eMedicine Specialties > Neurology > Neuro-oncology

Leptomeningeal Carcinomatosis: Treatment & Medication

Author: R Andrew Sewell, MD, Clinical Instructor in Psychiatry and Mental Illness Research, Education, and Clinical Center (MIRECC) Fellow, Veterans Affairs Connecticut Health Care System, Yale University School of Medicine
Coauthor(s): Lawrence D Recht, MD, Professor of Neurology and Neurosurgery, Department of Neurology and Clinical Neurosciences, Stanford University Medical School
Contributor Information and Disclosures

Updated: Nov 23, 2009

Treatment

Medical Care

Treatment goals of leptomeningeal carcinomatosis (LC) include improvement or stabilization of the patient's neurologic status, prolongation of survival, and palliation. Some clinicians are hesitant to even treat LC, given the short duration of survival and risk of neurotoxicity, but a high index of suspicion and prompt treatment can prevent serious and irreversible neurologic damage. The lack of large randomized controlled trials has made the correct choice of treatment controversial. Most patients require a combination of surgery, radiation, and chemotherapy.

• Decide the intensity of treatment based on the presence of a systemic cancer that is responsive to treatment and preexisting neurologic damage and relatively preserved functionality.
• Treat the systemic cancer, as the patient is likely to die from that.
• Treat the entire neuraxis, as tumor cells are disseminated widely by CSF flow. The standard therapies are (1) radiation therapy to symptomatic sites and regions where imaging has demonstrated bulk disease and (2) intrathecal chemotherapy.
  • Radiation palliates local symptoms, relieves CSF flow obstruction, and treats areas such as nerve-root sleeves, Virchow-Robin spaces, and the interior of bulky lesions that chemotherapy does not reach. Even without evidence of bulky disease, patients may benefit from radiation. Radiation therapy typically consists of 2400 rads given in 8 doses over 10-14 days. Radiation is directed to the site of major clinical involvement and planned so that myelosuppression is acceptable and does not compromise efforts to eliminate malignant cells from the CSF. Dosages can range from 20 Gy in 1 week to 30 Gy over 3-4 weeks. The dosage for lymphomatous and leukemic meningitis is usually 30 Gy given over 10 doses.
  • Intrathecal chemotherapy treats subclinical leptomeningeal deposits and tumor cells floating in the CSF, preventing further seeding.³
    • Three agents are routinely given; methotrexate (MTX), cytarabine (Ara-C), and thiotepa.
    • Cytararabine is the first-choice agent (in its liposomal form only); it is not effective for solid tumors but is useful in leukemic and lymphomatous meningitis. It is now available in liposome-encapsulated form (DepoCyt) that can be administered every 2 weeks rather than 2-3 times a week and results in a longer time to disease progression and higher quality of life than therapy with MTX.
    • Thiotepa, the second-line agent after MTX and cytarabine, is cleared from CSF within minutes and has survival curves similar to those of MTX with less neurologic toxicity than MTX.
    • The superiority of combination intrathecal therapies over single agents is controversial. Six randomized trials have shown no difference between single-agent methotrexate and combined therapy, and combination treatments may be more neurotoxic than single agents.
    • For patients who respond well to treatment, start treatment with radiation to bulky tumors and symptomatic sites, and place a ventricular catheter if possible. Scan CSF flow, and follow this with intrathecal chemotherapy if CSF flow is not obstructed. Also, optimally manage any systemic cancers.
• For patients with a fair response to treatment, local radiation therapy and intrathecal chemotherapy delivered by means of LP may be appropriate.
• For patients who are classified as poor risk, offer radiation therapy to symptomatic sites or supportive measures only (eg, analgesics, anticonvulsants, and steroids). Treatment is difficult and primarily palliative, and results are generally poor because of the presence of many metastases.
• A number of other therapies are under development.
  • Mafosfamide is a form of cyclophosphamide that is active intrathecally and has little neurotoxicity aside from headaches, but only phase II trials have been conducted.
  • Rituximab has been given intrathecally and is also in Phase II trials (LC from lymphoma only).⁴
  • Trastuzumab has been given intrathecally to treat LC from breast cancer.⁵
  • Diaziquone is effective in hematologic tumors. Adverse effects include headaches and immunosuppression. It can be given at a dosage of 2 mg twice weekly.
  • Temozolomide, in combination with Ara-C, has completed Phase I/II trials.
  • Another drug, 4-hydroperoxycyclophosphamide (4-HC) is in phase I trials and is apparently effective in treating medulloblastoma.
  • Topotecan, a topoisomerase I inhibitor, has completed phase II trials.
  • A drug available for high-dose systemic administration, 6-mercaptopurine (6-MP), has shown efficacy in some patients.
  • There are case reports of LC from non—small cell lung cancer (NSCLC) or breast cancer responding to intrathecal gemcitabine, trastuzumab, letrozole, and tamoxifen.
  • One patient with LC from prostate cancer responded to hormonal manipulation.
  • Intrathecal busulfan, currently in phase I trials, may be active against cyclophosphamide-resistant neoplasms and other tumors.
  • Another drug, 3-(4-amino-2-methyl-5-pyrimidinyl) methyl-1-(2-chloroethyl)-1-nitrosourea hydrochloride (ACNU) is modestly effective in animal studies; however, it is neurotoxic and not yet available for use in humans.
  • Immunotoxins, such as monoclonal antibodies coupled with a protein toxin or radioisotope, seem effective and are being studied.
  • Gene therapy based on the herpes simplex virus thymidine kinase gene combined with ganciclovir is under study but not yet available.
• Supportive care: Offer analgesia with opioids, anticonvulsants for seizures, antidepressants, and anxiolytics to all patients as needed. Treat attention problems and somnolence from whole-brain radiation with psychostimulants or modafinil.

Surgical Care

• Place an intraventricular or subgaleal catheter if necessary for the administration of cytotoxic drugs.
• In patients with symptomatic increased ICP (ie, severe intractable headache, papilledema, stupor, and repetitive plateau waves on EEG), placement of a ventriculoperitoneal shunt may be necessary if the increased ICP is not ameliorated by steroids.
• Administer intrathecal chemotherapy by means of LP rather than an Ommaya device if a shunt is present to ensure that the medication reaches the basal cisterns and spinal leptomeninges.
• Resect parenchymal brain metastases, if present.

Medication

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 LC 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.

Chemotherapeutic agents

These agents inhibit cell growth and proliferation.

Methotrexate (Folex PFS, Rheumatrex)

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; Cytosine arabinoside (Cytosar-U)

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

Third-line agent, cleared from CSF within minutes and has survival curves similar to those of 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, inhibiting of RNA, DNA, and protein synthesis and thus cell proliferation.

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