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Report of the Brain Tumor Progress Review Group

INTRODUCTION

Brain tumors represent a unique challenge in that they affect the organ that is the essence of the "self." Furthermore, because each area of the brain serves a different but vital function, the therapy that is most effective for other cancers--surgical removal of either the entire organ or the tumor with a generous surround of normal tissue--cannot be used to cure brain tumors. Unfortunately, most brain tumors are relatively insensitive to other cancer treatment, including radiation and chemotherapy.

Coupled with the difficulty in treating brain tumors is the unique biology of the brain:
• Brain tumors occur in an organ that is enclosed in a bony canal that allows little room for growth of the tumor without compressing and damaging normal brain.

• Many brain tumors extensively invade normally functioning brain, making complete surgical removal impossible.

• In their early stages, brain tumors are protected behind a blood-brain barrier; even when this barrier is disrupted in the bulk of the tumor, infiltrating tumor cells at the growing edge remain protected.

• Disruption of the blood-brain barrier leads to edema, which the brain tolerates poorly because of the limited intracranial space and the lack of lymphatics to rid itself of the products of edema and other debris.

• The brain itself is rich in expressed genes and therefore is a fertile field for the growth of both primary tumors and metastases.

• The brain and brain tumors appear to be less susceptible to attack by the immune system than are tumors in other organs. Even the term brain tumor, which suggests a single type of tumor, can be misleading. There are a bewildering variety of central nervous system tumors; the World Health Organization lists 126. Many of these tumors are not, strictly speaking, in the brain but arise from structures intimately associated with that organ, such as tumors of the covering membranes (meningiomas) and adjacent cranial and paraspinal nerves (schwannomas). Brain tumors range from benign (most meningiomas) to highly aggressive (glioblastomas). They affect both adults and children (although the distribution of tumors varies) and are often highly resistant to treatment.

The term brain cancer is also misleading. Most cancers that arise elsewhere in the body cause damage by metastasizing to other organs (including the brain). Primary brain tumors, however, rarely metastasize, although they may widely infiltrate the nervous system. Conversely, many cancers metastasize to the brain, making metastatic brain tumors much more common than primary brain tumors.

Throughout this document, the term brain tumor is used to refer to all tumors that grow inside the skull. The issues discussed in this document, however, also extend to tumors growing within the spinal canal.

STRUCTURE AND PROCESS OF THE PRG MEETING

For the reasons described in the introduction to this report, the Brain Tumor Progress Review Group (BT-PRG) required input from participants with much more diverse expertise than was needed in previous PRGs. In addition to experts on cancer biology and genetics, the BT-PRG required expertise in neurobiology, including areas such as progenitor cells, cellular migration, and blood-brain barrier function. Clinically, expertise was required from both oncology and the clinical neurosciences, including neurosurgery and neurology. In addition, to ensure inclusion of the wide diversity of brain tumors, breakout sessions were held not only for those topics that apply to all solid tumors, including brain tumors, but also (different from other PRGs) for specific types of brain tumors (i.e., intraaxial tumors, extraaxial tumors, pediatric tumors, and metastases). A total of 16 breakout groupswere therefore convened (see box). Each participant attended three breakout sessions.
STRUCTURE OF THE BT-PRG BREAKOUT GROUPS
Basic Biology

Clinical Biology

Specific Tumors
• Models

• Cancer Biology and Etiology

• Neurobiology: Progenitor Cells

• Neurobiology: Migration and Trafficking

• Cancer Genetics

• Tumor Immunology

• Detection, Diagnosis, and Prognosis

• Epidemiology, Prevention, and Outcomes

• Imaging

• Radiation Biology

• Therapeutic Targeting: Blood-Brain Barrier, Gene Therapy, and Vascular Biology

• Treatment

• Extraaxial Tumors

• Intraaxial Tumors

• Pediatric Tumors

• Metastases

The participants in each of these 16 breakout sessions were asked to identify three important research priorities in their assigned areas. It was recognized that it might not be possible to place all of the research priorities formulated by the groups into an overall hierarchy. Although all of the priorities included in the appendices are important and meritorious, some arose in multiple breakout sessions and therefore appear to be of overarching importance. This report delineates those priorities considered by the BT-PRG to be overarching. The appendix contains the full reports of the individual breakout sessions and their priorities.

This report is divided into two sections. Section I, "Scientific Priorities," describes the overarching priorities in both the basic and the clinical sciences. These scientific research priorities are hypothesis driven. To meet them will require the scientific resources described in Section II. The resource priorities in Section II can be considered as hypothesis generating in that their development will generate hypotheses for further research.

SECTION I: SCIENTIFIC PRIORITIES

Three separate sets of breakout sessions addressed the scientific priorities. One set was devoted to fundamental biology and included sessions on models, neurobiology of progenitor cells and of cellular migration and dispersal, cancer biology, immunobiology, and cancer genetics. Another set of sessions was related to clinical issues, ranging from detection and diagnosis to treatment and outcomes. A third set was devoted to specific tumors. Several overarching scientific priorities emerged from all of these sessions and are described here.

Basic Biology

Brain tumors are phenotypically and genotypically heterogeneous. Significant gaps exist in current understanding of the molecular pathways involved in the genesis, progression, and biological and clinical behavior of brain tumors. Brain tumors are unique among human cancers because of their complex interaction with the brain itself, which greatly complicates the use of existing therapies as well as the development of novel ones.

A cardinal feature of the most common malignant brain tumors--their diffuse infiltration into the surrounding brain--presents substantial barriers to the effective delivery of therapeutic agents and increases the possibility of therapeutic toxicity to a vital organ whose function greatly affects the patient's quality of life. Other obstacles to effective therapy include the blood-brain barrier and the difficulties it creates for therapeutic delivery, as well as the relative lack of information on the unique immunological aspects of brain tumors and the cerebral environment.

The biology of brain tumors is distinct from that of many other human tumors. Although tumors are named as though their lineage were understood (e.g., astrocytoma from astrocytes), the cells of origin for most human brain tumors remain enigmatic, complicating the interpretation of data that require a comparison between brain tumor cells and their "normal" counterparts. Highlighting these issues are childhood brain tumors, especially primitive neuroectodermal tumors that arise during brain development. Insights into the normal and aberrant regulation of neurodevelopmental genes may be significant in understanding the etiology of both childhood and adult brain tumors. Likewise, elucidating the genetic alterations in brain tumors may yield new insights into brain development. Achieving significant advances in the diagnosis, prognosis, therapy, and prevention of brain tumors requires unraveling and understanding many aspects of the cellular and molecular biology of brain tumors and their interactions with normal brain elements. These advances must proceed along a number of different fronts and will require the interaction of several disciplines in order to achieve the greatest chance of success (see "Communication" in Section II of this report).

Many of the priorities generated by the breakout sessions of the BT-PRG overlapped, particularly those concerning needed resources (see Section II). The highest scientific priorities in basic biology identified by such overlap are as follows:
• Understand the complex biology of brain tumors, both primary and metastatic, and their interaction with normal brain elements as they relate to oncogenesis, progression, tumor cell dispersal, and heterogeneity.
-- Define the genetic changes and molecular pathways involved in brain tumor initiation and maintenance.

-- Characterize the interactions of brain tumor cells with the normal brain. • Provide a detailed molecular classification of the cells of origin for distinct tumor types and define their lineage associations, as well as the signal transduction pathways that regulate cell fate and the mechanisms by which the local environment of the brain influences cell migration and differentiation.

• Understand genotypic influences on phenotypic behavior, tumor type, age at onset, anatomical position, cell of origin, and cellular biology.

• Isolate the genes that predispose to human brain tumors and understand their relationship to the genes that regulate normal development.

• Identify the genes that regulate patients' responses to chemotherapy and radiotherapy and those that mediate tumor chemoresistance and radioresistance.

• Characterize both central nervous system and systemic immune responses in patients with brain tumors.

• Understand the blood-brain barrier and its regulation.

• Understand the mechanisms underlying the spread and establishment of metastases in the central nervous system.
Epidemiology

Little is known about the epidemiology of brain tumors. Germ line mutations (familial brain tumor syndromes) account for no more than 7% of patients. The only unequivocally established risk factors for nonfamilial brain tumors--therapeutic irradiation to the brain and chronic immunosuppression (e.g., AIDS)--are also infrequent causes of brain tumors. Other suggested etiologies, such as nonionizing radiation (e.g., from cellular telephones or high-tension wires), viral agents, household chemicals, or foods, have not been established as causal. In addition, little is known about the interaction of genetic factors and environmental toxins in the genesis of brain tumors.

Because identification of the risk factors for brain tumors may aid prevention and suggest effective treatments, high-quality epidemiological studies are extremely important. Factors that inhibit epidemiological studies include the relatively small number of patients affected by brain tumors and the large number of histopathological types of these tumors. These factors complicate the design of research protocols and limit the statistical power of the data collected. In addition, existing tumor registries are neither linked nor structured to facilitate the collection of large numbers of samples for meaningful epidemiological research. Important epidemiological scientific priorities, therefore, include the following:
• Support the linking of existing databases to provide larger numbers of samples for epidemiological studies.

• Expand and enhance databases to include all primary brain and spinal tumors--malignant and nonmalignant, adult and pediatric--and to have the flexibility to accommodate new histological and molecular classifications of tumors.

• Develop epidemiological studies of patients' susceptibility to the toxic effects of current treatment modalities and investigate risk and protective factors with study designs that incorporate biological measures.

• Use validated animal models (see "Models," Section II) to study the potential causal factors of brain tumors and of treatment-induced neurotoxicity.
Detection and Diagnosis

Because brain tumors are an extraordinarily heterogeneous group of lesions, accurate diagnosis is essential to proper management. Current imaging techniques provide a sensitive means for delineating the anatomical features of brain tumors but have not provided an effective means for early detection. Early detection could also be complicated by the ethical problems created by presymptomatic diagnosis of tumors for which there may not be effective treatment, and in an organ whose proper function is essential to quality of life. Nonetheless, early detection of brain neoplasms, particularly in the pediatric population, where these lesions are often treatable, could be facilitated by appropriate education of pediatricians, parents, school officials, and other caregivers.

The diagnosis of brain tumors is currently based on histological examination of brain tumor tissues after radiological characterization and surgical biopsy. These approaches are successful in classifying and grading most cases, but in many situations they do not allow accurate prediction of therapeutic responses or of prognosis. The situation may be further complicated by the small size of some diagnostic biopsy samples. There is therefore a critical need to improve the diagnosis of brain tumors in order both to improve current therapeutic management strategies and to form a basis for the evaluation of novel approaches.

The ability to characterize tumors comprehensively at the molecular level raises the possibility that diagnosis could be based on molecular profiling, either alone or with histological examination, rather than on histological phenotype alone. Once such techniques become possible and practical, molecular profiling could be accomplished by tissue analysis or imaging. In the future, molecular markers could also form the basis for screening at-risk individuals or populations. In light of such possibilities, the following priorities in the detection and diagnosis of brain tumors were identified:
• Develop a molecular- and imaging-based classification scheme for brain tumors that can be used to predict tumor behavior and to guide treatment decisions more accurately and objectively than is possible with current histopathological methods.

• Develop techniques that can reliably detect brain injury related to tumor or treatment and use such techniques to assess the efficacy of neuroprotective interventions.
Treatment

Treatment options for patients with brain tumors have been limited and, for most types of tumors, have provided only modest benefits. Some of the likely reasons for these limitations (see "Introduction") include the unique structural and physiological aspects of the central nervous system, especially its vulnerability to damage from many therapies as well as from neoplastic processes themselves. Research in the treatment of brain tumors has been hampered by the lack of clinically predictive model systems; by a minimal understanding, until quite recently, of fundamental tumor biology; and by a narrow range of available therapeutic agents for testing that have had little expected specificity for brain tumors. The major challenge for the future is to develop more effective techniques to treat brain tumors without damaging the brain.

Marked progress is currently being made in dissecting the molecular mechanisms of neoplasia in the brain and elsewhere. These advances are enabling the rapid identification of relevant molecular targets, and the result is a vast array of potential therapeutic approaches and agents in the development pipeline. At the same time, advances in neuroimaging are raising the tantalizing possibility of clinically assessing the capacity of an agent to alter its intended target. It therefore seems reasonable to expect an improved rate of success in research on the treatment of brain tumors. Because the special characteristics of these tumors will continue to present problems and challenges, however, the following priorities were identified:
• Facilitate the development of novel therapeutic agents and approaches for adult and pediatric brain tumors. These approaches should include, but not be limited to, chemotherapeutic, immunologic, antiangiogenic, genetic, and viral agents.

• Increase knowledge about the mechanisms of existing therapies for both adult and pediatric brain tumors.

• Improve the therapeutic index of new agents that are specifically relevant to the central nervous system.

• Enhance the therapeutic ratio for radiation therapy for brain tumors. (Overcome radioresistance of primary brain tumors; overcome normal tissue toxicity such as necrosis/edema and functional deficits.)

• Develop novel drug targeting systems that enhance the uptake by brain tumors of small- and large-molecule diagnostic and therapeutic agents.

• Develop clinical consortia for immunotherapy that are similar to those for radiation and chemotherapy.

• Develop therapies that are less toxic than existing therapies to both the mature and the immature nervous system.
Outcomes

Traditional outcome measurements used in brain tumor studies have included overall and recurrence-free patient survival and, in some instances, radiological response to therapy. Such measurements, however, largely ignore crucial issues relating to quality of life and biological endpoints of response. These issues are of particular importance in tumors for which effective therapies may not exist and in pediatric tumors, for which effective tumor control may be associated with significant long-term morbidity. For these reasons, there is an immediate and crucial need for better measurement tools and surrogate markers to assess patient quality of life and tumor response to therapy. Such outcome markers would facilitate the assessment of neurotoxicity, thereby providing an opportunity to discard potentially neurotoxic therapies sooner. They would also facilitate more accurate assessment of therapeutic response, thereby allowing effective therapies to be continued while ineffective therapies are discontinued. The following priorities were therefore identified:
• Improve techniques for measurement of quality of life and include such measurements in all clinical trials of brain tumor.

• Refine the ability to detect response to existing therapies, such as radiation, and to novel treatments, using surrogate markers measured either by imaging or in biological fluids (e.g., serum or cerebrospinal fluid).

• Establish clinical and imaging markers of neurotoxicity from existing therapies, such as radiation, and from novel treatments.

• Extend the use of such markers to preclinical evaluations in animal models.