Medication Summary

Chemotherapy is best administered intrathecally so that chemotherapeutic agents, which are usually hydrophilic, do not encounter the blood–brain barrier and easily reach tumor cells in the CSF or leptomeninges. The preferred route of administration is through an implanted subcutaneous reservoir (eg, Rickham or Ommaya reservoir) and ventricular catheter rather than LP, for 4 reasons. First, intraventricular injection through an Ommaya reservoir is easy and ensures entry into the CSF. Second, when injected into the ventricle, the drug follows normal CSF flow and thus reaches all parts of the CSF space. Third, repetitive LPs are arduous and painful for the patient. Fourth, about 10–15% of LPs do not deliver all of the drug intended to reach the subarachnoid space.

CSF flow abnormalities are common in patients with increased ICP and hydrocephalus, and 70% of patients with leptomeningeal metastases (LM) have ventricular outlet obstructions, abnormal spinal canal flow, or impaired flow over the cortical convexities, but these can be reversed with local radiation therapy. A CSF-flow study is recommended for all patients at the initiation of intrathecal chemotherapy, and such therapy should be deferred if an obstruction is noted. Systemic therapy can be useful if the blood–brain barrier already has been disrupted or if the chemotherapeutic agent is lipid soluble.

Methotrexate (MTX), cytarabine (Ara-C), and thiotepa are administered intrathecally for LM. Additionally, several case reports have shown improved prognosis and decreased progression of LM following intrathecal trastuzumab.^{[26, 27, 28, 29]}

Class Summary

These agents inhibit cell growth and proliferation.

Methotrexate (Folex PFS, Rheumatrex)

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Mainstay of treatment. Because meningeal infiltration interferes with drug clearance, CSF concentrations can be unpredictable. Monitor and maintain concentration near 10^-6 M, and coadminister with folinic acid and hydrocortisone if necessary.

Cytarabine (Cytosar-U)

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Second-line agent used if MTX not tolerated or ineffective. Not effective for solid tumors but useful in leukemic and lymphomatous meningitis. Half-life longer in CSF than serum. Sustained-release form available in United States; extends half-life to >140 h.

Thiotepa

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Third-line agent that acts as an alkylating agent. Intrathecal administration is an off-label use in the United States. It is cleared from CSF within minutes and has survival curves similar to those of methotrexate (MTX) with less neurologic toxicity (most common being transient limb paresthesias). Unlike MTX, no antidote for resulting myelosuppression is available. Causes cross-linking of DNA strands, inhibition of RNA, DNA, and protein synthesis, and thus cell proliferation.

Trastuzumab (Herceptin)

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Off-label intrathecal (IT) administration of trastuzumab has been described in several case reports. Trastuzumab is a monoclonal antibody that inhibits growth of tumor of tumor cells that overexpress HER2. It is an effective systemic treatment of breast cancer, and as such, the potential use of IT administration for LC secondary to breast cancer has shown improved prognosis and decreased progression in several case reports.

Questions

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Author

Herbert H Engelhard, III, MD, PhD, FACS, FAANS Affiliated Professor of Bioengineering, University of Illinois at Chicago

Herbert H Engelhard, III, MD, PhD, FACS, FAANS is a member of the following medical societies: American Association for Cancer Research, American Association of Neurological Surgeons, American College of Surgeons, American Medical Association, Congress of Neurological Surgeons, Illinois State Medical Society

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Jorge C Kattah, MD Head, Associate Program Director, Professor, Department of Neurology, University of Illinois College of Medicine at Peoria

Jorge C Kattah, MD is a member of the following medical societies: American Academy of Neurology, American Neurological Association, New York Academy of Sciences

Disclosure: Nothing to disclose.

Chief Editor

Stephen A Berman, MD, PhD, MBA Professor of Neurology, University of Central Florida College of Medicine

Stephen A Berman, MD, PhD, MBA is a member of the following medical societies: Alpha Omega Alpha, American Academy of Neurology, Phi Beta Kappa

Disclosure: Nothing to disclose.

Additional Contributors

Michael J Schneck, MD, MBA Vice Chair and Professor, Departments of Neurology and Neurosurgery, Loyola University, Chicago Stritch School of Medicine; Associate Director, Stroke Program, Director, Neurology Intensive Care Program, Medical Director, Neurosciences ICU, Loyola University Medical Center

Michael J Schneck, MD, MBA is a member of the following medical societies: American Academy of Neurology, American Society of Neuroimaging, Neurocritical Care Society, Stroke Council of the American Heart Association

Disclosure: Nothing to disclose.

Frederick M Vincent, Sr, MD Clinical Professor, Department of Neurology and Ophthalmology, Michigan State University Colleges of Human and Osteopathic Medicine

Frederick M Vincent, Sr, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, American College of Forensic Examiners Institute, American College of Legal Medicine, American College of Physicians

Disclosure: Nothing to disclose.

Acknowledgements

Lawrence D Recht, MD Professor of Neurology and Neurosurgery, Department of Neurology and Clinical Neurosciences, Stanford University Medical School

Lawrence D Recht, MD is a member of the following medical societies: American Academy of Neurology, American Association for Cancer Research, American Neurological Association, and Society for Neuroscience

Disclosure: Nothing to disclose.

R Andrew Sewell, MD Associate Research Scientist in Psychiatry and Mental Illness Research, Education,Veterans Affairs Connecticut Health Care System, Yale University School of Medicine

R Andrew Sewell, MD is a member of the following medical societies: American Academy of Neurology, American Headache Society, American Pain Society, and American Psychiatric Association

Disclosure: Nothing to disclose.