Leptomeningeal

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The optimal treatment for tumors with a predilection for leptomeningeal metastases is preventative or presymptomatic therapy. This approach has been successfully employed for the vast majority of children with leukemias or lymphomas and, to a somewhat lesser extent, for medulloblastoma or supratentorial PNET through utilization of CNS-targeted treatment approaches with intrathecal chemotherapy or CSI. CNS-directed treatment approaches have also been increasingly successful in the treatment of initial isolated CNS leukemic relapses as well for some CNS tumors with leptomeningeal metastases at diagnosis, including medulloblastoma and low- grade gliomas. Unfortunately, for the majority of children who have refractory CNS leukemia, leptomeningeal medulloblastoma after neuraxis radiation, or leptomeningeal metastases from most other underlying solid or CNS tumors, the outlook is dismal with rapid progression over a period of weeks to months. The remainder of this section will focus on treatment considerations for these latter patients with high-risk, poor prognosis disease.

The initial evaluation of a child with high risk, poor prognosis leptomeningeal metastases requires a thorough initial assessment of symptoms or neurologic deficits that may be palliated that may be preserved with early therapeutic intervention(s). Examples of such signs and symptoms include headache, pain, cranial nerve palsies, visual loss, weakness, or loss of neurologic function. Treatment with analgesics, steroids, and/or focal radiation therapy to areas of bulk disease should be considered. Patients with acute loss of function are more likely to be completely or partially restored with a therapeutic intervention than those with sub-acute or chronic deficits. Interventions for acute or rapidly progressive lesions must occur as expeditiously as possible in order to maximize improved or restored function.

The extent of leptomeningeal metastases, as well as the status of the primary underlying malignancy, must also be defined. This information, coupled with an assessment of the performance status and rate of disease progression, serves as a guide in evaluating whether or not the patient is a candidate for enrollment in ongoing clinical trials. In general, children who have advanced disease and a poor performance status are offered symptomatic or palliative therapy; children who have an adequate performance status and less advanced disease should be considered as potential candidates for ongoing phase I or phase II clinical trials.

The decision to treat with a systemic or intrathecal agent should be guided in part by a knowledge of the extent of the leptomeningeal metastases. Children with extensive and "bulky" leptomeningeal disease are less likely to benefit from an intrathecal approach than children with positive cytology or minimal leptomeningeal enhancement, due to the limited tissue penetration 3-4 mm) of intrathecally administered chemotherapy.103 In addition, as previously discussed, extensive leptomeningeal disease may also cause alterations in CSF flow (e.g. obstruction) that may preclude intrathecal drug administration.104 For such patients, it may therefore be preferable to pursue systemic chemotherapy, preferably with an agent that penetrates the blood-CSF barrier.

Agents for intrathecal administration that are currently being evaluated in phase I and phase II clinical trials include topotecan, a topoisomerase I poison; mafosfamide, a pre-activated analog of cyclophosphamide; liposomal cytarabine, a sustained release formulation of cytarabine, and busulfan, an alkylating agent. The role of these agents in the treatment of leptomeningeal metastases in childhood cancer has not yet been defined.

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