Oligodendroglioma

Clinical Presentation, Pathology, Molecular Biology, Imaging, and Treatment

Nina A. Paleologos, Herbert B. Newton

• Publisher: Academic Press
• Year: 2019
• Print ISBN: 9780128131589
• eBook ISBN: 9780128131596
• Topic: Medicine
• Subtopic: Neurology

Oligodendroglioma: Clinical Presentation, Pathology, Molecular Biology, Imaging, and Treatment features the latest "cutting-edge" molecular biology, molecular therapeutics, imaging, immunotherapy, and research methods on the topic of oligodendrogliomas. The most detailed and comprehensive resource on the subject, it provides up-to-date information on clinical presentation, pathology, molecular biology, and treatment methods, including immunotherapy. This book is a critical for students, physicians and researchers in the fields of neuroscience, neuro-oncology, neurosurgery, radiation oncology, medical oncology, and others working in research or with patients.- Provides the most up-to-date information regarding the clinical presentation, pathology, molecular biology, and methods for the treatment of oligodendroglioma brain tumors, including surgical therapy, radiotherapy, molecular therapeutics, chemotherapy, and immunotherapy- Broadly appeals to anyone interested in the field of neuro-oncology and the treatment of patients with oligodendrogliomas- Useful to clinicians interested in a thorough overview of the basic science and treatment of oligodendrogliomas- Includes a section on immunotherapy, with updates on the use of vaccines and immune-based treatment approaches applied to oligodendrogliomas

Section F

Chemotherapy and immunotherapy

Chapter 27

Basic principles of brain tumor chemotherapy

Kester A. Phillips*; David Schiff^† * Inova Medical Group Hematology Oncology, Inova Fairfax Hospital, Falls Church, VA, United States
^† Neuro-Oncology Center, University of Virginia Health System, Charlottesville, VA, United States

Abstract

The use of chemotherapy for brain tumors has been an age-old challenge for Neuro-Oncologists. Brain tumor entities are vast and represent a biologically distinct and heterogenous group of diseases with complex tumor heterogeneity and genomic landscapes that govern growth rates and response to therapy. The presence of the blood-brain barrier is also a major hurdle for effective drug delivery to the tumor niche and has garnered research attention for decades. Despite robust research efforts aimed at developing new agents to treat patients with malignant brain tumors such as glioblastoma, high-grade meningioma, childhood atypical teratoid/rhabdoid tumor, and diffuse intrinsic pontine glioma, survival rates remain low. Yet, with advances in cancer genomics, pharmacogenomics, cancer immunology, and new next-generation therapies are on the horizon and offer a glimmer of hope for an improved patient outcome. In this chapter, we provide a comprehensive, broad overview of chemotherapy in Neuro-Oncology and highlight the major challenges of drug development and emerging strategies to improve the standard of care for patients with brain tumors.

Keywords

Antineoplastic; Blood-brain barrier; Cancer; Chemotherapy; Glioblastoma; Lomustine; Procarbazine; Temozolomide; Vincristine

Introduction

In an era of modern medicine, knowledge of the molecular underpinnings of tumorigenesis has led to substantial improvements in the outcome of cancer patients. Though patient survivorship is on the rise, the development of effective antineoplastic agents against some of the most menacing forms of brain tumors remains a formidable task. Nowadays, clinical trial research methodology utilizing scientific model-based statistical tests has outweighed the historical empiricism of drug development. However, when compared to the strides made in chemotherapy for systemic tumors, the brain tumor armamentarium is disappointingly inadequate and barriers to drug advancement remain a dire plight. Glioblastoma is the epitome of chemotherapy-resistant brain tumors and despite a flurry of investigational agents against this tumor entity, the pace of growth over the last 15 years has been stagnant. Currently, there are only four drugs and one treatment device approved by the FDA for the management of newly diagnosed glioblastoma (Table 1), while there is no consensus for second-line treatment for disease progression or recurrence.

Table 1

FDA approved drugs/device for the treatment of several brain tumors

Year	Agent/device	Class	Indication
1970s	Lomustine	Nitrosoureas	Newly diagnosed glioblastoma and recurrent glioma
1997	Gliadel	Nitrosoureas	Newly diagnosed glioblastoma and recurrent glioma
1999	Temozolomide	Methylating	Recurrent anaplastic astrocytoma
2005	Temozolomide	Methylating	Newly diagnoses glioblastoma
2009	Bevacizumab	VEGF inhibitor	Recurrent glioblastoma
2010	Everolimus	mTOR inhibitor	Subependymal giant cell astrocytoma
2011	Optune device	N/A	Recurrent glioblastoma
2015	Optune device	N/A	Newly diagnosed glioblastoma

Lately, brain tumor research has been heavily steeped in the investigation of molecularly targeted anticancer agents against a wide spectrum of adult and pediatric brain tumors (Table 2). In 2009 the pharmaceutical company Genentech received accelerated approval from the FDA for the use of bevacizumab against recurrent glioblastoma, but since then studies aimed at expanding the treatment landscape for relapsed high-grade glioma (HGG) has produced a paucity of results. Regrettably, the efficacy of targeted therapy against both adult and childhood primary brain tumors have been limited and remains experimental. On the upside, this shift in the treatment paradigm has shown promise for brain metastases with actionable mutations such as BRAF V600E mutant melanoma, and EGFR-mutant and ALK-rearranged non-small cell lung cancer (NSCLC). Most recently, cancer immunotherapy has made headway in the neuro-oncology arena, and preliminary data suggest a benefit of immune checkpoint inhibitors against some secondary brain tumors, particularly brain metastasis from melanoma. For patients with meningioma, surgical resection remains the gold standard of treatment and a role for antineoplastic agents remains to be defined. Additionally, there are no FDA approved agents for adult low-grade glioma (LGG) and the off-label use of nitrosoureas and temozolomide for this brain tumor entity is widely accepted. Furthermore, chemotherapy has not been standardized and remains investigational for the treatment of pediatric brain tumors such as primitive neuroectodermal tumor (e.g., medulloblastoma), astrocytoma, and ependymoma.

Table 2

Molecularly targeting agents for brain tumors

Agent	Pathway	Target	Clinical application
Gefitinib, Erlotinib, Lapatinib	RTK/RAS/PI3K	EGFR	NSCLC, HER2 + BC BM
Bevacizumab	VEGF pathway	VEGF-A	GBM, meningioma, schwannoma
Sunitinib	VEGF pathway	VEGFR	Meningioma, RCC BM
Crizotinib	ALK pathway	c-Met/(HGFR)TK	EML4-ALK fusion NSCLC
Everolimus	PI3K/AKT/mTOR	mTOR	SEGA, meningioma, GBM
Dabrafenib	RAS/RAF/MEK/ERK	BRAF	Melanoma BM
Trametinib	RAS/RAF/MEK/ERK	MEK ½	Melanoma BM
Vemurafenib	RAS/RAF/MEK/ERK	BRAF	Melanoma BM
Pazopanib	VEGF pathway	VEGFR	RCC BM

The road map to the discovery of new brain tumor therapies over the past decade has been fraught with many bumps and dead ends that have counteracted the translation of novel therapies. Most notably, it is well recognized that brain tumor entities are vast and represent a biologically distinct group of diseases with complex tumor heterogeneity and genomic landscapes that govern growth rates and response to treatment, so the “one-size-fits-all” approach to therapy is impractical. Moreover, certain brain tumor subtypes carry inherent or acquired genotypic signatures such as mutations and/or epigenetic changes that confer drug resistance. Additionally, drug delivery presents a unique challenge specific to brain tumors because of the impact of the blood-brain barrier (BBB), and methods to circumvent this hurdle are desperately needed. Furthermore, issues with trial design, patient selection, low accrual rates, and endpoint analysis further thwart the advancement of novel treatment options. For instance, overall survival (OS) is typically the primary endpoint in phase III trials in patients with brain metastasis. However, most patients with brain metastases succumb to their disease because of systemic progression independently of intracranial disease control.^1,2 Likewise, the introduction of molecular profiling of brain tumors coupled with advancements in pharmacogenomic techniques has opened the door to personalized medicine. Consequently, new trials testing targeted therapies require the recruitment of patients with tumor-specific mutations, which makes recruitment for large-scale randomized trials problematic since patients with rare brain tumors must share similar cytogenetics. Lastly, the pitfalls in neuroimaging to reliably discriminate viable tumor from treatment-related change represent a major conundrum in the assessment of response to treatment. In this chapter, we provide a comprehensive, broad overview of chemotherapy in neuro-oncology and highlight the major challenges of drug development and ongoing research aimed at addressing these difficulties. A tho...

Table of contents

• Cover image
• Title page
• Table of Contents
• Copyright
• Dedication
• Contributors
• Foreword
• Section A: Clinical presentation and quality of life
• Section B: Pathology and molecular biology
• Section C: Neuro-imaging
• Section D: Surgical therapy
• Section E: Radiation therapy
• Section F: Chemotherapy and immunotherapy
• Index