TOXICITY OF INTRA-CSF BIOLOGIC AGENTS IN PATIENTS WITH NEOPLASTIC MENINGITIS

Open Access
Author:
Bernstein, Aaron Jacob
Area of Honors:
Science
Degree:
Bachelor of Science
Document Type:
Thesis
Thesis Supervisors:
  • Dr. Michael Glantz, Thesis Supervisor
  • Dr. Ronald Markle, Honors Advisor
Keywords:
  • neoplastic meningitis
  • cancer
  • neuro-oncology
  • neurosurgery
  • epidemiology
Abstract:
Neoplastic meningitis (NM) is a profoundly morbid, almost inevitably fatal, and increasingly common complication of cancer. Despite multimodal therapy, prognosis is dismal with a median survival of 2-3 months. Disease resistance has usually been blamed for this poor outcome, but therapeutic nihilism and a paucity of treatments considered suitable for intra-CSF administration may play a more important role. Biologic agents represent one of the most active therapies for extra-CNS malignancies, but often have limited access to the CSF when administered systematically, and have not been widely used for intra-CSF administration. We describe the safety and efficacy of tumor-specific, intra-CSF biologic therapy in a large group of patients with neoplastic meningitis. We interrogated the database of an international neoplastic meningitis registry (NeMeRe) to identify all patients with neoplastic meningitis who received at least one dose of an intrathecal biologic agent as part of their neoplastic meningitis-directed therapy. Patient demographics, treatments, toxicity, and outcome data were extracted and analyzed. We identified 110 patients who received an intrathecal biologic agent as part of a histology and molecular profile-adjusted intraventricular chemotherapy treatment approach. These agents included rituximab (45 patients with lymphoma, 193 cycles), trastuzumab (40 patients, 207 cycles in patients with malignant primary brain tumors, 13 patients and 138 cycles in patients with breast cancer), panitumumab (2 patients with lung cancer, 3 cycles), and alpha-interferon (7 patients with melanoma, 22 cycles). Grade III toxicity occurred in 8.8% of rituximab, 4.6% of trastuzumab, and 0% of panitumumab and alpha-interferon-containing cycles. There was no grade IV or V toxicity. Median survival in patients with lymphomatous meningitis (348 days), solid tumor NM from primary brain tumors (219 days), HER-2+ breast cancer (315 days), and melanoma (307 days) was encouraging. No difference in survival was seen between patients with or without treatment-related toxicity in any histologic group. This large patient series suggests that rituximab, trastuzumab, panitumumab, and alpha-interferon may be safely administered into the CSF, and, as part of a multi-agent intra-CSF treatment regimen, does not appear to compromise survival. More widespread use of these agents, and prospective evaluation in appropriate patient populations is warranted.