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Co-Chairs: J. Gregory Cairncross, M.D., and Donna Neuberg, Sc.D.

Participants: Rebecca Betensky Jaclyn A. Biegel Peter M. Black James Boyette Pim Brouwers Greta Bunin Peter Burger R. Edward Coleman

Faith G. Davis Lisa DeAngelis Pam Del Maestro Stuart A. Grossman Alison Hannah Bruce R. Korf Craig Lustig Ravi Menon

Roger Packer Roy A. Patchell David Ramsay Lynn A. Ries Lucy B. Rorke Malcolm Smith Michael Walker Mark Yarborough

STATEMENT OF THE PROBLEM

Brain tumors are a heterogeneous group of central nervous system neoplasms that arise within or adjacent to the brain. Some are curable by surgical resection, but many cannot be eradicated by current treatments, and, when they are, disabling neurological injury often ensues. Moreover, the location of the tumor within the brain has a profound effect on the patient's symptoms, surgical therapeutic options, and the likelihood of obtaining a definitive diagnosis. The location of the tumor in the brain also markedly alters the risk of neurological toxicities that alter the patient's quality of life.

At present, brain tumors are detected by imaging only after the onset of neurological symptoms. No early detection strategies are in use, even in individuals known to be at risk for specific types of brain tumors by virtue of their genetic makeup. Current histopathological classification systems, which are based on the tumor's presumed cell of origin, have been in place for nearly a century and were updated by the World Health Organization in 1999. Although satisfactory in many respects, they do not allow accurate prediction of tumor behavior in the individual patient, nor do they guide therapeutic decision-making as precisely as patients and physicians would hope and need. Current imaging techniques provide meticulous anatomical delineation and are the principal tools for establishing that neurological symptoms are the consequence of a brain tumor.

CHALLENGES

Detection

Early detection has not been an area of interest or focus in neurooncology. Because early treatment for many types of brain tumors does not improve quality or prolong length of life, early detection strategies have not been a priority and their use may not be ethical. In this respect, brain tumors are different from cancers of the breast, prostate, and colorectum, for which screening strategies are now broadly used in healthy populations. Moreover, because the causes of brain tumors are not known, it is not yet possible to identify special populations that are at increased risk due to environmental or occupational exposure.

Imaging, the obvious screening strategy for brain tumors, is extraordinarily costly, especially given the relative rarity of brain tumors in comparison with breast or prostate cancer. Genetic testing, a second option, is desirable as a screening tool because it is based on a simple blood test, but this modality is not yet a reality for sporadically occurring brain tumors, which by far constitute the majority of brain tumors. Hence, the question arises as to whether there is a role for early detection strategies in neurooncology.

Detection can also be defined to include prompt diagnosis in symptomatic patients, early recognition of tumor recurrence in previously diagnosed or treated patients, and the ability to distinguish between recurrence and radionecrosis. In pediatric populations, early symptoms of brain tumor can be misdiagnosed as migraine, school phobia, anorexia, or other common pediatric problems. In very young children, the symptoms of brain tumor may be dismissed as minor developmental delays. An intense educational effort is required to ensure that children as well as adults receive prompt and thorough neurological assessment for lingering symptoms. Imaging methods need to be able to identify early recurrence and to distinguish recurrent disease from other pathologies.

Diagnosis and Prognosis

The current histopathological approach to the diagnosis and classification of brain tumors is satisfactory in many respects. In virtually all instances, brain tumors can be accurately placed into broad diagnostic categories, such as gliomas, meningiomas, or metastases. Within these categories, however, some tumors are not further classifiable; concordance in histological diagnoses between pathologists is sometimes poor; and tissue samples, when small, render confident classification difficult. Increasingly, tissue samples are small because stereotactic biopsy procedures are the preferred means to establish a diagnosis of brain tumor. In addition, when the tumor is located deep within the brain or adjacent to eloquent cortex, only stereotactic biopsies are feasible. Occasionally a brain tumor is treated in the absence of a histopathological diagnosis because its location precludes safe sampling.

Another limitation of the current histopathological basis of brain tumor classification is the inability to accurately predict tumor behavior or response to therapy . Tumors that look similar may behave quite differently, and conversely, tumors that look quite different may behave identically. Currently, when histopathological diagnosis is augmented by clinical and radiographic features such as patient age and tumor enhancement, prognostication for survival in individual patients improves but remains inexact. Predicting response to treatment by histologic, clinical, and radiographic features therefore remains elusive.

Given the rapid advances in gene expression profiling, the achievements in sequencing the human genome, and the continuing revolution in brain imaging, the question arises: What is the potential for molecular characterization and advanced imaging, alone or in combination, to augment or replace current histopathological diagnosis and tumor classification in neurooncology? More important, what is the potential of these approaches to predict tumor behavior and sensitivity to treatment? These possibilities are especially exciting because there are already suggestions that specific genetic alterations in glial tumors may predict survival outcomes after specific therapies.

A further exciting opportunity afforded by advances in molecular medicine and imaging might be the ability to predict response to existing and novel therapies, and to do so soon after administering the intervention. The ability to streamline the assessment of therapeutic maneuvers would permit ineffective therapies to be discarded quickly. This would be especially welcome to patients, who perceive that the evaluation process is slow, inefficient, and imprecise. Having an earlier endpoint by which to declare a therapy ineffective would address these important concerns. Moreover, early identification of effective therapies quickly resets the clinical research agenda to include quality of life as well as efficacy.

RESEARCH AND SCIENTIFIC PRIORITIES

The successful achievement of the following priorities will require advances in brain tumor imaging and genetics and will have important implications for brain tumor treatment. epidemiology, and outcomes.

Priority 1: Develop a molecular- and imaging-based classification for brain tumors that is capable of predicting tumor behavior and guiding treatment decisions more accurately and objectively than are current histopathological methods.

Corollary: Investigate whether imaging methods can be developed to capture the tumor's molecular signature. This is important because the amount of tumor tissue available at diagnosis may be limited, and tissue is not available for serial sampling after therapy. Priority 2: Refine the ability to detect response to novel treatments so that ineffective therapies can be discarded quickly while active compounds are evaluated fully in clinical trials that assess quality as well as length of life. Non-anatomical magnetic resonance signals, rather than change in tumor size, may have the potential to accurately detect early response. Corollary: Refine the ability to predict response to existing treatments so that patients receive active agents prescribed optimally, and do not receive toxic ineffective therapies. Molecular markers or imaging signals may have the potential to accurately predict response. Priority 3: Identify serum markers of individual brain tumor types in preparation for screening programs in at-risk individuals or in populations. Screening, using serum markers, will be important and ethical only when it is clear that early treatment unequivocally improves patient outcomes.

RESOURCES NEEDED

Tissue banks linked to clinical databases are needed for both pediatric and adult brain tumors of all types. Tissue banks should include both paraffin-embedded and frozen tumor, serum, normal DNA from peripheral blood or buccal mucosa, and, in certain instances, cerebrospinal fluid. For frozen tissue, guidelines for quality assurance and tissue preparation need to be developed. The clinical database should contain information about patient characteristics, family history of brain tumor or unusual cancer susceptibility, imaging features (including tumor location), therapy administered, response to therapy, and survival.

A decentralized banking model is envisioned. Public and professional educational efforts will be required to ensure that both common and rare brain tumors are submitted to the banks. Large numbers of samples will be important to sustain a concerted research effort that can address the heterogeneity of these diseases and the many scientific questions that will arise. When available, serial samples should be banked on an individual basis. An oversight structure will be needed to control access to this precious resource, and patient consent issues will need to be carefully considered.

Last updated February 09, 2005