. Arch Neurol, 60, 563–568.

Friedman, M. A., Meyers, C. A., & Sawaya, R. (2003). Neuropsychological effects of third ventricle tumor

surgery. Neurosurgery, 52(4), 791–8; discussion 798.

Golden, C. J., Purisch, A. D., & Hammeke, T. A. (1985). Luria-Nebraska Neuropsychological Battery Forms I and II (Manual). Los Angeles: Western Psychological Services.

Gouvier, W., Ryan, L., O’Jile, J., Parks-Levy, J., Webster, J., & Blanton, P. (1997). Cognitive Retraining with

Brain-Damaged Patients. In Horton, A., Wedding, D., &Websterm, J. (Eds.). The Neuropsychology Handbook, Volume 2. Springer Publishing Company: New York.

Green, H. J., Pakenham, K. I., Headley, B. C., Yaxley, J., Nicol, D. L., Mactaggart, P. N., Swanson, Watson,

C. E., Gardiner, R. A. (2004). Quality of life compared during pharmacological treatments and clin-

ical monitoring for non-localized prostate cancer: a randomized controlled trial. BJU International, 93(7), 975–979.

Hahn, C. A., Dunn, R. H., Logue, P. E. et al., (2003). Prospective study of neuropsychologic testing and

quality of life assessment of adults with primary malignant brain tumors. International Journal of

Radiat Oncol Biol Phys, 55, 992–999

Hama, T., Kushima, Y., Miyamoto, M., Kubota, M., Takei, N., & Hatanaka, H. (1991). Interleukin-6

improves the survival of mesencephalic catecholaminergic and septal cholinergic neurons from

postnatal, two-week-old rats in cultures. Neuroscience, 40(2), 445–452.

Harila-Saari, A. H., Paakko, E. L., Vainionpaa, L. K., Pyhtinen, J., & Lanning, B. M. (1998). A longitudinal

magnetic resonance imaging study of the brain in survivors in childhood acute lymphoblastic

leukemia. Cancer, 83(12), 2608–2617.

Harris, L. (1999). Early theory and research on hemispheric specialization. Schizophrenia Bulletin, 35.

11–39

Haykin, M. E., Gorman M, van Hoff J, et al. (2006). Diffusion-weighted MRI correlates of subacute meth-

otrexate-related neurotoxicity. J Neurooncol, 76, 153–157.



Helfre S, Pierga J (1999). Cerebral metastases: radiotherapy and chemotherapy. Neuro-Chirurgie 45(5),

382–392.

Herr, H. W., & O’Sullivan, M. (2000). Quality of life of asymptomatic men with nonmetastatic prostate

cancer on androgen deprivation therapy. The Journal of Urology, 163(6), 1743–1746.

Hewitt M, Greenfi eld S, Stovall E (eds.) (2006). From Cancer Patient to Cancer Survivor: Lost in Transition.

Washington DC: National Academies Press.

Hirsch, F. R., Paulson, O. B., Hansen, H. H., et al. (1982). Intracranial metastases in small cell carcinoma of

the lung: correlation of clinical and autopsy fi ndings. Cancer, 50, 2433–2437.

Hochberg, F. H., Slotnick B (1980). Neuropsychologic impairment in astrocytoma survivors. Neurology, 30, 172–177.

Holzbeierlein, J. M., Castle, E., & Thrasher, J. B. (2004). Complications of androgen deprivation therapy:

prevention and treatment. Oncology, 18(3), 303–9; discussion 310, 315, 319.

Hook, C. C., Kimmel, D. W., Kvols, L. K., Scheithauer, B. W., Forsyth, P. A., Rubin, J., . . . Rodriguez, M.

(1992). Multifocal infl ammatory leukoencephalopathy with 5-fl uorouracil and levamisole. Annals of Neurology, 31(3), 262–267.

Imperato, J. P., Paleologos, N. E., Vich, N. A. (1990). Effects of treatment on long-term survivors with

malignant astrocytomas. Ann Neurol, 28, 818–822.

Inagaki, M., Yoshikawa, E., Matsuoka, Y., Sugawara, Y., Nakano, T., Akechi, T., . . . Uchitomi, Y. (2007).

Smaller regional volumes of brain gray and white matter demonstrated in breast cancer survivors

exposed to adjuvant chemotherapy. Cancer, 109(1), 146–156.

Iop, A., Manfredi, A. M., & Bonura, S. (2004). Fatigue in cancer patients receiving chemotherapy: an

analysis of published studies. Annals of Oncology, 15(5), 712–720.

Jacobson, N. S., & Truax, P. (1991). Clinical signifi cance: a statistical approach to defi ning meaningful

change in psychotherapy research. Journal of Consulting and Clinical Psychology, 59(1), 12–19.

Janus, T. J., & Yung, W. F.A. (2007). Primary Neurological Tumors. In, C. G. Goetz (Ed.). Textbook of

Clinical Neurology (3rd Ed.). Saunders Elsevier: Philadelphia (pp.1053–1080).

Kayl, A. E., Wefel, J. S., Meyers, C. A. (2006). Chemotherapy and cognition: effects, potential mechanisms

and management. Am J Ther, 13, 362–369.

Kingma, A., van Dommelen, R. I., Mooyaart, E. L., Wilmink, J. T., Deelman, B. G., & Kamps, W. A. (2001).

Slight cognitive impairment and magnetic resonance imaging abnormalities but normal school

levels in children treated for acute lymphoblastic leukemia with chemotherapy only. The Journal of Pediatrics, 139(3), 413–420.

Korkman, M., Kirk, U., Kemp, S. (1998). NEPSY: A developmental neuropsychological assessment manual. San

Antonio, TX: The Psychological Corporation.

Kreukels, B. P. C., Schagen, S. B., Ridderinkhof, K. R., et al. (2006). Effects of high-dose and conventional-dose

adjuvant chemotherapy in patients with breast cancer; an electro-physiologic study. Clin Breast Cancer, 7, 67–78.

Lang, F. F., Wildrick, D. M., Sawaya R (2000). Metastatic brain tumors. In Bernstein M, Berger, M. S. (eds.).

Neuro-Oncology: The Essentials (pp. 329–337). New York: Thieme Medical Publishers.

Langer T, Martus P, Ottensmeier H, et al. (2002). CNS late-effects after ALL therapy in childhood. Part

III. Neuropsychological performance in long-term survivors of childhood ALL: impairments in

concentration, attention, and memory. Med Pediatr Oncol, 38, 320–328.

Largillier R, Etienne-Grimaldi, M. C., Formento, J. L., et al. (2006). Pharmacogenetics of capecitabine in

advanced breast cancer patients. Clin Cancer Res, 12, 5496–5502.

Laws, E. R., Shaffrey, M. E., Morris A, et al. (2003). Surgical management of intracranial gliomas – does

radical resection improve outcome? Acta Neurochir Suppl, 85, 47–53.

Lee, B. N., Dantzer, R., Langley, K. E., Bennett, G. J., Dougherty, P. M., Dunn, A. J., Meyers, C.

A., . . . Cleeland, C. S. (2004). A cytokine-based neuroimmunologic mechanism of cancer-related

symptoms. Neuroimmunomodulation, 11(5), 279–292.

Lesnik, P. G., Ciesielski, K. T., Hart, B. L., Benzel, E. C., & Sanders, J. A. (1998). Evidence for cerebel-

lar-frontal subsystem changes in children treated with intrathecal chemotherapy for leu-

kemia: enhanced data analysis using an effect size model. Archives of Neurology, 55(12),

1561–1568.



Levin, V. A., Yung, W. K., Bruner, J., Kyritsis, A., Leeds, N., Gleason, M. J., Hess, K. R., . . . Maor, M. H.

(2002). Phase II study of accelerated fractionation radiation therapy with carboplatin followed

by PCV chemotherapy for the treatment of anaplastic gliomas. International Journal of Radiation Oncology, Biology, Physics, 53(1), 58–66.

Lezak, M. D., Howieson, D. B., & Loring, D. W. (2004). Neuropsychological Assessment (4th ed.). New York,

NY: Oxford University Press.

Lieberman, A. N., Foo, S. H., Ransohoff J, et al. (1982). Long term survival among patients with malignant

brain tumors. Neurosurgery, 10, 450–453.

Lien, H. H., Blomlie, V., Saeter, G., Solheim, O., & Fosså, S. D. (1991). Osteogenic sarcoma: MR sig-

nal abnormalities of the brain in asymptomatic patients treated with high-dose methotrexate.

Radiology, 179(2), 547–550.

Litofsky, N. S., Farace E, Anderson F Jr., et al. (2004). Depression in patients with high-grade glioma:

results of the Glioma Outcomes Project. Neurosurgery, 54, 358–366; discussion, 366–367.

Luria, A. R. (1964). Neuropsychology in the local diagnosis of brain injury. Cortex, 1, 3.

Luria, A. R. (1966). Higher cortical functions of man. New York, NY: Basic Books.

Madhyastha S, Somayaji, S. N., Rao, M. S., et al. (2002). Hippocampal brain amines in methotrexate-

induced learning and memory defi cit. Can J Physiol Pharmacol, 80, 1076–1084.

Maki, P. M., Rich, J. B., Rosenbaum, R. S. (2002). Implicit memory varies across the menstrual cycle:

Estrogen effects in young women. Neuropsychologia, 61, 801–806.

Malik, U. R., Makower, D. F., & Wadler, S. (2001). Interferon-mediated fatigue. Cancer, 92(6 Suppl),

1664–1668.

Marcopulos, B. A., Fujii, D., O’Grady, J., Shaver, G., Manley, J., & Aucone, E. (2008). Providing neuropsy-

chological services for persons with schizophrenia: A review of the literature and prescription for

practice. In, J. E. Morgan & J. H. Rickers (Eds.), Textbook of clinical neuropsychology (pp. 743–761).

New York, NY: Taylor & Francis.

May, M. (1968) Introduction in Galen on the Usefulness of the Parts of the Body. Ithaca, NY: Cornell University

Press.

McNeely, M. L., & Courneya, K. S. (2010). Exercise programs for cancer-related fatigue: evidence and

clinical guidelines. J Natl Compr Canc Netw, 8, 945–953.

Mehta, M. P., Tremont-Lukas, I. (2004). Radiosurgery for single and multiple metastases. In R. Sawaya

(Ed.) Intracranial metastases: Current management strategies (pp. 139–164). Malden, MA: Blackwell.

Meyers, C. A., Albitar, M., & Estey, E. (2005). Cognitive impairment, fatigue, and cytokine levels in

patients with acute myelogenous leukemia or myelodysplastic syndrome. Cancer, 104(4), 788–793.

Meyers, C. A., Byrne, K. S., & Komaki, R. (1995). Cognitive defi cits in patients with small cell lung cancer

before and after chemotherapy. Lung Cancer, 12(3), 231–235.

Meyers, C. A., Geara, F., Wong, P. F., & Morrison, W. H. (2000). Neurocognitive effects of therapeutic irra-

diation for base of skull tumors. International Journal of Radiation Oncology, Biology, Physics, 46(1),

51–55.

Meyers, C. A., Hess, K. R., Yung, W. K., & Levin, V. A. (2000). Cognitive function as a predictor of survival

in patients with recurrent malignant glioma. Journal of Clinical Oncology, 18(3), 646–650.

Meyers, C. A. (2000). Quality of life of brain tumor patients. In Bernstein M, Berger, M. S. (Eds.). Neuro-Oncology: The Essentials. New York, NY: Thieme Medical Publishers.

Meyers, C. A., Hess,, K. R. (2003). Multifaceted end points in brain tumor clinical trials: cognitive deterio-

ration precedes MRI progression. Neurooncology, 5, 89–95.

Meyers, C. A., Smith, J. A., Bezjak A, et al. (2004). Neurocognitive function and progression in patients

with brain metastases treated with whole-brain radiation and motexafi n gadolinium: Results of a

randomized phase III trial. J Clin Oncol, 22, 157–165.

Moleski M (2000). Neuropsychological, neuroanatomical and neurophysiological consequences of CNS

chemotherapy for acute lymphoblastic leukemia. Arch Clin Neuropsychol, 15, 603–630.

Monje, M. L., Mizumatsu, S., Fike, J. R., & Palmer, T. D. (2002). Irradiation induces neural precursor-cell

dysfunction. Nature Medicine, 8(9), 955–962.

Monje, M. L., Toda, H., & Palmer, T. D. (2003). Infl ammatory blockade restores adult hippocampal neuro-

genesis. Science, 302(5651), 1760–1765.



Mulhern, R. K., & Butler, R. W. (2005). Neuropsychological late effects. In Brown, R. T. (Ed.). Pediatric hematology/oncology: A biopsychosocial approach. New York, NY: Oxford University Press.

Nakagawa, M., Bellinzona, M., Seilhan, T. M., Gobbel, G. T., Lamborn, K. R., & Fike, J. R. (1996). Microglial

responses after focal radiation-induced injury are affected by alpha-difl uoromethylornithine.

International Journal of Radiation Oncology, Biology, Physics, 36(1), 113–123.

Nakaya, K., Hasegawa, T., Flickinger, J. C., Kondziolka, D. S., Fellows-Mayle, W., & Gobbel, G. T. (2005).

Sensitivity to radiation-induced apoptosis and neuron loss declines rapidly in the postnatal mouse

neocortex. International Journal of Radiation Biology, 81(7), 545–554.

Noggle, C. A., & Dean, R. S. (2011). Brain tumors. In C.A. Noggle, R.S. Dean, & A. M. Horton Jr. (Eds.),

Encyclopedia of neuropsychological disorders (pp. 145–153). New York, NY: Springer.

O’Shaughnessy, J. A., Svetislava, J. V., Holmes, F. A., et al. (2005). Feasibility of quantifying the effects of

epoetin alpha therapy on cognitive function in women with breast cancer undergoing adjuvant or

neoadjuvant chemotherapy. Clin Breast Cancer, 5, 439–446.

Packer, R. J., Miller, D. C., Shaffrey, M. S., et al. (1998). Intracranial neoplasms. In Rosenberg, R. N.,

Pleasure, D. E. (Eds.), Comprehensive neurology (2nd ed.). New York, NY: John Wiley &Sons.

Paganini-Hill, A., & Clark, L. J. (2000). Preliminary assessment of cognitive function in breast cancer

patients treated with tamoxifen. Breast Cancer Research and Treatment, 64(2), 165–176.

Pahlson, A., Elk, L., Ahlstronm, G., & Smits, (2003). Pitfalls in the assessment of disability individuals

with low-grade gliomas. J Neurooncol, 65, 149–158.

Pellmar, T. C., & Lepinski, D. L. (1993). Gamma radiation (5–10 Gy) impairs neuronal function in the

guinea pig hippocampus. Radiation Research, 136(2), 255–261.

Pelosof, L. C. & Gerber, D. E. (2010, September). Paraneoplastic syndromes:An approach to diagnosis and

treatment. Mayo Clin Proc, 85(9), 838–854

Penson, R. T., Kronish K, Duan Z, et al. (2000). Cytokines IL-1beta, IL-2, IL-6, IL-8, MCP-1, GM-CSF and

TNF alpha in patients with epithelial ovarian cancer and their relationship to treatment with pacli-

taxel. Int J Gynecol Cancer, 1, 33–41.

Pusztai L, Mendoza, T. R., Reuben, J. M., et al. (2004). Changes in plasma level of infl ammatory cytokines

in response to paclitaxel chemotherapy. Cytokine, 25, 94–102.

Rachal Pugh, C., Fleshner, M., Watkins, L. R., Maier, S. F., & Rudy, J. W. (2001). The immune system

and memory consolidation: a role for the cytokine IL-1beta. Neuroscience and Biobehavioral Reviews,

25(1), 29–41.

Ransohoff, R. M., & Benveniste, E. (1996). Cytokines and the CNS. New York, NY: CRC Press.

Reddick, W. E., Shan, Z. Y., Glass, J. O., Helton, S., Xiong, X., Wu, S., . . . & Mulhern, R. K. (2006). Smaller

white-matter volumes are associated with larger defi cits in attention and learning among long-

term survivors of acute lymphoblastic leukemia. Cancer, 106(4), 941–949.

Reddick, W. E., Laningham, F. H., Glass, J. O., & Pui, C. H. (2007). Quantitative morphologic evaluation

of magnetic resonance imaging during and after treatment of childhood leukemia. Neuroradiology,

49(11), 889–904.

Reinhold, H. S., Calvo, W., Hopewell, J. W., & van der Berg, A. P. (1990). Development of blood ves-

sel-related radiation damage in the fi mbria of the central nervous system. International Journal of Radiation Oncology, Biology, Physics, 18(1), 37–42.

Respini D, Jacobsen, P. B., Thors C, et al. (2003). The prevalence and correlates of fatigue in older cancer

patients. Crit Rev Oncol Hematol, 47, 273–279.

Robbins, M. E., & Zhao, W. (2004). Chronic oxidative stress and radiation-induced late normal tissue

injury: a review. International Journal of Radiation Biology, 80(4), 251–259.

Robinson, T. M. (1970). Plato’s Psychology. University of Toronto Press: Toronto.

Roman, G. C., Tatemichi, T. K., Erkinjuntti T, et al. (1993). Vascular dementia: diagnostic criteria for

research studies. Report of the NINDS-AIREN International Workshop. Neurology, 43, 250–260.

Roth, R. M., Isquith, P. K., & Gioia, G. A. (2005). Behavior rating inventory of executive functions. Lutz,

FL: PAR, Inc..

Salander, P., Karlsson, T., Bergenheim, T., et al. (1995). Long-term memory defi cits in patients with malig-

nant gliomas. J Neurooncol, 25, 227–238.



Schatz J, Kramer, J. H., Ablin A, et al. (2000). Processing speed, working memory, and IQ: a developmen-

tal model of cognitive defi cits following cranial radiation therapy. Neuropsychology, 14, 189–200.

Scheibel, R. S., Meyers, C. A., & Levin, V. A. (1996). Cognitive dysfunction following surgery for intracere-

bral glioma: infl uence of histopathology, lesion location, and treatment. Journal of Neuro-Oncology, 30(1),

61–69.

Sheline, G. E., Wara, W. M., Smith V (1980). Therapeutic irradiation and brain injury. Int J Radiat Oncol Biol Phy, 6, 1215–1228.

Shilling V, Jenkins V, Morris R, et al. (2005). The effects of adjuvant chemotherapy on cognition in

women with breast cancer - preliminary results of an observational longitudinal study. Breast, 14, 142–150.

Silverman, D. H., Dy, C. J., Castellon, S. A., et al. (2007). Altered frontocortical, cerebellar, and basal gan-

glia activity in adjuvant-treated breast cancer survivors 5–10 years after chemotherapy. Breast Cancer Res Treat, 103(3), 303–311.

Speck, R. M., Courneya, K. S., Mâsse, L. C., Duval S, & Schmitz, K. H. (2010). An update of controlled

physical activity trials in cancer survivors: a systematic review and meta-analysis. J Cancer Surviv, 4(2),87–100.

Spiegel D (1996). Cancer and depression. Br J Psychiatry Suppl, 30, 109–116.

Sundaresan N, Galicich, J. H., Deck, M. D., et al. (1981). Radiation necrosis after treatment of solitary

intracranial metastases. Neurosurgery, 8, 329–333.

Tannock, I. F., Ahles, T. A., et al., (2004). Cognitive impairment associated with chemotherapy for cancer:

Report of a workshop. J Clin Oncol, 22 (11), 2233–2239.

Taphoorn, M. J. B., Schiphorst, C. P., Snoek, J. F., et al. (1994). Cognitive functions and quality of life in

patients with low-grade gliomas: The impact of radiotherapy. Ann Neurol, 36, 48–54.

Tsavaris, N., Kosmas, C., Vadiaka, M., et al. (2002). Immune changes in patients with advanced breast

cancer undergoing chemotherapy with taxanes. Br J Cancer, 87, 21–27.

Tucha, O, Smely, C., Preier, M., & Lange, K. W. (2000). Cognitive defi cits before treatment among patients

with brain tumors. Neurosurgery, 47, 324–333

Wagner, L. I., Sweet, J. J., Desa, J, et al. (2005). Prechemotherapy hemoglobin (Hgb) and cognitive impair-

ment among breast cancer patients. J Clin Oncol, 23, 760S.

Wefel, J. S., Lenzi R, Theriault R, et al. (2004). The cognitive sequelae of standard dose adjuvant chemo-

therapy in women with breast cancer: results of a prospective, randomized, longitudinal trial.

Cancer, 100, 2292–2299.

Zillmer, E. & Spiers, M. (2001). Principles of neuropsychology. Belmont, CA: Wadsworth.


The Neuropsychology of Cancer and Oncology -

Documents

Transcript of The Neuropsychology of Cancer and Oncology -