Lymphomatous Meningitis in Primary Central Nervous System Lymphoma

Marc C. Chamberlain, M.D.

Disclosures

Neurosurg Focus. 2006;21(5) 

In This Article

Chemotherapy Management

Chemotherapy is the only modality that can treat the entire neuraxis and can be administered systemically or intrathecally.[11,36,60,63,70] The most effective drug used in patients with newly diagnosed primary CNS lymphoma is high-dose methotrexate.[1,4,5,6,27,28,29,30,32,42,44,52,53,54,55,61,70] When this drug is administered in gram quantities (high dose), cytotoxic CSF levels are achieved. Following a single dose of intravenous methotrexate at 8 g/m2, CSF methotrexate levels greater than 1.0 μM are obtained and sustained for 24 to 48 hours.[36] In a study by Glantz and colleagues[36] of 16 patients with solid tumors and leptomeningeal metastases, methotrexate was administered intravenously at 8 g/m2 over 4 hours and accompanied by serial sampling of CSF and blood.[21] In this study, there was also a parallel group of patients who received intra-CSF methotrexate at a standard dose and schedule. After a single intravenous dose, methotrexate levels of 1.0 μM were maintained in the CSF for, on average, 48 hours and 0.1 μM for up to 93 hours. In the patients who received a single intra-CSF methotrexate dose, levels of 1.0 μM were maintained for 35 to 48 hours and 0.1 μM levels were maintained for approximately 57 hours. Therefore, on these drug schedules and at these doses, the duration of cytotoxic drug exposure in the CSF was similar in patients who received intravenous or intra-CSF methotrexate.

The treatment of concomitant LM in the setting of recurrent parenchymal primary CNS lymphomas is challenging. Most systemic chemotherapy treats LM inadequately due to the insufficient CSF drug levels as seen in cases in which temozolomide, PCV (procarbazine, CCNU, and vincristine), rituximab, or topotecan are used. Exceptions are seen when using high-dose methotrexate, cytosine arabinoside, or thiotepa—chemotherapy agents with demonstrated activity against leptomeningeal metastases. Alternatively, intraventricular chemotherapy can be used, which, although limited to three agents (methotrexate, cytosine arabinoside, and thiotepa), has demonstrated activity and palliative benefit in patients with LM.[16,26,71] However, intra-CSF chemotherapy is primarily effective against small tumor burden and disease involving the CSF and 1 to 2 mm of the leptomeningeal surface.[16,26,71] Larger subarachnoid or parenchymal tumors are ineffectively treated by intra-CSF chemotherapy and, if present, require concomitant systemic chemotherapy or involved-field radiotherapy.[16,17,26,71]

The authors of a retrospective study of 14 patients with recurrent primary CNS lymphomas complicated by LM compared two approaches: seven patients received intraventricular chemotherapy, systemic chemotherapy, and involved-field radiotherapy and seven other patients received high-dose methotrexate or cytarabine systemic chemotherapy and involved-field radiotherapy.[20] Both patient groups were similar in age and prior adjuvant therapies. No significant difference was seen in outcome defined by the percentage of patients with disease-free survival (28%), death due to progressive primary CNS lymphomas (72%), and median survival in patients dying of primary CNS lymphomas (range 5-6 months). Furthermore, in disease-free survivors the incidences of clinically apparent and clinically inapparent imaging-documented leukoencephalopathy were comparable in both treatment groups. Toxicity differed between the treatment groups: in patients who underwent intraventricular chemotherapy, treatment-related aseptic meningitis manifested, whereas mucositis and myelosuppression was seen in patients treated with high-dose methotrexate or cytosine arabinoside.

These results suggest that either treatment approach is valid and equally efficacious. Therefore, the decision of how to treat patients with recurrent primary CNS lymphomas complicated by LM includes two comparable regimens that differ primarily in the use of an intraventricular catheter and reservoir system and frequent outpatient treatments compared with a 3- to 4-day period of hospitalization twice per month. In addition to these considerations, a clear difference exists between toxicity with these treatment approaches. Consequently, recurrent primary CNS lymphomas complicated by LM can be effectively treated by either intraventricular chemotherapy or high-dose systemic chemotherapy using either methotrexate or cytosine arabinoside. Approximately one quarter of patients can be expected to be long-term survivors following treatment; however, 50% will have symptomatic treatment-related leukoencephalopathy.

Notwithstanding the aforementioned study, intra-CSF chemotherapy is the mainstay of treatment for LM. Retrospective analysis or comparison with historical series suggests that CSF chemotherapy improves the outcome of patients with LM.[9,16,34,38,39,43,46,64,71] It is noted, however, that the authors of most series will exclude patients who are too sick to receive any treatment, which may be as many as one third of patients with LM.[38,39] Three agents are routinely used: methotrexate, cytarabine (including extended-release liposomal cytarabine or DepoCyt), and thiotepa. No difference in response has been seen when comparing single-agent methotrexate with thiotepa or when using multiple-agent (methotrexate, thiotepa, and cytarabine or methotrexate and cytarabine) compared with single-agent methotrexate treatment. A sustained-release form of cytarabine (DepoCyt) results in cytotoxic cytarabine levels in the CSF for greater than or equal to 10 days; when given bimonthly and compared with biweekly methotrexate, it resulted in greater duration before neurological progression in patients with LM.[38] Furthermore, the data pertaining to the quality of life and cause of death favored DepoCyt over methotrexate. These findings have been confirmed in a study of LM and in an open-label study, suggesting that DepoCyt should be considered the drug of first choice in the treatment of LM.[39,46]

Complications of intra-CSF chemotherapy include those related to the ventricular reservoir and those related to the chemotherapy agent(s) administered.[19,64] The most frequent complications of ventricular reservoir placement are malposition (range of reported rates 3-12%), obstruction, and infection (usually skin flora). Cerebrospinal fluid infection occurs in 2 to 13% of patients undergoing intra-CSF chemotherapy. Patients with CSF infection commonly present with headache, changes in neurological status, fever, and malfunction of the reservoir. Cerebrospinal fluid pleocytosis is commonly encountered. The most frequently isolated organism is Staphylococcus epidermidis. Treatment requires intravenous administration of antibiotics with or without oral and intraventricular agents. Some authors have advocated the routine removal of the ventricular reservoir, whereas others believe that removal of the device should be reserved for cases in which antibiotic therapy does not resolve the infection. Routine culturing of CSF samples is not recommended because of the high rate of contamination with skin flora in the absence of infection. Myelosuppression can occur after administration of intra-CSF chemotherapy agents, and it is recommended that folinic acid rescue (10 mg every 6 hours for 24 hours) be given orally after the administration of methotrexate to avoid this complication. Chemical aseptic meningitis occurs in nearly 50% of patients treated by intra-CSF administration, and its symptoms manifest as fever, headache, nausea, vomiting, meningismus, and photophobia. In most patients, this inflammatory reaction can be treated in the outpatient setting with oral antipyretic, antiemetic, and corticosteroid agents. Rarely, treatment-related neurotoxicity occurs and can result in a symptomatic subacute leukoencephalopathy or myelopathy. In patients with LM and prolonged survival, however, the combination of radio- and chemotherapy frequently results in a late-onset leukoencephalopathy evident on imaging studies and occasionally causing symptoms.[34,38,39,43,46,62]

The rationale for giving intra-CSF chemotherapy is based on the presumption that most chemotherapeutic agents, when administered systemically, have poor CSF penetration and do not reach therapeutic levels. Exceptions to this would be systemic high-dose methotrexate, cytarabine, and thiotepa, all of which result in cytotoxic CSF levels. Their systemic administration is limited, however, by systemic toxicity and by the difficulty of integrating these regimens into other chemotherapeutic programs being used to manage a patient's systemic disease. Additionally, in patients with recurrent primary CNS lymphomas and previous treatment with high-dose methotrexate, alternative systemic therapies are used without compelling evidence of CSF penetration or the ability to eradicate the CSF compartment. Some authors have argued that intra-CSF chemotherapy does not add to improved outcome in the treatment of LM, because systemic therapy can reach the subarachnoid deposits through tumor vascular supply.[62]

Nonetheless, intrathecal chemotherapy remains the preferred treatment route for LM at this time. New intra-CSF drugs are being explored to try to improve efficacy, including mafosphamide, diaziquone, topotecan, interferon-α, etoposide, rituximab, and temozolomide. Gene therapy and immunotherapy using interleukin-2 and interferon-α, 131I-radiolabeled monoclonal antibodies are other modalities being explored in clinical trials.

Not all patients with LM are candidates for the aggressive treatment outlined in this review. Most authors agree that combined-modality therapy should be offered to patients with a life expectancy greater than 3 months and a Karnofsky Performance Scale score greater than 60.

Certain supportive care measures should be offered to every patient, regardless of whether they receive LM-directed therapy. These therapies include anticonvulsant agents for seizure control (seen in 10-15% of patients with LM), adequate analgesia with opioid drugs, as needed, and antidepressant and anxiolytic medications if necessary. Corticosteroid agents are of limited use in LM-related neurological symptoms but can be useful to treat vasogenic edema associated with intraparenchymal or epidural metastases or for the symptomatic treatment of nausea and vomiting together with routine antiemetic agents. Decreased attention and somnolence secondary to whole-brain radiotherapy can be treated with psychostimulants.

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