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Co-chairs: Keith L. Black, M.D., Ph.D., and Stuart A. Grossman, M.D.

Participants: J. Gregory Cairncross Webster Cavenee E. Antonio Chiocca Pam Del Maestro Richard A. Fishel Ramon Gilberto Gonzalez James F. Gusella Bruce R. Korf

Andreas Kurtz Linda M. Liau Craig Lustig Robert L. Martuza Ed Oldfield Luis Parada David Parkinson David Ramsay

Sandra Rempel Tom Rozman John H. Sampson Arthur W. Toga Mark Yarborough Han Ying Richard Youle

STATEMENT OF THE PROBLEM

A wide variety of extraaxial tumors arise in the spinal and cranial nerves and sometimes affect the brain by compression. Extraaxial tumors are uniquely interesting for brain tumor research for a number of reasons:

• Extraaxial tumors tend to be more homogeneous than parenchymal brain neoplasms such as gliomas.

• The location of extraaxial tumors extrinsic to the brain encourages novel approaches to targeted therapy and facilitates acquisition of tissue for research.

• The early genetic changes underlying some extraaxial tumors are well characterized, including in hereditary syndromes, such as neurofibromatosis 2, that predispose to these lesions.

Extraaxial tumors that affect the brain and spinal cord include meningiomas, schwannomas, neurofibromas, and pituitary tumors, as well as mesenchymal tumors of the skull, spine, and dura mater. Although all of these entities may present problems in clinical management, two lesions, meningiomas and schwannomas, are priorities for further research because they are common and may be difficult to manage. Although surgical resection is a mainstay of treatment for these neoplasms, some cannot be resected and others may recur despite resection. Furthermore, some of these tumors remain dormant and do not require intervention, whereas others may grow and become refractory to standard therapy.

Unfortunately, current neuroimaging techniques do not provide substantial preoperative information about the predicted rate of tumor growth or the likelihood of tumor recurrence, and current histopathological classification and grading are not adequately predictive in many cases. Longitudinal studies of tumor growth are hampered by the sometimes long intervals between presentation and recurrence, and many standard registries do not capture information on these lesions. Finally, ancillary therapies are primarily restricted to radiation therapy, and few other options are available.

CHALLENGES AND QUESTIONS

• To predict which meningiomas and schwannomas will remain dormant and will not require surgical intervention--Such information will direct surgery toward those patients who are most likely to benefit from it and will spare potential complications for other patients.

• To predict which meningiomas and schwannomas will have a greater likelihood of recurrence after surgical resection--Such information would allow follow-up strategies and therapies to be directed toward those patients in need while sparing unnecessary therapy and potential complications for those patients whose tumors will not recur.

• To develop novel therapies for meningiomas and schwannomas that are not amenable to surgery or that recur after surgery--Current approaches are primarily restricted to radiation therapy, which also has potential neurotoxicity in extraaxial lesions.

• To identify clinical and neuroimaging endpoints for the evaluation of meningioma and schwannoma growth and of therapeutic efficacy--Current endpoints, such as tumor growth, time to recurrence, and survival, are problematic given the slow growth characteristics of many of these tumors.

RESEARCH AND SCIENTIFIC PRIORITIES

Priority 1: Understand the natural history of meningiomas and schwannomas, as well as their response to therapies.

• Neuroimaging strategies should be developed that will allow prognostic information, anatomical or molecular, to be derived before surgical intervention.

• Tissue-based approaches should focus on refined diagnoses based on molecular profiling.

• Population-based studies must be enabled to allow follow-up of large numbers of patients over long periods and of unique populations of patients, such as those with neurofibromatosis 2.

Priority 2: Develop outcome measurements for evaluating the efficacy of therapies for extraaxial tumors and the effects of tumor and therapy on quality of life.

Priority 3: Develop novel therapies for extraaxial tumors on the basis of on their unique biological qualities.

• Molecular biological research should elucidate the pathways responsible for meningioma and schwannoma tumorigenesis. Initial avenues for research would include study of pathways regulated by merlin (the protein encoded by the neurofibromatosis 2 gene). Such information could contribute to biologically rational approaches to therapy.

• Targeted therapies should be investigated on the basis of the localized and physically separate nature of these tumors, as well as on their biological characteristics. A wide variety of therapeutic approaches could be of interest, from small-molecule inhibitors to antiangiogenesis to immunological to gene therapy.

RESOURCES NEEDED • Integrated registries, tissue banks, and databases for meningiomas and schwannomas, including neurofibromatosis 2

• Funding mechanisms to support long-term (e.g., >10-year) longitudinal studies of tumor growth rates and the natural history of tumors in specific patient populations (such as those with neurofibromatosis 2). Current Department of Defense grants address only vestibular schwannoma growth in patients with neurofibromatosis 2.

Last updated February 09, 2005