TREATMENT OPTIONS

Management of patients with neoplastic meningitis is ideally multimodal. Determining the status of the underlying systemic disease is the first step in treatment planning. Identification of any extraneural sites of metastasis via positive emission tomography (PET), MRI, or other imaging studies is also necessary.10 Treatment focuses on controlling progression of the underlying disease in patients with advanced cancer, palliating distressing symptoms, and delaying neurologic progression and the advent of new focal deficits.2 Standard treatment approaches typically include focal radiation to lesions that are bulky, obstruct CSF flow, or produce debilitating symptoms.1 Distressing symptoms should be treated aggressively.


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Intrathecal chemotherapy agents administered directly into the CSF is another standard component of the treatment regimen for neoplastic meningitis.1 Methotrexate, cytarabine, and cytarabine liposome are cell cycle specific cytotoxic agents used for intrathecal chemotherapy. Trials that used other chemotherapeutic agents (rituximab, trastuzumab, and topotecan as single agents and in combination with the standard treatments) have been published. Intrathecal chemotherapy agents can be administered via a lumbar puncture or through an intraventricular access device. Methotrexate and cytarabine have significantly shorter durations of cytotoxic concentration compared with liposomal cytarabine; therefore, they require more frequent dosing (ie, twice a week for methotrexate and cytarabine vs once every 2 weeks for liposomal cytarabine).2,10 Short-term use of the corticosteroid dexamethasone is always required during peritreatment with liposomal cytarabine to prevent or ameliorate chemical meningitis, also known as arachnoiditis; dexamethasone may also be required during peritreatment with methotrexate and cytarabine.13 A patient on a chronic corticosteroid may require a stress dose, or temporary increase, that mirrors the required dose. Patients with a long term exogenous source of corticosteroid, such as dexamethasone, experience a shutdown of the adrenal glands, where these corticosteroids are produced endogenously. Therefore, they cannot respond to an increased need spontaneously, and the dose needs to be increased to substitute what would have been the body’s natural response.

Methotrexate and cytarabine are well-established treatments. Although liposomal cytarabine may be less familiar to some clinicians, the literature suggests that its structure—cytarabine encapsulated in a lipid complex—allows the cytotoxicity of the drug to be extended and results in more efficacious clearing of malignant cells from the CSF.14 In addition, the extended cytotoxicity of this drug is advantageous when an intralumbar route is utilized.13,15 Lastly, some published data suggest that patients treated with the liposomal preparation have improved Karnofsky performance scores and longer neurologic stability.8,15

Intrathecal chemotherapy is typically administered in the outpatient setting (a clinic, the office, or an infusion center). No premedication (other than dexamethasone), hydration, or special monitoring is required. Standard lumbar puncture kits contain most of the necessary supplies, including sterile gauze pads, an alcohol swab, a 23-gauge butterfly needle, a three-way stopcock, and four 10-ml syringes; sterile gloves and betadine solution (not swabs) are also needed. As mentioned above, preserving the cytology specimen at the bedside in 10% formalin fixative (usually in a 50-ml centrifuge tube) is recommended. The importance of maintaining sterility cannot be overstated; contamination of an intraventricular device can result in bacterial meningitis, which may necessitate reservoir removal.16 Standard chemotherapy precautions are necessary with all three drugs and includes monitoring immediate adverse reactions and sterilizing any areas that may have come in contact with contaminants.

Patients may experience headache and fatigue while receiving intrathecal chemotherapy. Arachnoiditis, or chemical meningitis, is the most common side effect and 8,13,17 manifests as headache, fever, stiff neck, and general malaise. Patients may also have signs of mental status change or experience seizures. CSF WBCs may be elevated even in the absence of infection.18 Patients usually respond to a marked but temporary increase in dexamethasone, followed by a slow taper as symptoms become better controlled. True infection can be ruled out with a CSF culture.5

The recommended treatment duration for intrathecal cytotoxic agents is not clearly delineated in the literature. The usual treatment regimen for methotrexate or cytarabine is two treatments per week for 4 weeks, and then continuing until the CSF consistently demonstrates no evidence of malignant cells or until the patient’s functional status declines, precluding their candidacy for treatment.13 Liposomal cytarabine is administered on a 5×5 regimen, which is a regimen utilized in several clinical trials. The first five doses are given at 2-week intervals and the remaining five are given at monthly intervals, again with sensitivity to the patient’s condition and tolerance of the drug.8,17 Patients should be screened at each visit for disease progression or regression via a thorough neurologic examination and CSF analysis. Close questioning of patients and caregivers, using repetitive phrasing, regarding the patient’s functional status can lend valuable insight into treatment response, as the overall goal is palliation.

TREATMENT PROGNOSIS

The prognosis for patients with neoplastic meningitis remains poor despite aggressive, multimodal treatment directed at the CNS as well as the underlying disease, where appropriate; median survival from the point of diagnosis is 2 to 6 months.1,10,19 Although the presence and severity of any underlying or concurrent systemic disease impacts outcomes, neoplastic meningitis is resistant to treatment and significantly increases patient morbidity and mortality.

Early identification and early aggressive treatment may stabilize or slow disease progression, especially if symptoms are limited to a single CNS domain and the patient retains normal or near-normal neurologic function.2,14,19 If treatment is instituted after a neurologic deficit manifests, disease typically does not regress or improve but usually does stabilize. This stabilization benefits patients’ quality of life and eases the burden on caregivers. Maintaining neurologic function is an important quality-of-life factor; research suggests that many patients would elect to have treatment that has no demonstrable survival advantage if functional status could be protected for a period of time.13 Given the scope and severity of symptoms that a patient with neoplastic meningitis might experience, raising awareness about the disease would clearly benefit patients.