METASTASIS

Co-chairs: Bertrand C. Liang, M.D., and Roy A. Patchell, M.D.

Participants: Darell D. Bigner Peter M. Black Ronald G. Blasberg Carol Kruchko Rolando Del Maestro Glenn Dranoff Lester Drewes

Brian Fuller Peter Inskip Lois Lampson Jay Loeffler William M. Pardridge Lynn A. Ries

Harald Sontheimer Philip J. Tofilon Jeannine Walston Carol Wikstrand Jeanne Young John S. Yu

STATEMENT OF THE PROBLEM

Central nervous system (CNS) metastases are a serious and common problem in patients with systemic cancer. Brain metastases are at least 10 times more frequent than primary brain tumors. Leptomeningeal metastasis affects about 5% of cancer patients, and spinal cord compression due to metastases occurs in 5-10% of patients with systemic malignancies. Despite refinements in surgery and radiotherapy, many patients die from CNS metastases, and long-term survivors often suffer devastating side effects of their treatment.

Despite the large number of patients affected, metastatic disease to the nervous system is an area that has been largely neglected by investigators. CNS metastases are an "orphan" area falling between the classic areas of tumor biology/medical oncology and neuroscience, as shown by the dearth of extramurally funded grants in the National Cancer Institute (NCI) and National Institute of Neurological Disorders and Stroke (NINDS) portfolios. As a result, understanding of the general cellular and molecular mechanisms involved in metastasis has lagged behind that of other advances in the basic sciences related to oncology and neuroscience.

CHALLENGES

The main problem in the area of CNS metastatic disease is the scarcity of data on the biology of the disease that can be applied to clinical approaches to prevention and treatment. Other challenges are as follows:

• Obtaining tissue from both the primary tumor and the CNS metastasis in order to understand the fundamental biology of metastases to the nervous system.

• Including patients with CNS metastasis in protocols for treatment of systemic disease. All too often, innovative protocols for the treatment of cancer specifically exclude brain and other CNS metastases because of the belief that metastases in the CNS do not respond to treatments that affect the cancer elsewhere in the body.

• Increasing the interest of the neuroscience and neuro-oncological community in the biology and treatment of CNS metastases.

RESEARCH AND SCIENTIFIC PRIORITIES

Priority 1: Identify genetic/cellular/molecular factors that allow metastatic disease to establish itself in the CNS.

These factors include:

• Biology of the CNS microenvironment

• Basement membrane biology

• Interaction of genotypic/phenotypic metastatic cells with the CNS microenvironment

• Immune system interactions within the phenotype of metastatic cells into the nervous system

Priority 2: Identify factors that may prevent metastases to the nervous system:

• Develop new animal models of de novo metastatic disease to the CNS.

• Evaluate potential markers in systemic cancers that predict CNS metastasis.

• Develop agents to prevent CNS metastasis.

Priority 3: Identify targets of established disease:

• Develop new imaging techniques to identify CNS metastases earlier than is presently possible.

• Develop appropriate clinical endpoints for clinical trials of prevention and therapy as well as instruments to measure quality of life.

RESOURCES NEEDED

• A tissue bank to include tissue from a primary tumor and tissue from its CNS metastases.

• New animal models for brain and leptomeningeal metastasis.

• A Progress Review Group that deals exclusively with metastasis.

• Specific NIH initiatives to study metastatic disease to the nervous system.