Neurosurgical Diseases E-Book

• Herausgeber: Thieme Medical Publishers
• Kategorie: Fachliteratur
• Sprache: Englisch

Veröffentlichungsjahr: 2021

Beschreibung

A structured, evidence-based approach to neurosurgical decision-making for brain pathologies

Evidence-based neurosurgery is one of the most important pillars upon which to build decision management pathways. Effective delivery of care involves understanding the natural history of the disease and the evidence behind available treatment options. Neurosurgical Diseases: An Evidence-Based Approach to Guide Practice by esteemed neurosurgeons Leon T. Lai, Cristian Gragnaniello, and expert contributors covers cranial pathologies neurosurgeons commonly encounter in everyday practice.

The book combines a structured approach to evidence-based neurosurgery with expert opinions, analysis of up-to-date clinical data, understanding of patient preferences and values, and firsthand experiences to facilitate translation of evidence into clinical practice. Twenty-seven consistently formatted chapters are each dedicated to a different disease state, including brain tumors, cerebrovascular disease, Cushing's disease, traumatic brain injury, trigeminal neuralgia, and normal pressure hydrocephalus. All chapters include an introduction, current statistics and data, natural history of the pathology, selected papers for further reading, procedural options and outcomes, and recommended treatment protocols from the authors.

Key Features

• Key content summarized in reader-friendly bullets, diagrams, tables, and illustrative figures enhances acquisition of knowledge
• Discussion of new developments including treatment recommendations for primary and metastatic brain tumors
• Statistical data on cerebral aneurysm treatment outcomes and recommendations for treatment
• New protocols for treating head trauma, closed head injuries, and spontaneous intracranial hemorrhage

This essential resource will help neurosurgical residents and junior neurosurgeons make challenging surgical treatment decisions for complex conditions, clearly and concisely and based on the best evidence.

This book includes complimentary access to a digital copy on https://medone.thieme.com.

Leseprobe

Neurosurgical Diseases

An Evidence-Based Approach to Guide Practice

Leon T. Lai, MBBS, PhD, FRACS Associate Professor of Neurological Surgery Department of Surgery Monash University; Head of Cerebrovascular Surgery and Skull Base Neurosurgeon Department of Neurosurgery Monash Health Melbourne, Australia

Cristian Gragnaniello, MD, PhD Assistant Professor of Neurological Surgery Department of Neurological Surgery University of Texas Health Science Center at San Antonio San Antonio, Texas, USA

149 illustrations

ThiemeNew York • Stuttgart • Delhi • Rio de Janeiro

Library of Congress Cataloging-in-Publication Data is available with the publisher.

© 2022 Thieme. All rights reserved.

Thieme Medical Publishers, Inc. 333 Seventh Avenue, 18th Floor, New York, NY 10001, USA +www.thieme.com [phone], [email protected]

Cover design: © Thieme Cover image source: Stamp © konstantant/stock.adobe.com, Head Foreground © Erica Guilane-Nachez/stock.adobe.com, Brain © User Ancheta Wis on en.wikipedia, Public domain, via Wikimedia Commons, Skull © Di Ieva A, Lee JM, Cusimano MD. Handbook of Skull Base Surgery. 1st ed. Thieme; 2016 Typesetting by TNQ Technologies, India

Printed in USA by King Printing Company, Inc.                       5 4 3 2 1

ISBN: 978-1-68420-051-1

Also available as an e-book: eISBN (PDF): 978-1-68420-052-8 eISBN (epub): 978-1-63853-639-0

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This book is dedicated to our patients and their families, who are our greatest clinical teachers.They impart in us the highs and lows of neurosurgery and the importance of humility in everyday practice.

To our mentors, who have poured so much into us and made us see hope.

Leon T. Lai, MBBS, PhD, FRACS

Cristian Gragnaniello, MD, PhD

Contents

Foreword

Preface

Acknowledgments

Contributors

1.Natural History and Management Options of Recurrent Glioblastoma

Benjamin H.M. Hunn and Katharine J. Drummond

1.1Introduction

1.2Selected Papers on the Natural History of Recurrent Glioblastoma

1.3The Natural History of Recurrent Glioblastoma

1.4Selected Papers on the Treatment Outcomes of Recurrent Glioblastoma

1.5Treatment Options for Recurrent Glioblastoma

1.5.1Repeat Surgery

1.5.2Further Radiotherapy

1.5.3Further Chemotherapy

1.6Authors’ Recommendations

2.Natural History and Management Options of Unruptured Brain Arteriovenous Malformation

Michael Kerin Morgan

2.1Introduction

2.2Selected Papers on the Natural History of Unruptured bAVM

2.2.1Comparing Future Risk of ICH for Unruptured bAVM

2.2.2Factors that Impact on the Risk of First ICH

2.2.3The Expected Outcome from bAVM ICH

2.2.4Understanding the Cause for ICH Associated with bAVM

2.3Selected Papers on the Treatment Options for Unruptured Brain AVM

2.4Treatment Options for Unruptured Brain AVM

2.4.1Embolization

2.4.2Radiosurgery

2.4.3Surgery with or without Planned Preoperative Embolization

2.4.4Results of Surgery

2.4.5Combined Treatment

2.4.6Conclusion Regarding Treatment

3.Natural History and Surgical Management of Spontaneous Intracerebral Hemorrhage

Jonathan Rychen and David Bervini

3.1Introduction

3.2Selected Papers on the Natural History of Spontaneous ICHs

3.3Natural History of Spontaneous ICHs

3.4Natural History of Spontaneous Supratentorial ICH

3.5Natural History of Spontaneous Infratentorial ICH

3.6Selected Papers on Surgical Management of Spontaneous ICHs

3.7Surgical Management Options for Spontaneous ICHs

3.8Surgical Management of Spontaneous Supratentorial ICH

3.9Surgical Management of Spontaneous Infratentorial ICH

3.10Surgical Management for Spontaneous ICH Associated with Intraventricular Hemorrhage

3.11Medical Management of Spontaneous ICH

3.12Authors’ Recommendations

3.12.1Medical Management of Spontaneous ICH

3.12.2Management of Supratentorial Hemorrhage

3.12.3Management of Infratentorial Hemorrhage

3.12.4Management of Intraventricular Hemorrhage

4.Natural History and Management Options of Pineal Cyst

Michael J. Mulcahy and Behzad Eftekhar

4.1Introduction

4.2Selected Papers on the Natural History of Pineal Cyst

4.3Natural History

4.4Selected Papers on the Treatment Options for Pineal Cyst

4.5Treatment Options for Pineal Cysts

4.6Authors’ Recommendations

5.Natural History and Management Options of Colloid Cysts

Anthea H. O’Neill, Cristian Gragnaniello, and Leon T. Lai

5.1Introduction

5.2Selected Papers on the Natural History of Colloid Cysts

5.3Natural History of Colloid Cysts

5.4Predicting the Risk of Sudden Death

5.5Selected Papers on the Treatment Outcomes of Colloid Cysts

5.6Treatment Options

5.7Authors’ Recommendations

6.Natural History and Management Options of Vestibular Schwannomas

Jordan Jones, Andrew H. Kaye, and Andrew Morokoff

6.1Introduction

6.2Selected Papers on Natural History

6.3Natural History

6.3.1Rate of Growth

6.3.2Risk Factors for Growth

6.3.3Growth in Neurofibromatosis Type 2 Vestibular Schwannomas

6.4Selected Papers on Treatment

6.5Treatment

6.5.1Microsurgery

6.5.2Stereotactic Radiosurgery

6.5.3Microsurgery and Stereotactic Radiosurgery

6.5.4Neurofibromatosis Type 2

6.6Authors’ Recommendations

7.Natural History and Management Options of Acromegaly

Mendel Castle-Kirszbaum and Tony Goldschlager

7.1Introduction

7.2Pathology

7.3Clinical Signs and Presentation

7.4Imaging

7.5Diagnosis and Follow-up

7.6Selected Papers on the Natural History of Acromegaly

7.7Natural History of Acromegaly

7.8Selected Papers on the Management Options for Acromegaly

7.9Management Options

7.9.1Surgery

7.9.2Stereotactic Radiosurgery

7.9.3Medical Therapy

7.10Authors’ Recommendations

8.Natural History and Management Options for Cushing’s Disease

Benjamin H.M. Hunn and James A.J. King

8.1Introduction

8.2Selected Papers on the Natural History of Cushing’s Disease

8.3The Natural History of Cushing’s Disease

8.4Selected Papers on the Treatment Outcomes of Cushing’s Disease

8.5Treatment of Cushing’s Disease

8.5.1Surgical Resection

8.5.2Radiation Therapy

8.5.3Medical Treatment

8.5.4Recurrent Cushing’s Disease

8.6Authors’ Recommendations

9.Natural History and Management Options of Traumatic Brain Injury

Stephen Honeybul

9.1Introduction

9.2Selected Papers on the Natural History of Traumatic Brain Injury

9.3Natural History of Traumatic Brain Injury

9.4Predicting Outcomes Following Traumatic Brain Injury

9.5Assessment of the Primary Brain Injury

9.6Assessment of Secondary Brain Injury

9.7Selected Papers on the Treatment Outcomes

9.8Treatment Options

9.9Medical Management of Severe Traumatic Brain Injury

9.10Surgical Management of Severe Traumatic Brain Injury

9.11Decompressive Craniectomy Following Severe Traumatic—not Hemicraniectomy Brain Injury

9.12Authors’ Recommendations

10.Natural History and Management Options of Angionegative Subarachnoid Hemorrhage

Jorn Van Der Veken, Aye Aye Gyi, and Amal Abou-Hamden

10.1Introduction

10.2Selected Papers on the Natural History of Angionegative SAH

10.3Natural History

10.4Selected Papers on the Management Options of Angionegative SAH

10.5Treatment Options

10.6Authors’ Recommendations

11.Natural History and Management Options of Low-Grade Glioma

Rebecca J. Limb, Cristian Gragnaniello, and Leon T. Lai

11.1Introduction

11.2Selected Papers on the Natural History of LGG

11.3Natural History of Low-Grade Glioma

11.4Rate of Progression to High-Grade Glioma

11.5Selected Papers on the Treatment Outcomes of LGGs

11.6Treatment Options

11.6.1Surveillance Alone

11.6.2Radical Surgical Resection

11.6.3Radiotherapy

11.6.4Chemotherapy

11.7Prognostication

11.8Authors’ Recommendations

12.Natural History and Management Options of Nonfunctional Pituitary Adenoma

Vincent Dodson, Neil Majmundar, Wayne D. Hsueh, Jean Anderson Eloy, and James K. Liu

12.1Introduction

12.2Selected Papers on the Natural History of NFPAs

12.3Natural History of NFPAs

12.4Selected Papers on the Management Options of NFPAs

12.5Management Options

12.5.1Endocrine Evaluation

12.5.2Ophthalmologic Evaluation

12.5.3Surgery

12.5.4Radiation Therapy

12.5.5Medical Therapy

12.6Authors’ Recommendations

13.Natural History and Management Options of Craniopharyngioma

Harshad R. Purandare and Basant K. Misra

13.1Introduction

13.2Selected Papers on the Natural History of Craniopharyngioma

13.3Natural History of Craniopharyngioma

13.4Selected Papers on the Management of Craniopharyngioma

13.5Treatment Options

13.5.1Surgery

13.6Our Experience

13.7Authors’ Recommendations

14.Natural History and Management Options of Idiopathic Intracranial Hypertension

Kevin Liu and Helen V. Danesh-Meyer

14.1Introduction

14.2Selected Papers on Natural History

14.3Natural History of Idiopathic Intracranial Hypertension

14.3.1Factors Predicting Blindness or Poor Visual Outcome

14.4Selected Papers on Management Options for Idiopathic Intracranial Hypertension

14.5Management Options for Idiopathic Intracranial Hypertension

14.5.1Weight Loss Including Bariatric Surgery

14.5.2Pharmaceutical Treatments

14.5.3Surgical Treatments

14.6Authors’ Recommendations

15.Natural History and Management Options of Chronic Subdural Hematoma

Dana C. Holl, Angelos G. Kolias, Ruben Dammers, and Ivan Timofeev

15.1Introduction

15.2Selected Papers on the Natural History of Chronic Subdural Hematoma

15.3Natural History

15.3.1Inflammation

15.3.2Angiogenesis

15.3.3Hyperfibrinolysis

15.4Selected Papers on the Management of Chronic Subdural Hematoma

15.5Treatment Options

15.5.1Surgical

15.5.2Middle Meningeal Artery Embolization for Chronic Subdural Hematoma

15.5.3Nonsurgical

15.6Authors’ Recommendations

16.Natural History and Management Options of Unruptured Intracranial Aneurysms

Hugo Andrade-Barazarte, Behnam Rezai Jahromi, Felix Goehre, Ajmal Zemmar, Weixing Bai, Zhiyuan Sheng, Guangmin Duan, Zhongcan Cheng, Tianxiao Li, and Juha Hernesniemi

16.1Introduction

16.2Selected Papers on Natural History of UIAs

16.3Natural History of UIAs

16.4Lifelong Rupture Risk of Intracranial Aneurysms Depends on Risk Factors

16.4.1Aneurysm-Related Risk Factors

16.5Serial Imaging Surveillance

16.6Selected Papers on Management Options for UIAs

16.7Management Options for UIAs

16.8Endovascular and Surgical Repair: Outcomes and Obliteration Rates

16.9Authors’ Recommendations

17.Natural History and Management Options of Aneurysmal Subarachnoid Hemorrhage

Michael A. Silva and Nirav J. Patel

17.1Introduction

17.2Selected Papers on the Natural History of Aneurysmal Subarachnoid Hemorrhage

17.3Natural History of Aneurysmal Subarachnoid Hemorrhage

17.3.1Vasospasm

17.3.2Chronic Hydrocephalus

17.3.3Seizure

17.4Selected Papers on the Management Options for Aneurysmal Subarachnoid Hemorrhage

17.5Management Options for Aneurysmal Subarachnoid Hemorrhage

17.5.1Intracranial Pressure Management

17.5.2Seizure Prophylaxis

17.5.3Timing of Treatment

17.5.4Overview of Treatment Modalities

17.5.5Comparing Treatment Modalities

17.5.6Procedural and Periprocedural Complications

17.5.7Rerupture after Treatment

17.6Authors’ Recommendations

18.Natural History and Management Options of Cerebral Cavernous Malformation

Juri Kivelev, Jaakko Rinne, Mika Niemela, and Juha Hernesniemi

18.1Introduction

18.2Selected Papers on the Natural History of Cavernous Malformations

18.3Natural History of Cavernous Malformation

18.3.1Risk of Hemorrhage

18.3.2Risk of Rebleeding

18.3.3Risk of Seizures

18.3.4Associated Vascular Abnormalities

18.4Limitations of Studies on the Natural History of Cavernomas

18.5Selected Papers on the Treatment Outcomes for Cavernous Malformations

18.6Treatment Options for Cavernous Malformations

18.6.1Recommendations for Treatment

18.7Authors’ Recommendations

19.Natural History and Management Options of Skull Base Chordoma

Vinayak Narayan, Fareed Jumah, Bharath Raju, and Anil Nanda

19.1Introduction

19.2Selected Papers on the Natural History of Skull Base Chordoma

19.3Natural History of Skull Base Chordoma

19.4Selected Papers on the Treatment Outcomes of Skull Base Chordoma

19.5Treatment Options and Surgical Outcome

19.6Authors’ Recommendations

20.Natural History and Management Options of Chiari 1 Malformation

Samuel Wreghitt, Bryden H. Dawes, and Augusto Gonzalvo

20.1Introduction

20.1.1CM-1-Associated Syringomyelia

20.1.2Pathophysiology of ChiariMalformation Type1

20.2Selected Papers on the Natural History of Chiari Malformation Type 1

20.3Natural History of Chiari Malformation Type 1

20.3.1Asymptomatic Chiari Malformation Type 1

20.3.2Symptomatic Chiari Malformation Type 1

20.4Selected Papers on the Management Options of Chiari Malformation Type 1

20.4.1Adults

20.4.2Pediatrics

20.5Management Options for Chiari Malformation Type 1

20.6Authors’ Recommendations

21.Natural History and Management Options of Cranial Dural Arteriovenous Fistulas

Hugo Andrade-Barazarte, Felix Goehre, Behnam Rezai Jahromi, Zhao Tongyuan, Jiangyu Xue, Zhongcan Cheng, Ajmal Zemmar, Tianxiao Li, and Juha Hernesniemi

21.1Introduction

21.1.1Pathophysiology

21.1.2Classification

21.1.3Clinical Presentation and Imaging Evaluation

21.2Selected Papers on the Natural History of Cranial Dural Arteriovenous Fistula

21.3Natural History of DAVFs

21.3.1Natural History of Low-Grade DAVFs

21.3.2Natural History of High-Grade DAVFs

21.4Selected Papers on Treatment Outcomes of DAVFs

22.Natural History and Management Options of Cerebral Metastases

Anthea H. O’Neill, Mendel Castle-Kirszbaum, Cristian Gragnaniello, and Leon T. Lai

22.1Introduction

22.2Selected Papers on the Natural History of Cerebral Metastases

22.3Natural History of Cerebral Metastases

22.4Selected Papers on the Treatment Outcomes of Cerebral Metastases

22.5Treatment Options for Cerebral Metastases

22.5.1Supportive

22.5.2Surgery

22.5.3Whole Brain Radiotherapy

22.5.4Stereotactic Radiosurgery

22.5.5Chemotherapy and Novel Agents

22.5.6Treatment Outcomes by PrimaryMalignancy

22.6Authors’ Recommendations

23.Natural History and Management Options of Convexity Meningioma

Chien Yew Kow and Arnold Bok

23.1Introduction

23.2Selected Papers on the Natural History of Convexity Meningioma

23.3Natural History of Incidental Convexity Meningioma

23.3.1Size

23.3.2Growth Rate and Tumor Doubling Time

23.4Risk Factors That Predict Tumor Growth

23.5Recurrence

23.6Selected Papers on the Treatment Options for Convexity Meningioma

23.7Treatment Options for Convexity Meningioma

23.8Observation

23.9Surgery

23.10Radiotherapy

23.11Authors’ Recommendations

24.Natural History and Management Options of Ruptured Brain Arteriovenous Malformation

Darius Tan, Helen Huang, and Leon T. Lai

24.1Introduction

24.2Selected Papers on the Natural History of Ruptured bAVMs

24.3Natural History of Ruptured bAVM

24.4Risk of Recurrent Hemorrhage

24.5Other Factors

24.6Associated Aneurysms

24.7Infratentorial Brain Arteriovenous Malformations

24.8Deep Venous Drainage

24.9Selected Papers on the Treatment of Ruptured bAVMs

24.10Treatment Options for Ruptured bAVM

24.11Surgery

24.11.1Timing of Intervention

24.12Stereotactic Radiosurgery

24.12.1Timing of Radiosurgery

24.13Embolization

24.13.1Role of Embolization

24.13.2Timing of Embolization

24.13.3Outcomes of Embolization

24.14Authors’ Recommendations

25.Natural History and Management Options of Trigeminal Neuralgia

Adrian Praeger, Peter Teddy, Sarah Cain, Andranik Kahramanian, and Bhadrakant Kavar

25.1Introduction

25.2Selected Papers on the Natural History of Trigeminal Neuralgia

25.3Natural History of Trigeminal Neuralgia

25.4Selected Papers on the Treatment of Trigeminal Neuralgia

25.5Treatment Options of Trigeminal Neuralgia

25.5.1Medical Therapy

25.5.2Microvascular Decompression

25.5.3Percutaneous Ablative Procedures

25.5.4Percutaneous Radiofrequency Thermocoagulation

25.5.5Glycerol/Alcohol Injection

25.5.6Balloon Compression

25.5.7Stereotactic Radiosurgery

25.6Trigeminal Neuralgia in Multiple Sclerosis

25.7Authors’ Recommendations

26.Natural History and Management Options of Cerebral Lymphoma

Jordan Elizabeth Cory and Mohammed Awad

26.1Introduction

26.2Diagnosis and Evaluation

26.2.1Imaging

26.3Selected Papers on Natural History of PCNSL

26.4Natural History of PCNSL

26.5AIDS-Associated PCNSL

26.6Selected Papers on Treatment Outcomes of PCNSL

26.7Treatment Outcomes of PCNSL

26.7.1The Role of Steroids Prior to Biopsy

26.7.2Induction Therapy

26.7.3Consolidation Therapy

26.7.4Surgery

26.8Authors’ Recommendations

27.Natural History and Management Options of Normal-Pressure Hydrocephalus

Bob Homapour and Chris Xenos

27.1Introduction

27.2Selected Papers on the Natural History of Idiopathic Normal Pressure Hydrocephalus

27.3Natural History

27.4Selected Papers on the Treatment Options of Idiopathic Normal Pressure Hydrocephalus

27.5Treatment Options

27.6Treatment Outcomes

27.7Authors’ Recommendations

Index

Foreword

Perhaps obvious to most but worth restating, evidencebased neurosurgery is one of the most important pillars upon which to build a decision on management pathways. In no other discipline of medicine is a wrong decision fraught with a greater potential for immediate and catastrophic outcome. A neurosurgeon does not have to think for long before he or she can recall a life lost, a person damaged by deficit or pain, or a family devastated from a neurosurgical procedure performed or withheld. The performance of a procedure can be demonstrated by honest audit and other methods of monitoring competence. This can be judged by the patient, the surgeon, the surgeon’s peers, and other work colleagues. A neurosurgeon should rightly feel proud of a more than competent performance. A good and proud performer of a procedure can influence a patient by body language, attitudes, reputation, and exuding confidence that the recommended decision should be followed. This persuasive influence on patients may be for good or bad. Performance of surgery is just one aspect of a good decision. It is also apt to apply the maxim that it is not only being busy that counts, but also what you are busy about. The best performance without support from evidence is nothing more than charlatan behavior. This was excusable in the early days of the barber surgeon, when so little was known, but inexcusable if good-quality evidence runs contrary to the pathway chosen.

Ascertaining the best evidence is a complex problem. There has been a recent belief that unless there is a randomized controlled trial of significant quality there is no evidence. This is not the real world nor is it even true. Neurosurgery often deals with diseases that do not lend themselves to randomized controlled trials for many reasons: the conditions are often rare; the manifestations may be complex; there are a range of outcomes; innovations of treatment may occur during the trial; the difficulty of randomizing patients with the potential for immediate, permanent, significant consequences; the time scale of measuring results may be too long for most trial designs; multiple treatment options need to be considered; the outcomes are not related to predictable biological performance, such as a medication, but dependent on the uncertainties of teams of people in a social system; and the results may not be able to be applied generally. Then there is the biostatistics, now so complex that close collaboration with a biostatistician is essential to interpret journal articles.

Evidence-based decisions take into account the difficulties in amassing information and take the best evidence available and attempt to extract an honest interpretation that will help guide the decision makers. Leon T. Lai and Cristian Gragnaniello, both from the earliest days in their neurosurgical careers, have pursued expertise in evidencebased neurosurgery. They have put together a book of collaborators, who are experts in their fields, which is a synthesis of the best evidence. This book, made for the practitioner of brain surgery and those involved in management pathways, will give a basis for confidently considering management pathways. In the end, the complex decision, based on best evidence, can be made clearly and concisely.

Michael Kerin Morgan, AO, DSc, MD, MMedEd, MBBS, FRACS Professor of Cerebrovascular Neurosurgery Department of Clinical Medicine Macquarie University Sydney, Australia

Preface

Effective delivery of care involves understanding the natural history of the disease and the evidence behind available treatment options. Although conventional paradigms based on pathophysiology and clinical experience are necessary as premises in evidence-based practice, they alone are inadequate to guide clinical decision making. We live in great times for science, where new information that becomes available continues to expand our insights. Disease management changes rapidly with technological advancement and so does the available evidence in the literature. It becomes imperative, therefore, to know and understand not only the latest treatment modalities but also one that better balances the natural history, risks, and outcomes.

Most published textbooks provide us with broad guidelines and indications on how to treat certain conditions. At times these are based on the confrontation between experts in different techniques, their algorithms, and results. There are limited texts that discuss treatment of conditions affecting the CNS, “contextualizing” the natural history and evidence of the different treatment modalities, to help guide the decision makers.

This book covers cranial pathologies commonly encountered in clinical neurosurgery practice. It aims to provide a structured approach to evidence-based neurosurgery, combined with experts’ opinions and experience to facilitate the translation of evidence into practice. Each chapter follows a uniform format for ease of reading, including an introduction to the topic, the natural history, treatment options, and authors’ recommendation. It integrates clinical expertise and judgment, understanding of patient’s preferences and values, and the best available research evidence to provide a framework for patient care.

We hope that you will enjoy reading this text as much as we enjoyed preparing it.

Leon T. Lai, MBBS, PhD, FRACS Cristian Gragnaniello, MD, PhD

Acknowledgments

We would like to thank Dr. Anthea O’Neill, who provided endless hours of systematic literature research in the preparation of this book.

We are also thankful to our families for their unrelenting patience, understanding, and devotion.

Leon T. Lai, MBBS, PhD, FRACS Cristian Gragnaniello, MD, PhD

Contributors

Amal Abou-Hamden, MBBS, BMedSc (Hons), FRACSSenior Consultant NeurosurgeonDepartment of NeurosurgeryThe Royal Adelaide HospitalAdelaide, Australia;Clinical Associate ProfessorDepartment of SurgeryThe University of AdelaideAdelaide, Australia

Hugo Andrade-Barazarte, MD, PhDAssociate Professor in NeurosurgeryDepartment of NeurosurgeryJuha Hernesniemi International Center for NeurosurgeryHenan People’s Provincial HospitalUniversity of ZhengzhouZhengzhou, China

Mohammed Awad, BSc, MBChB, MPhil, FRCS(SN), FRACSNeurosurgeonDepartment of NeurosurgeryRoyal Melbourne HospitalMelbourne, Victoria, Australia

Weixing Bai, MDInterventional NeurosurgeonDepartment of NeurosurgeryJuha Hernesniemi International Center for NeurosurgeryHenan People’s Provincial HospitalUniversity of ZhengzhouZhengzhou, China

David Bervini, MD, MAdvSurgAttending NeurosurgeonDepartment of NeurosurgeryInselspitalBern University HospitalBern, Switzerland

Arnold Bok, MBChB, MMed, FCSSA, FRACSNeurosurgeonDepartment of NeurosurgeryAuckland City HospitalAuckland, New Zealand

Sarah Cain, MBBS, BSc (Hons)RegistrarDepartment of NeurosurgeryRoyal Melbourne HospitalMelbourne, Victoria, Australia

Mendel Castle-Kirszbaum, MBBS (Hons)RegistrarDepartment of NeurosurgeryMonash HealthMelbourne, Australia

Zhongcan Cheng, MDDepartment of NeurosurgeryJuha Hernesniemi International Center for NeurosurgeryHenan People’s Provincial HospitalUniversity of ZhengzhouZhengzhou, China

Jordan Elizabeth Cory, BSc, MBBS, GradDip Surgical AnatomyRegistrarDepartment of NeurosurgeryRoyal Melbourne HospitalMelbourne, Victoria, Australia

Ruben Dammers, MD, PhDNeurosurgeonDepartment of NeurosurgeryErasmus Medical CentreErasmus MC Stroke CentreRotterdam, The Netherlands

Helen V. Danesh-Meyer, MBChB, MD, FRANZCO, PhDHead of Academic Glaucoma and Neuro-ophthalmology;Sir William and Lady Stevenson Professor of OphthalmologyDepartment of OphthalmologyUniversity of AucklandAuckland, New Zealand

Bryden H. Dawes, MS, FRACSNeurosurgeonDepartment of NeurosurgerySt Vincent’s HospitalMelbourne, Australia

Vincent Dodson, MDResidentDepartment of Neurological SurgeryRutgers New Jersey Medical SchoolNewark, New Jersey, USA

Katharine J. Drummond, AM, MBBS, MD, FRACSDirector of NeurosurgeryDepartment of SurgeryRoyal Melbourne HospitalUniversity of MelbourneParkville, Victoria, Australia

Guangmin Duan, MDNeurosurgeonDepartment of NeurosurgeryJuha Hernesniemi International Center for NeurosurgeryHenan People’s Provincial HospitalUniversity of ZhengzhouZhengzhou, China

Behzad Eftekhar, MD, MPH, FRACS, MAdvSurg, AFRACMAProfessor of NeurosurgeryHead of DepartmentDepartment of NeurosurgeryNepean HospitalThe University of SydneyNew SouthWales, Australia

Jean Anderson Eloy, MD, FACSProfessor of OtolaryngologyDepartment of Otolaryngology – Head and Neck SurgeryRutgers New Jersey Medical SchoolNewark, New Jersey, USA;Center for Skull Base and Pituitary SurgeryNeurological Institute of New JerseyRutgers New Jersey Medical SchoolNewark, New Jersey, USA;Department of Neurological SurgeryRutgers New Jersey Medical SchoolNewark, New Jersey, USA;Department of Otolaryngology and Facial Plastic SurgerySaint Barnabas Medical Center – RWJ Barnabas HealthLivingston, New Jersey, USA

Felix Goehre, MD PhDNeurosurgeonDepartment of NeurosurgeryBG Klinikum Bergmannstrost HalleHalle, Germany

Tony Goldschlager, MBBS, DCH, PhD, FRACSNeurosurgeonDepartment of NeurosurgeryMonash HealthMelbourne, Australia;Associate ProfessorDepartment of SurgeryMonash UniversityMelbourne, Australia

Augusto Gonzalvo, MD, FRACSAssociate Professor of NeurosurgeryDepartment of NeurosurgeryAustin HealthMelbourne, Victoria, Australia;The University of Melbourne,Melbourne, Victoria, Australia

Cristian Gragnaniello, MD, PhDAssistant Professor of Neurological SurgeryDepartment of Neurological SurgeryUniversity of Texas Health Science Center at San AntonioSan Antonio, Texas, USA

Aye Aye Gyi, MPhil, PhDResearch OfficerDepartment of NeurosurgeryThe Royal Adelaide HospitalAdelaide, Australia

Juha Hernesniemi, MD, PhDProfessor of Neurological SurgeryDepartment of NeurosurgeryJuha Hernesniemi International Center for NeurosurgeryHenan People’s Provincial HospitalUniversity of ZhengzhouZhengzhou, China

Dana C. Holl, MScRegistrarDepartment of NeurosurgeryErasmus Medical CenterErasmus MC Stroke CenterRotterdam, The Netherlands

Bob Homapour, FRCS(SN) MScNeurosurgeonDepartment of NeurosurgeryMonash HealthMelbourne, Australia

Stephen Honeybul, FRCS (SN), FRACSConsultant NeurosurgeonStatewide Director of NeurosurgeryWestern Australia;Head of DepartmentDepartment of NeurosurgerySir Charles Gairdner Hospital and Royal Perth HospitalWestern Australia, Australia

Wayne D. Hsuen, MDAssistant ProfessorDepartment of Otolaryngology – Head and Neck SurgeryRutgers New Jersey Medical SchoolNewark, New Jersey, USA;Center for Skull Base and Pituitary SurgeryNeurological Institute of New JerseyRutgers New Jersey Medical SchoolNewark, New Jersey, USA;Department of Otolaryngology and Facial Plastic SurgerySaint Barnabas Medical Center – RWJ Barnabas HealthLivingston, New Jersey, USA

Helen Huang, MBBS (Hons), BMedSc (Hons)RegistrarDepartment of NeurosurgeryMonash HealthMelbourne, Australia

Benjamin H.M. Hunn, MBBS, DPhilRegistrarDepartment of NeurosurgeryRoyal Melbourne HospitalMelbourne, Victoria, Australia

Behnam Rezai Jahromi, MDResidentDepartment of NeurosurgeryHelsinki University Hospital and University of HelsinkiHelsinki, Finland

Jordan JonesRegistrarDepartment of NeurosurgeryRoyal Melbourne HospitalMelbourne, Victoria, Australia;Department of SurgeryUniversity of MelbourneMelbourne, Australia

Fareed Jumah, MDPostdoctoral Research FellowDepartment of NeurosurgeryRutgers-RobertWood Johnson Medical School and University HospitalNew Brunswick, New Jersey, USA

Andranik Kahramanian, MD, MBMSc, BMedSci (Hons I)RegistrarDepartment of NeurosurgeryRoyal Melbourne HospitalMelbourne, Victoria, Australia

Bhadrakant Kavar, MBChB, FCS, FRACSNeurosurgeonDepartment of NeurosurgeryRoyal Melbourne Hospital;Honorary LecturerUniversity of MelbourneMelbourne, Victoria, Australia

Andrew H. Kaye, MBBS, MD, FRACSProfessorDepartment of NeurosurgeryHadassah Hebrew UniversityJerusalem, Israel;Department of SurgeryUniversity of MelbourneMelbourne, Australia

James A.J. King, MBBS, PhD, FRACSConsultant Neurosurgeon, Director of Training, and Head of Pituitary SurgeryDepartment of NeurosurgeryRoyal Melbourne HospitalMelbourne, Victoria, Australia;Department of SurgeryUniversity of MelbourneMelbourne, Australia

Juri Kivelev, MD PhDNeurosurgeonDepartment of NeurosurgeryTurku University HospitalTurku, Finland

Angelos G. Kolias, PhD, FRCSNeurosurgeonDepartment of NeurosurgeryAddenbrooke’s Hospital;Cambridge University Hospitals NHS Foundation TrustNIHR Global Health Research Group on NeurotraumaUniversity of CambridgeCambridge, UK

Chien Yew Kow, MBBSRegistrarDepartment of NeurosurgeryAuckland City HospitalAuckland, New Zealand

Leon T. Lai, MBBS, PhD, FRACSAssociate Professor of Neurological SurgeryDepartment of SurgeryMonash UniversityMelbourne, Australia;Head of Cerebrovascular Surgery and Skull Base NeurosurgeonDepartment of NeurosurgeryMonash HealthMelbourne, Australia

Tianxiao Li, MDDepartment of NeurosurgeryJuha Hernesniemi International Center for NeurosurgeryHenan People’s Provincial HospitalUniversity of ZhengzhouZhengzhou, China

Rebecca J. Limb, BMBS, BMedSciRegistrarDepartment of NeurosurgeryMonash HealthMelbourne, Australia

James K. Liu, MDProfessor of Neurological Surgery;Director, Cerebrovascular/Skull Base & Pituitary Surgery;Co-Director, Endoscopic Skull Base Surgery ProgramNeurological Institute of New JerseyRutgers New Jersey Medical SchoolNewark, New Jersey, USA

Kevin Liu, MBChBNeuro-ophthalmology Clinical Research FellowDepartment of OphthalmologyUniversity of AucklandAuckland, New Zealand

Neil Majmundar, MDChief ResidentDepartment of Neurological SurgeryRutgers New Jersey Medical SchoolNewark, New Jersey, USA

Basant K. Misra, MBBS, MS, MCh, DNB, PDCConsultant Neurosurgeon;Head of the DepartmentDepartment of Neurosurgery & Gamma Knife SurgeryP D Hinduja National Hospital & Medical Research CentreVeer Savarkar Marg, Mumbai, India

Michael Kerin Morgan, AO, DSc, MD, MMedEd, MBBS, FRACSProfessor of Cerebrovascular NeurosurgeryDepartment of Clinical MedicineMacquarie UniversitySydney, New SouthWales, Australia

Andrew Morokoff, MBBS, PhD, FRACSAssociate ProfessorDepartment of NeurosurgeryRoyal Melbourne HospitalMelbourne, Victoria, Australia;Department of SurgeryUniversity of MelbourneMelbourne, Australia

Michael J. Mulcahy, BMed, MSc (Surgical Science), MS (Neurosurgery)RegistrarUniversity of NewcastleAustralia

Anil Nanda, MD, MPH, FACSProfessor and ChairmanDepartment of NeurosurgeryRutgers-RobertWood Johnson Medical School and University HospitalNew Brunswick, New Jersey, USA

Vinayak Narayan, MDFellowDepartment of NeurosurgeryRutgers-RobertWood Johnson Medical School and University HospitalNew Brunswick, New Jersey, USA

Mika Niemela, MD PhDProfessor of Neurological SurgeryDepartment of NeurosurgeryHelsinki University HospitalHelsinki, Finland

Anthea H. O’Neill, MBBS, MPHRegistrarDepartment of NeurosurgeryMonash Medical CentreMelbourne, Australia

Nirav J. Patel, MD, MAAssistant Professor of NeurosurgeryDepartment of NeurosurgeryHarvard Medical School, Brigham and Women’s Hospital,Neurosciences CentreBoston, Massachusetts, USA

Adrian Praeger, MBBS BA Dip. Ant. FRACSNeurosurgeonDepartment of NeurosurgeryMonash HospitalMelbourne, Australia

Harshad R. Purandare, MBBS, MS, MChConsultant NeurosurgeonJupiter HospitalEastern Express HighwayThane, Maharashtra, India

Bharath Raju, MD, MChPostdoctoral Research FellowDepartment of NeurosurgeryRutgers-RobertWood Johnson Medical School and University HospitalNew Brunswick, New Jersey, USA

Jaakko Rinne, MD PhDProfessor of Neurological SurgeryDepartment of NeurosurgeryTurku University HospitalTurku, Finland

Jonathan Rychen, MDAttending NeurosurgeonDepartment of NeurosurgeryUniversity Hospital of BaselBasel, Switzerland

Zhiyuan Sheng, MDResidentDepartment of NeurosurgeryJuha Hernesniemi International Center for NeurosurgeryHenan People’s Provincial HospitalUniversity of ZhengzhouZhengzhou, China

Michael A. Silva, MDNeurosurgeonDepartment of NeurosurgeryUniversity of Miami Miller School of MedicineJackson Memorial HospitalMiami, Florida, USA

Darius Tan, MBBS, MScRegistrarDepartment of NeurosurgeryMonash HealthMelbourne, Australia

Peter Teddy, DPhil, FRACS, FFPMANZCAClinical ProfessorDepartment of NeurosurgeryRoyal Melbourne HospitalUniversity of MelbourneMelbourne, Victoria, Australia

Ivan Timofeev, PhD, FRCSConsultant NeurosurgeonDepartment of NeurosurgeryDepartment of Clinical NeurosciencesUniversity of Cambridge,Cambridge, UK

Zhao Tongyuan, MDJuha Hernesniemi International Center for NeurosurgeryHenan Provincial People’s HospitalUniversity of ZhengzhouZhengzhou, China

Jorn Van Der Veken, MDNeurosurgery FellowDepartment of NeurosurgeryThe Royal Adelaide HospitalAdelaide, Australia

Samuel Wreghitt, MBChBRegistrarDepartment of NeurosurgeryAustin HealthMelbourne, Victoria, Australia

Chris Xenos, FRACSNeurosurgeonDepartment of NeurosurgeryMonash HealthMelbourne, Australia

Jiangyu Xue, MDDepartment of InterventionJuha Hernesniemi International Center for NeurosurgeryHenan Provincial People’s HospitalUniversity of ZhengzhouZhengzhou, China

Ajmal Zemmar, MD, PhDDepartment of NeurosurgeryJuha Hernesniemi International Center for NeurosurgeryHenan People’s Provincial HospitalUniversity of ZhengzhouZhengzhou, China

1 Natural History and Management Options of Recurrent Glioblastoma

Benjamin H.M. Hunn and Katharine J. Drummond

Abstract

Glioblastoma (GBM) is the most common primary brain cancer in adults and carries a dismal prognosis. At first diagnosis, the standard of care for GBM is maximal safe resection, with subsequent radiotherapy and chemotherapy, a regimen that extends survival by months to years. Unfortunately, recurrence is inevitable and occurs, on average, 7.8 months after initial diagnosis. There is no standard of care for the treatment of recurrent disease and median survival is just 6.4 months. Younger patients, those with a higher performance status, and those with less diffuse disease may have extended survival. Delineating true tumor recurrence from “pseudoprogression” is critical. At GBM recurrence, no available salvage treatment has been clearly shown to improve survival. Retrospective analysis of repeat resection suggests improved survival; however, prospective data are lacking. Resection of recurrent GBM may be performed to relieve mass effect, or to gain tissue for further investigations, particularly for clinical trials of targeted agents. Surgery to prolong survival should be performed rarely, in younger patients with good performance status and tumor in a favorable location. Consensus expert opinion suggests that the benefit of reirradiation is higher when there is a greater disease-free interval since initial radiotherapy, and if GBM recurs in a noneloquent location. Stereotactic radiosurgery is also an unproven option for discrete recurrent GBM. No chemotherapy has been demonstrated to improve survival in recurrent GBM, but bevacizumab is frequently used and may control symptoms. Given treatment of recurrent GBM has a poor evidence base with little to commend any specific treatment, clinical trials are encouraged.

Keywords: glioblastoma recurrence surgery systematic review

1.1 Introduction

Glioblastoma (GBM) is a World Health Organization (WHO) grade IV malignant tumor of presumed neuroglial origin and conveys an overall poor prognosis (Fig. 1.1).1 It is the most common primary brain cancer in adults, with an estimated incidence of between 3 and 5 cases per 100,000 person-year.1,​2,​7 GBM may occur de novo (primary), or arise from a lower-grade astrocytoma (secondary). Primary GBM accounts for over 90% of cases and has a slight male preponderance (1.3 times higher) with affected individuals generally older at presentation (mean age: 60 years).2,​3 Secondary GBM are less common and affect younger patients (mean age: 30–50 years) with no clear sex predilection.2,​4,​5,​6

Fig. 1.1 Radiological and histological features of recurrent glioblastoma. (a) Contrast-enhanced T1-weighted axial magnetic resonance imaging (MRI) scan of left posterior temporal glioblastoma at diagnosis. (b) Contrast-enhanced T1-weighted axial MRI scan on the first postoperative day following resection of the tumor. (c) Contrast-enhanced T1-weighted axial MRI scan performed 12 months following initial resection of the tumor showing no recurrence. (d) Contrast-enhanced T1-weighted axial MRI scan performed 21 months following initial resection, demonstrating recurrent left temporal glioblastoma at the margin of the resection. (e) Low-power and (f) high-power hematoxylin and eosin stained photomicrographs of recurrent glioblastoma demonstrating extensive necrosis, pseudopalisading of malignant nuclei and proliferation of endothelial cells. Thanks to Dr. Tewhiti Rogers (Royal Melbourne Hospital) for assistance with photomicrographs.

Mutations in the genes encoding isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) are now used to separate primary from secondary GBM; IDH wild-type tumors are synonymous with primary GBM, whereas IDH mutations signify secondary GBM.9 In general, IDH mutant GBM is associated with longer survival.5 Primary GBM is further characterized by deletions of chromosome 10, amplification of the epidermal growth factor receptor (EGFR) gene, and mutations of the phosphate and tensin homolog (PTEN) tumor suppressor gene.10 Secondary GBM commonly acquires TP53 mutations as part of progression from lower-grade astrocytoma.11 Methylation of the promoter of the deoxyribonucleic acid (DNA) repair gene O6-methylguanine-DNA methyltransferase (MGMT) is a positive prognostic factor in both primary and secondary GBM.12

Since 2005, the mainstay treatment at diagnosis involves maximal safe resection (or biopsy) with concurrent radiotherapy and temozolomide chemotherapy followed by adjuvant temozolomide chemotherapy. Surgery is performed to obtain tissue diagnosis, relieve mass effect, improve vasogenic edema, facilitate tolerance to adjuvant therapy, and provide additional tissue for research and clinical trial inclusion. Complete resection of GBM is difficult because of the inherent infiltrative nature of the disease, and the extent of resection (EOR) largely depends on the proximity of eloquent functional brain tissue. In general, resection of all contrast-enhancing tissue seen on the preoperative magnetic resonance imaging (MRI) is the accepted standard. A meta-analysis of 41,117 GBM patients demonstrated that increased EOR at first operation positively correlated with longer progression-free and overall survival,15 notwithstanding the inherent limitations of selection bias and retrospective data. Some authors have attempted to derive a prognostic threshold for EOR; typically, the best outcomes are seen after 70 to 80% resection.16,​17 One randomized prospective trial demonstrates that survival is correlated with the initial EOR, where 5-aminolevulinic acid was used to guide tumor resection.14

Efficacy of radiotherapy in prolonging survival in GBM is well established. A meta-analysis of six randomized controlled trials demonstrated that radiotherapy reduces risk of death within 1 year by 19%.18 Efficacy of temozolomide chemotherapy primarily comes from the Stupp study, which showed the addition of temozolomide to standard surgery and radiotherapy increased the number of patients surviving 2 years from 10.4 to 26.5%.19 Extended analysis of these patients demonstrated temozolomide increased survival after 5 years from 1.9 to 9.8%.12

GBM recurrence is inevitable, with recurrence within 2 cm of the original tumor margin in 90% of patients.8,​13 The therapeutic approach to recurrent GBM is less well defined. This chapter examined published literature on the natural history of recurrent GBM and available treatment options and recommendations.

1.2 Selected Papers on the Natural History of Recurrent Glioblastoma

●Michaelsen SR, Christensen IJ, Grunnet K, et al. Clinical variables serve as prognostic factors in a model for survival from glioblastoma multiforme: an observational study of a cohort of consecutive non-selected patients from a single institution. BMC Cancer 2013;13(1):402.

●van Linde ME, Brahm CG, de Witt Hamer PC, et al. Treatment outcome of patients with recurrent glioblastoma multiforme: a retrospective multicenter analysis. J Neurooncol 2017;135(1):183–192.

●Bette S, Barz M, Huber T, et al. Retrospective analysis of radiological recurrence patterns in glioblastoma, their prognostic value and association to postoperative infarct volume. Sci Rep 2018;8(1):4561.

1.3 The Natural History of Recurrent Glioblastoma

Recurrent GBM is invariably associated with substantial morbidity and mortality. A summary of studies that examine the natural history of recurrent GBM is provided in Table 1.1 (Fig. 1.2). These data demonstrate that GBM typically recurs within 4 to 14 months of diagnosis, either during or after first-line treatment. If recurrent GBM is untreated, death occurs within 2 to 7 months, although there is likely to be strong selection bias in those studies that suggest that treatment may prolong survival (overall survival: 5.8–14.0 months).

Table 1.1 Summary of studies examining the natural history of recurrent glioblastoma

Study

Study period

Patients

Female (%)

Age (y)

Time to recurrence (mo)

OS all patients (mo)

OS no treatment (mo)

OS salvage treatment (mo)

Kappelle et al

31

1994–1998

63

25.4

46

a

9.8

b

NA

NA

8.3

c

Hau et al

30

1997–2001

168

38.7

55

a

6.0

b

7.5

2.3

8.3

Stupp et al

12

d

2000–2002

287

35.5

56

a

6.9

6.2

NA

6.2

Ciammella et al

28

2007–2012

83

44.6

NA

9.0

b

7.7

2.5

9.5

e

De Bonis et al

29

2002–2008

76

43.4

59

f

NA

7.0

5.0

14.0

g

Michaelsen et al

33

2005–2010

199

35.6

h

59

a,h

8.0

5.9

NA

NA

McNamara et al

32

2004–2011

584

37.8

59

a

7.8

NA

NA

7.1

i

Amini et al

26

2007–2014

60

41.7

57

a

9.5

5.3

b

NA

NA

Socha et al

35

2010–2013

84

45.2

 > 50

j

4.0

3.8

2.3

5.8

Parakh et al

34

2006–2008

194

33.5

61

a,b

7.0

5.0

b

3.0

7.0

Azoulay et al

27

2005–2012

188

37.8

58

a

7.4

6.6

7.0

k

10.3

i,k

van Linde et al

36

2005–2014

299

32.4

58

b,f

14.2

b

6.5

3.1

8.5

Summary (median, range)

2,285

37.8 (25.4–45.2)

58.0 (46.0–61.0)

7.8 (4.0–14.2)

6.4 (3.8–7.7)

3.0 (2.3–7.0)

8.3 (5.8–14.0)

Abbreviations: NA; not available; OS, overall survival following recurrence.

a

Median.

b

Calculated from reported data.

c

Procarbazine, lomustine and vincristine (PCV) chemotherapy as salvage treatment.

d

Radiotherapy and temozolomide cohort.

e

Radiotherapy as salvage treatment.

f

Mean.

g

Surgery and chemotherapy as salvage treatment.

h

Refers to entire study cohort of which 199/225 suffered recurrence.

i

Repeat operation as salvage treatment.

j

Data not given in study; all patients were older than 50 years.

k

Survival for no treatment/salvage subgroups reported as a case/control subset.

The key prognostic factors to consider at tumor recurrence include the following (Fig. 1.2):

●Age: Younger patients have improved survival.33,​36

●Performance status: In general, higher performance status at recurrence predicts improved survival.33,​37,​38,​39,​40

●Extent of disease: Local recurrence is associated with a better prognosis than diffuse disease. Evidences of ventricular contact and ependymal spread are poor prognostic factors.36,​39,​40

●Presence of neurological symptoms: Symptomatic recurrence correlates with a poor prognosis (median survival: 3 months), compared to 10 months for radiologic recurrence.26

●Secondary GBM: In one of the few reports to distinguish between primary and secondary GBM, Da Fonseca et al demonstrated increased survival time in six patients with secondary GBM in their series of 89 GBM patients, although it must be noted that patients with secondary GBM were almost 20 years younger.41 A separate analysis by Mandel et al was underpowered to detect any difference between patients based on IDH status.42 Further research should examine the impact of IDH mutations on the natural history of recurrent GBM.

It is critical to delineate true tumor progression from “pseudoprogression,” which represents treatment response. This determination is important as it will ultimately affect treatment options. Typically, pseudoprogression occurs in the first 12 weeks following completion of chemoradiotherapy, in 15 to 30% of patients.20,​21,​22,​23 Most pseudoprogression (67%) is asymptomatic, whereas most true progression (67%) is symptomatic.20

Fig. 1.2 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) chart demonstrating the systematic search process for the natural history of recurrent glioblastoma.

To guide separation between true progression and pseudoprogression, the Response Assessment in Neuro-Oncology (RANO) criteria were developed (Table 1.2); these supersede the older MacDonald criteria.24 In general, the RANO criteria dictate that progressive disease should be diagnosed if any of the following is observed at any time:

●Development of a new lesion outside of the radiation field.

●Histological evidence of progression.

Table 1.2 Summary of the response assessment in neuro-oncology (RANO) criteria

Complete response

Partial response

Stable disease

Progressive disease

Criteria required

All

of the following:

All

of the following:

All

of the following:

Any

of the following:

T1-Gad  + lesions

None

 ≥ 50% ↓

 < 50% ↓ to  < 25% ↑

 ≥ 25% ↑

T2/FLAIR lesions

Stable or ↓

Stable or ↓

Stable or ↓

↑

New lesions

None

None

None

Present

Corticosteroids

None

a

Stable or ↓

Stable or ↓

NA

Clinical status

Stable or ↑

Stable or ↑

Stable or ↑

↓

b

Abbreviations: FLAIR, fluid attenuated inversion recovery; Gad  + , gadolinium contract enhancement; NA, not applicable; T1, T1-weighted MRI; T2, T2-weighted MRI.Note: Patient should be assessed more than 12 weeks following cessation of chemoradiotherapy. Imaging features should be sustained for at least 4 weeks.

a

Physiological replacement doses permitted.

b

Not attributable to nontumor causes or steroid dose reduction.

In addition, progressive disease should be diagnosed if any of the following occurs more than 12 weeks following cessation of chemoradiotherapy:

●Increase in volume of gadolinium-enhancing tumor of  ≥ 25%.

●Increase in T2 or fluid-attenuated inversion recovery (FLAIR) signal extent.

●Worsening of clinical state attributable to GBM.

A modification of the RANO criteria adapted for use in the context of immunological therapies (iRANO) has also been developed, to allow for delayed effects of immunotherapeutic agents and the development of treatment effects that mimic progressive disease.25

1.4 Selected Papers on the Treatment Outcomes of Recurrent Glioblastoma

●Park C-K, Kim JH, Nam D-H, et al. A practical scoring system to determine whether to proceed with surgical resection in recurrent glioblastoma. Neurooncol 2013;15(8):1096–1101.

●Tully PA, Gogos AJ, Love C, Liew D, Drummond KJ, Morokoff AP. Reoperation for recurrent glioblastoma and its association with survival benefit. Neurosurgery 2016;79(5):678–689.

●Lu VM, Jue TR, McDonald KL, Rovin RA. The survival effect of repeat surgery at glioblastoma recurrence and its trend: a systematic review and meta-analysis. World Neurosurg 2018;115:453–459.e3.

1.5 Treatment Options for Recurrent Glioblastoma

Following recurrence of GBM, no available salvage treatment has clearly achieved improved survival (Fig. 1.3). At present, treatment choices should be individualized, and clinical trials strongly considered. In patients with good performance status, more active treatment options can be considered; patients who are nonambulatory or heavily dependent on others at the time of recurrence are best managed with supportive care alone. Conventional treatment of recurrent GBM is predominantly palliative, with the patient’s quality of life the primary concern.

1.5.1 Repeat Surgery

The role of repeat resection as a cytoreductive measure to prolong survival following tumor recurrence is unclear. Tumor location and size determine whether reoperation is feasible. The objective may be to alleviate mass effect, to improve tolerance of further adjuvant therapy, or, increasingly, to provide further tissue samples that may discern eligibility to a clinical trial. A recent meta-analysis by Lu et al of 1906 recurrent GBM patients has demonstrated that repeat resection is associated with a 28% improvement in survival.43 However, prospective randomized data to support this strategy are lacking. Available evidence are retrospective and subject to inherent selection bias, where surgery is performed in younger patients, with higher performance status and better general health.37,​38,​44 Additionally, patients who undergo repeat surgery may be more likely to also receive more aggressive adjuvant treatment. To address these limitations, Tully et al omitted patients who would be unlikely to be considered for repeat GBM surgery (patients older than 80 years and those with a poor performance status and brainstem or posterior fossa tumors) from an analysis comparing the survival of patients who did and did not undergo repeat surgery; this demonstrated no benefit of repeat surgery.37 In contrast, a case control study conducted by Wann et al suggested instead that repeat operation may improve survival.45

Fig. 1.3 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) chart demonstrating the systematic search process for the treatment outcomes of recurrent glioblastoma.

To simplify surgical decision-making for recurrent GBM, the National Institutes of Health (NIH) Recurrent Glioblastoma Scale has been proposed (Table 1.3).46,​47 Although these scales are based on retrospective data, and essentially repeat the same factors that promote survival in all patients, they provide some clinical guidance and facilitate discussions with patients.

Table 1.3 Simplified WHO Recurrent Glioblastoma Scale for survival after repeat resection

Calculating score

Patient factor

Threshold

Score

KPS

 ≤ 70

1 point

Ependymal enhancement

Present

1 point

Interpreting score

Score

Survival (mo)

Operative prospects

0

18

Good

1

10

Intermediate

2

4

Poor

Abbreviation: KPS, Karnofsky’s Performance Score.

Retrospective analyses have demonstrated that gross total resection of recurrent GBM is associated with an improved outcome; Oppenlander et al have proposed that a threshold of 80% resection is associated with a survival benefit.48 In contrast to primary resection of GBM, carmustine wafers do not show any evidence of benefit in recurrent GBM. Experimental surgical therapies may also be considered for treatment of recurrent GBM. An example is provided by Desjardins et al, who have shown a 36-month survival rate of 21% in patients treated with recombinant poliovirus therapeutic vector, compared with 4% survival in historical controls, with obvious concern regarding the use of historical controls given the history of poor translation of such promising phase II trials to meaningful therapies in phase III studies.49

1.5.2 Further Radiotherapy

Similarly, the role of re-irradiation for recurrent GBM is unclear, with most studies subjected to the limitation of retrospective data bias. Available evidence suggests some utility of repeat irradiation in selected patients with a reasonable performance status and small recurrent tumors.50 Consensus expert opinion suggests that benefit of re-irradiation is higher when there has been a prolonged time since the first course of radiotherapy, and GBM recurrence is in a noneloquent location.51 Stereotactic radiosurgery (SRS) may also be deployed to treat very localized recurrent GBM. Several groups have demonstrated improved survival and reduced complication rates from SRS when compared to repeat resection, raising SRS as a possible alternative to reoperation.52,​48

1.5.3 Further Chemotherapy

In contrast, the role of additional chemotherapy for recurrent GBM has been well studied in more than 100 clinical trials since 1995. However, no clear evidence has emerged to support use of any specific drugs, alone or in combination. The most commonly used treatments are bevacizumab, rechallenge with temozolomide (generally after a significant interval from last course), or other nitrosoureas.

A significant research effort has been spent examining the efficacy of bevacizumab, a monoclonal antibody that binds vascular endothelial growth factor. Phase I and II trials that examined the role of bevacizumab for recurrent GBM did not find consistent evidence to support its use as a standard. More recently, a phase III trial (EORTC 26101) demonstrated a benefit of bevacizumab in combination with lomustine in prolonging progression-free survival, but not overall survival.49 A previous trial found no evidence of benefit for bevacizumab monotherapy.50

In the largest trial examining repeat temozolomide for recurrent GBM, the RESCUE study, 120 patients were administered continuous temozolomide for up to 1 year. RESCUE demonstrated 27% 1-year survival in patients who had recurred early in their initial chemoradiotherapy course, 15% survival in patients who stayed on temozolomide following their initial course, and 29% survival in patients who returned to temozolomide following a different drug.51

In the pre-temozolomide era, nitrosourea-based chemotherapy was standard treatment for GBM. Nitrosureas such as carmustine or fotemustine, either alone or in combinations such as procarbazine, lomustine (CCNU), and vincristine (PCV), have shown some evidence of activity. PCV was compared to temozolomide following recurrence of high-grade glioma in patients initially treated with radiotherapy alone; a 447 patient phase III trial (including 277 with recurrent GBM) showed no difference in survival between groups.52

1.6 Authors’ Recommendations

●Delineating true tumor recurrence from “pseudoprogression” due to treatment is important. The RANO criteria may be used to assist diagnosis.

●GBM invariably recurs; there are no treatments with a sound evidence base.

●Resection of recurrent GBM may be performed to relieve mass effect, or to gain tissue for further investigations.

●Surgery to prolong survival should be performed rarely, in younger patients with good performance status and tumors in favorable, resectable locations.

●Treatment of recurrent GBM has a poor evidence base with little to commend any specific treatment; clinical trials are strongly encouraged for patients with this condition.

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2 Natural History and Management Options of Unruptured Brain Arteriovenous Malformation

Michael Kerin Morgan

Abstract