Leptomeningeal Carcinomatosis Treatment & Management

Updated: Nov 27, 2017
  • Author: Michael J Schneck, MD, MBA; Chief Editor: Stephen A Berman, MD, PhD, MBA  more...
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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 previously reported 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 systemic disease.

For patients with lung cancer, systemic therapy with modern chemotherapeutic agents prolongs survival. In a study from Stanford University, a systemic regimen containing pemetrexed, bevacizumab, or a tyrosine kinase inhibitor was associated with mean survival of six months and a statistically significant decreased hazard of death (hazard ratio [HR], 0.24; P = .007). [33]

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. [2]

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.

Additional chemotherapeutic regimens have been associated with prolonged survival in systemic cancers and are discussed below.

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.

Other therapies in development

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). [8]

  • Trastuzumab has been given intrathecally to treat LC from breast cancer. [9, 38, 39, 40]

  • 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.

  • Epidermal growth factor receptor inhibitors (EGRG) as monotherapy or in combnation may be beneficial in treatment of LC due to non-small cell lung cancer. Example of these agents include afatinib, cetuximab, erlotinib, afatinib, pemetrexed, bevacizumab,  and orbevacizumab.

  • Bevacizumab has also demonstrated activity in CNS choroidal metastases and is used to treat radiation necrosis of the brain and glioblastoma multiforme.

  • Tyrosine kinase inhibitiors such as crizotinib, erlotinib, or gefitinib may also be helpful in patients with LC in the context of NSLC.

  • The survival benefit for NSLC patients with LC was also greater for patients treated with pemetrexed, an inhibitor of thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltransferase (GARFT), which are involved in purine and pyrimidine synthesis necessary for formation of new DNA and RNA.

  • 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

Placement of an intraventricular or subgaleal catheter is 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 (VP) shunt may be necessary if the increased ICP is not ameliorated by steroids. This should be done even with the risk of peritoneal seeding as the presence of LC in the context of systemic cancer implies that diffuse spread of the cancer has already occurred. Placment of a VP shunt is typically a palliative procedure however, because the presence of hydrocephalus portends poor survival.

In patients with LC and hydrocephalus, Lin et al found that placement of a combined reservoir-on/off valve-ventriculoperitoneal shunt system was safe, resulted in symptomatic improvement in most patients, and could effectively administer intrathecal chemotherapy. [10]

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.

Intrathecal (IT) administrations may be preferable to lumbar puncture (LP) for short half-life drugs such as methotrexate; for drugs with longer half-lives, route of administration (IT or LP) may be less critical. [36]

Resect parenchymal brain metastases, if present.