Gene Therapy for Meningeal Carcinomatosis 
1.0 BACKGROUND AND RATIONALE 
1.1 Disease Background/Current Treatment 
Carcinomas of the breast and lung are the leading causes of cancer-related death in women 
in the United States. These cancers are also the leading cause of leptomeningeal carcinomatosis 
(LMC) (2,29). It has been shown that 35-40% of all breast cancer patients have CNS involvement 
at some point in their disease and that 5% of breast cancer patients have leptomeningeal 
involvement (20,21,24,27,30). Approximately 2,000 women will have leptomeningeal 
carcinomatosis as a result of their primary disease. Leptomeningeal involvement can, less 
frequently, be the initial presentation of die primary disease (12). Other forms of cancer such as 
lymphoma, leukemia, and ovarian cancer, have also been reported to metastasize to the 
leptomeninges. Primary CNS malignancies, such as medulloblastoma and ependymoma, are 
frequently associated with leptomeningeal seeding in the form of drop metastases to the 
lumbosacral subarachnoid space and cauda equina leading to treatment failure despite adequate 
control of the primary tumor. 
Although visceral metastases from cancers are often associated with prolonged survival, 
meningeal involvement carries a very poor prognosis. Untreated patients, and patients 
unresponsive to treatment, survive less than two months (22,29,30). Patients who are able to 
tolerate optimal therapy (intrathecal methotrexate and whole-brain irradiation) survive for a mean of 
6 to 7 months (7, 18,29) while only 15% are still alive at one year (26). Meningeal involvement 
with cancer is not always a premorbid phenomenon and in two thirds to three quarters of cases 
with LMC, the systemic disease is stable or in complete remission (7,29). Effective therapy in 
these patients may extend survival and reduce morbidity. 
The clinical presentation of LMC is one of progressive neurological deficits followed by the 
ultimate demise of the patient. Symptoms such as headaches, changes in mental status, and 
seizures indicate cerebral involvement and occur in up to 50 % of patients with LMC. Cranial 
nerve symptoms occur in 38% of patients. Symptoms of spinal root involvement include pain, 
paresthesias, and weakness occur in 70% of patients and are distinct from spinal bony or epidural 
metastasis. The treatment of these progressive neurologic deficits with multiple cranial nerve 
involvement, dementia, and often severe, deep pain, represents a major therapeutic 
challenged, 18,26,29). 
The interval from initial presentation of the primary cancer to the development of 
leptomeningeal carcinomatosis varies from 5-90 months. A disturbing aspect of this presentation 
is that, in a number of patients, it occurs when the peripheral tumor is in remission or has been 
relatively contained. Thus, there is a subset of patients in whom the primary active component of 
their disease is solely within the CNS. This subgroup of patients can potentially be cured if the 
leptomeningeal involvement could be eradicated. 
Standard therapy for LMC includes radiation and chemotherapy. However, cancer is 
commonly radiation-resistant when it has spread to the leptomeningeal space, and significant side 
effects, such as severe bone marrow depression, may occur. There are a limited number of 
chemotherapeutic agents that can be used in the intrathecal compartment. Among the most well 
known and studied are methotrexate, cytosine arabinoside and thiotepa (3,7,11,13,23,25,26,29). 
Methotrexate is considered the most effective treatment for leptomeningeal spread of various 
tumors, including breast cancer (23). Long term use of methotrexate, particularly in patients who 
have received radiation, is associated with leukoencephalopathy, which can be detected by 
radiographic as well as cognitive testing. These changes are dose-dependent. 
Even with an aggressive approach of radiation and intrathecal chemotherapy, extension of 
survival is marginal. 
[598] 
Recombinant DNA Research, Volume 18 
