Handbook of Brain Tumor Chemotherapy, Molecular Therapeutics, and Immunotherapy

Herbert B. Newton

• Publisher: Academic Press
• Year: 2018
• eBook ISBN: 9780128121016
• Edition: 2
• Topic: Biological Sciences
• Subtopic: Neuroscience
• Index: Biological Sciences

Handbook of Brain Tumor Chemotherapy, Molecular Therapeutics, and Immunotherapy, Second Edition, provides a comprehensive overview of the molecular methodologies in the neuro-oncology field. There have been profound changes in the landscape of approaches to brain tumor therapy since the first edition—mainly in the areas of molecular biology and molecular therapeutics, as well as in the maturation of immunotherapy approaches (e.g., vaccines). This updated edition has a new, primary focus on multidisciplinary molecular methods, and is broadened to include the latest cutting-edge molecular biology, therapeutics, immunobiology and immunotherapy approaches.As the first comprehensive book to address the molecular research into these concepts, users will find it to be an invaluable resource on the topics discussed.- Provides the most up-to-date information regarding conventional forms of cytotoxic chemotherapy, as well as the basic science and clinical application of molecular therapeutics for the treatment of brain tumors- Broadly appeals to anyone interested in neuro-oncology and the treatment of brain tumors- Features updated chapters on molecular biology, molecular therapeutics, maturation of immunotherapy approaches, and a focus on multidisciplinary molecular methods- Includes a new section on the basic science of immunology, as well as thorough updates on the use of vaccine technology and immunotherapy for the treatment of brain tumors

Section IV

Chemotherapy for Specific Tumors—Adults

Chapter 29

Historical and Conventional Chemotherapy Approaches for High-Grade Astrocytomas

Herbert B. Newton Neuro-Oncology Center, Florida Hospital Cancer Institute, Florida Hospital Orlando, and Florida Hospital Medical Group, Orlando, FL, United States

Abstract

High-grade astrocytomas, such as anaplastic astrocytoma (AA) and glioblastoma multiforme (GBM), are frequently diagnosed tumors that continue to have a poor prognosis and protracted survival. Conventional chemotherapy has been demonstrated to provide a survival benefit in patients with AA and GBM, in addition to surgical resection and irradiation, by several meta-analyses. The improvement in survival has been modest and is mainly associated with the use of nitrosourea drugs such as BCNU and CCNU, as well as platinum compounds.

Keywords

Chemotherapy; Conventional; Historical; Anaplastic astrocytoma; Glioblastoma; GBM; BCNU; CCNU; Platinum compounds

Introduction

High-grade or malignant astrocytomas consist of anaplastic astrocytoma (AA) and glioblastoma multiforme (GBM), and represent the most commonly diagnosed brain tumors in adults [1–3]. These tumors account for 30%–35% of all newly diagnosed brain tumors in patients 18 years of age or older and affect an estimated 10,000 to 12,000 new patients each year in the United States. The overall incidence rates for AA and GBM are 0.13 and 3.24 per 100,000 person-years, respectively. The age of onset is different between the two forms of high-grade astrocytoma, with AA arising in patients between the ages of 45 and 55 years, and GBM typically affecting an older cohort between 55 and 65 years of age. There is usually a slight preponderance of male patients, with a male to female ratio of approximately 1.8:1 in most series [2,3]. The prognosis for patients with AA and GBM remains poor, with overall median survivals of 30–38 months and 14–18 months, respectively, for patients that have received standard treatment.

AAs and GBM are classified by the World Health Organization (WHO) as grade III and grade IV astrocytomas, respectively (see Chapter 1) [4]. Pathologically, AAs are characterized by the presence of high cellularity, prominent cellular and nuclear pleomorphism, nuclear atypia, and mitotic activity. The histological features of GBM are similar to AA, but with more pronounced cellular and nuclear anaplasia and the presence of microvascular proliferation and/or necrosis. Both AA and GBM are highly infiltrative tumors and commonly arise in the cerebral hemispheres or in the deep white matter.

Overview of Initial Treatment

The most common form of initial treatment for a high-grade astrocytoma is surgical intervention. Indications for surgery include reducing tumor burden, alleviating mass effect, confirmation of the histological diagnosis, diversionary shunting procedures in selected cases, and the introduction of local antineoplastic agents [5–7]. Recent advances in neurosurgical technology offer new approaches to tumor removal, such as frame-based and frameless stereotactic biopsy, intraoperative cortical mapping, neuronavigation, and the use of intraoperative magnetic resonance imaging (MRI) [6–9]. These techniques allow the surgeon to delineate tumor margins more carefully and preserve the surrounding regions of eloquent brain (e.g., Broca's area, primary motor cortex) and delicate vascular structures, while performing a more aggressive and thorough tumor resection. Although it remains debated in the literature, most neurosurgeons recommend a near-total or gross-total resection, whenever possible, of all enhancing tumor volume and regionally infiltrated brain as defined on T2 MRI images. Gross-total tumor resection has been associated with longer overall and progression-free survival in several studies [10,11]. For tumors that are diffusely infiltrative or multifocal, a stereotactic biopsy is more likely to preserve neurological function than an attempt at resection and, in most cases, will be able to provide a histological diagnosis to guide further treatment.

Fractionated external-beam radiation therapy is an appropriate form of treatment for virtually all patients with AA and GBM, and is similar for both tumor types [1,5,12–14]. Numerous randomized controlled trials have demonstrated a survival benefit for patients receiving surgical resection and irradiation in comparison to resection alone (approximately 34–38 weeks vs 14–18 weeks). The standard approach is administered in the early postoperative phase and uses initial radiation ports that encompass the T2-weighted target with a margin of 1–3 cm, using a dose of approximately 4500–4700 cGy in 180–200 cGy daily fractions. After this portion has been completed, a “cone down” is performed, targeting the T1-weighted contrast-enhancing volume of the tumor with a 1–3 cm margin, bringing the total dose to approximately 6000 cGy. Irradiation is performed over the course of 6–7 weeks, with the patient receiving treatment 5 days per week. Radiation therapy schedules can sometimes be modified with hypofractionation and/or an abbreviated treatment course for elderly patients or those with a low performance status, while maintaining a similar level of toxicity and overall survival [15,16]. More aggressive approaches to irradiation using hyperfractionation schemes have not been shown to improve tumor control and, in some reports, have been associated with worse outcomes [14]. Other techniques to increase localized radiation doses to the tumor resection cavity, such as brachytherapy with permanent or temporary radioactive seeds, have also had disappointing results in controlled trials [17].

Stereotactic radiosurgery (SRS), using a linear accelerator-based system or Gamma Knife to deliver a single high-dose radiation fraction to a defined volume using stereotactic localization, is another method to boost radiation doses in the tumor bed of a newly diagnosed or recurrent high-grade astrocytoma [18,19]. Retrospective and single-armed uncontrolled trials suggest an improvement in local tumor control rates and survival when using either radiosurgical system. However, these results have not been confirmed in randomized, controlled trials, which have been performed within the Radiation Therapy Oncology Group (RTOG).

Chemotherapy of AA and GBM—Historical Overview

In the 1960s and 1970s, surgical resection and postoperative external beam radiation therapy were established as the standard treatment approach for patients with AA and GBM [5,14]. However, in the late 1970s investigators began to evaluate chemotherapy as a potential treatment modality when it became obvious that surgical resection and radiation therapy were not curative in the vast majority of patients, and that other forms of treatment were desperately needed to improve survival [20–24]. Over the next 15 years, numerous chemotherapy agents were tested, alone and in combination, for efficacy against newly diagnosed and recurrent high-grade gliomas. Single-agent nitrosoureas (i.e., BCNU) and nitrosourea-based combination regimens (i.e., PCV; procarbazine, CCNU, vincristine) were most effective (outlined in more detail below), although only to a modest degree. However, most of the literatures regarding chemotherapy for patients with AA and GBM have methodological deficiencies that impair the ability to draw firm conclusions [25]. Overall, there are very few well-controlled, prospective, randomized clinical trials of chemotherapy in patients with AA and GBM. The reasons for this remain somewhat obscure, but include the relative rarity of these patients, the initial lack of clinical infrastructure to perform large multiinstitutional clinical trials, the frequent presence of therapeutic nihilism in physicians caring for AA and GBM patients, and the fact that many of these patients were treated by different groups of subspecialty physicians (e.g., neurosurgeons, neuro-oncologists, radiation oncologists, medical oncologists) that have varying levels of interest in referral to clinical trials for chemotherapy. Owing to poor accrual and the small numbers of patients in many clinical trials, statistical power has been limited, further hampering the efforts to draw meaningful conclusions from the available data. Another set of problems that have diluted the quality of published results are the inclusion of...

Table of contents

• Cover image
• Title page
• Table of Contents
• Copyright
• Contributors
• Section I: Pharmacological and Clinical Applications
• Section II: Innovative Chemotherapy Delivery
• Section III: Molecular Biology and Molecular Therapeutics
• Section IV: Chemotherapy for Specific Tumors—Adults
• Section V: Chemotherapy for Specific Tumors—Pediatrics
• Section VI: Immunotherapy of Brain Tumors
• Section VII: Response Assessment, Quality of Life, and Neuropsychology
• Index