Treatment of leptomeningeal metastases (carcinomatous meningitis)

INTRODUCTION — Cancer arising outside the central nervous system (CNS) can metastasize to any intracranial structure, including the membranes covering the brain. These membranes consist of the dura mater, and the arachnoid and pia mate, the latter two together are called the leptomeninges. The subarachnoid space lies between the arachnoid and pia mater and contains the cerebrospinal fluid (CSF) and arteries supplying the brain parenchyma. Tumor involvement of the leptomeninges is associated with spread of malignant cells throughout the subarachnoid space, producing signs and symptoms due to multifocal involvement.

GOALS OF TREATMENT — The goals of treatment include symptom palliation, improving or stabilizing neurologic function, and prolonging survival. However, the prognosis varies considerably, depending upon the extent of both neurologic and systemic disease; these factors can help determine the appropriate therapeutic approach for an individual patient.

Poor-risk patients — Patients with a low Karnofsky performance status (KPS) multiple, serious, fixed neurologic deficits, and extensive systemic cancer with limited therapeutic options have a poor prognosis even with active treatment. Management of LM in this setting focuses on alleviating symptoms. A palliative approach should also be considered for patients with leptomeningeal gliomatosis and those with encephalopathy due to extensive brain infiltration (carcinomatous encephalitis), since the prognosis is poor even with combined modality therapy

The palliative regimen can include the following components:

  • Radiation therapy (RT) can be useful for relief of symptoms caused by localized LM.
  • Analgesics are given for persistent pain.
  • Corticosteroids rarely reverse neurologic deficits from LM (except sometimes when LM is due to breast cancer, leukemia, or lymphoma), but they may improve headache and radicular pain more effectively than analgesics.
  • Anticonvulsants should be reserved for patients with seizures (10 to 20 percent of cases), and should not be administered prophylactically.
  • Serotonin reuptake inhibitors or stimulant medications  may be beneficial for patients with significant depression or fatigue.

Good-risk patients — Good-risk patients include those with a KPS of 60 or above, absence of or modest fixed neurologic deficits, minimal systemic disease burden, and/or a cancer for which there are reasonable treatment options. For these individuals, treatment is directed at controlling the tumor. RT is used to treat bulky or symptomatic areas of leptomeningeal disease, intrathecal (IT) or high-dose systemic chemotherapy is given to achieve therapeutic concentrations in the CSF, and extraneural tumor is treated aggressively.

GENERAL PRINCIPLES OF TREATMENT — Management of LM in good-risk patients must be directed toward the entire neuraxis. If therapy is limited to symptomatic areas, disease progression inevitably occurs in untreated sites.

Increased ICP — Elevated ICP is treated initially with dexamethasone, and a dose of 8 mg twice a day is usually effective. Dexamethasone should be started early and the dose reduced as quickly as possible until the lowest effective dose is achieved.

A ventriculoperitoneal shunt (VPS) can be used for symptom palliation if elevated ICP cannot be controlled with dexamethasone . However, this approach should be avoided unless absolutely necessary. In addition to perioperative morbidity and mortality, potential complications arising after VPS placement include infection, failure due to tumor deposition within the shunt, and tumor seeding of the abdominal cavity .

Administration of chemotherapy through a VPS is ineffective, because the dynamics of CSF flow are disturbed and drug distribution is compromised even if the valve is turned off. If the valve is left open, the shunt diverts drug into the peritoneal cavity.

Pretreatment CSF flow study — Prior to RT or IT chemotherapy, a CSF flow study via a radionuclide cisternogram is desirable. If there are areas of obstruction, IT chemotherapy will not be homogeneously distributed, potentially decreasing efficacy and increasing toxicity. RT to areas of obstruction, even if no lesion is identified by MRI, can reverse the flow abnormality, thereby improving the effectiveness of IT chemotherapy.

Abnormal CSF flow is seen in up to two-thirds of patients with LM, often without evidence of hydrocephalus or other abnormalities on conventional neuroimaging studies. Common sites of obstructed CSF flow include the base of the brain (ventricular outlet obstruction), within the spinal canal, and over the cortical convexities.

Response evaluation — Meticulous assessment of the response to therapy is essential to support the continued use of aggressive treatment. Documentation of failure to respond to the initial regimen permits an early change of therapy or the institution of palliative care when appropriate. The original abnormalities in both imaging and CSF studies should be carefully assessed for evidence of response or progression.

CSF cytology — Evaluation of CSF cytology is a critical component of response assessment during IT therapy [8]. CSF should be sampled at each site (lumbar and ventricular) from which malignant cells were originally identified to demonstrate normalization of cytology, since differences in response in ventricular and lumbar fluid are common. Many investigators require two successive negative evaluations from each site before reporting a cytologic response. However, in clinical practice, the requirement for multiple LPs in patients who do not have ventricular reservoirs is difficult to meet.

Other methods — The detection of chromosomal abnormalities by interphase cytogenetics using fluorescence in situ hybridization (FISH) may be useful for patients with known cytologic abnormalities in cells present in the CSF. Similarly, CSF flow cytometry or serial immunocytochemical staining may be useful in patients with lymphoma. These approaches may be more sensitive than cytology in detecting residual malignant cells in the CSF.

RADIATION THERAPY — RT relieves symptoms more rapidly than does IT chemotherapy. As a result, standard treatment for LM includes palliative RT (30 to 36 Gy in 3 Gy daily fractions) to sites of symptomatic or bulky disease. In addition, RT to sites of obstruction of CSF flow, as demonstrated by a radionuclide CSF flow study, should be performed prior to IT chemotherapy

To avoid excess myelosuppression, focal rather than craniospinal RT is preferred. Radiation is usually targeted to symptomatic areas:

  • Cranial irradiation is used in patients with isolated cranial neuropathies or focal collections of malignant cells causing noncommunicating hydrocephalus. Shunting of CSF should be performed in patients with symptomatic or communicating hydrocephalus that does not clear rapidly with treatment.
  • Patients with lower extremity weakness, or bladder or bowel dysfunction generally receive lumbosacral spine irradiation.

Major adverse effects of RT include myelosuppression, mucositis, esophagitis and leukoencephalopathy. Leukoencephalopathy may be especially prominent when RT is administered prior to or concurrently with IT or systemic chemotherapy, particularly methotrexate.

Although RT frequently alleviates radicular pain and encephalopathic symptoms, focal neurologic deficits generally do not improve. However, RT may delay or prevent the development of new neurologic deficits. In addition, involved-field RT can restore normal CSF flow dynamics if it reduces the bulky disease responsible for CSF obstruction. Most good-risk patients also receive IT chemotherapy.

INTRATHECAL CHEMOTHERAPY — IT chemotherapy is the mainstay of treatment for LM, although its effectiveness may be limited and its superiority compared to systemic treatment has not been established in randomized trials. Currently, three drugs are used for IT chemotherapy: methotrexate (MTX), liposomal cytarabine, and less often thiotepa. The role of intrathecal therapy of lymphomatous meningitis is discussed separately.

General principles — IT chemotherapy involves the injection of antitumor agents into the CSF, either directly into the lateral ventricle through a subcutaneous reservoir and ventricular catheter (eg, an Ommaya reservoir) or into the lumbar thecal sac by LP. IT chemotherapy is more likely to be effective for small leptomeningeal deposits and individual tumor cells floating in the CSF. However, it cannot reliably treat bulky disease, because diffusion of drug into tumor deposits thicker than 1 mm, along nerve root sleeves, and into the Virchow-Robin spaces is limited

Intraventricular as opposed to intralumbar IT administrationby LP offers several advantages:

  • Frequent LP is difficult for both the patient and physician, and results in the inadvertent introduction of drug into the epidural or subdural space in 10 percent of administrations
  • Even in the absence of obstruction to CSF flow, administration of chemotherapy via LP results in unpredictable drug concentrations in the ventricles and over the brain convexities  Drug levels in the ventricular CSF following LP are only one-tenth those achieved after an equivalent intraventricular dose. In contrast, administration through an Ommaya reservoir permits more uniform drug distribution throughout the neuraxis
  • A survival benefit has been suggested, although not proven, for intraventricular compared to lumbar IT chemotherapy, perhaps as a consequence of these issues . Whether the magnitude of this advantage is sufficient to outweigh the risks of surgery for reservoir placement and the increased risk of infection is unknown.

We recommend that, whenever possible, IT chemotherapy be administered through a subcutaneous reservoir and ventricular catheter directly into the lateral ventricle (eg, an Ommaya reservoir), rather than by LP. Repeat LP is required in patients who unable or unwilling to undergo surgical placement of a reservoir.

SYSTEMIC CHEMOTHERAPY — Several chemotherapy agents provide therapeutic concentrations within the CSF when given in appropriate doses. This fact has been exploited in regimens for hematologic malignancies to simultaneously treat both systemic and leptomeningeal disease.

Systemic chemotherapy offers several theoretical advantages compared to IT therapy in patients with LM

  • The risks of surgery for placement of a ventricular reservoir and of reservoir-associated complications are obviated.
  • Patients with an obstruction to normal CSF flow can be treated without correction of the flow abnormality.
  • A wider array of cytotoxic agents can be administered.
  • Systemic chemotherapy may provide more uniform drug distribution, and bulky disease may respond because drug is delivered both via the CSF and through the arterial circulation.

Although the blood-brain barrier may be disrupted in some areas of LM, the barrier is normal or only partially disrupted in other areas. Studies of systemic therapy have focused on agents that are either lipid-soluble or that can be given safely at high doses.

PROGNOSIS — Despite aggressive therapy, even good-risk patients with LM usually have a limited survival as illustrated by the following observations:

  • In a series of 59 patients with solid tumors treated with either intrathecal MTX or thiotepa, 75 percent progressed within the first eight weeks of therapy and no patient had meaningful improvement of neurologic deficits
  • In four randomized controlled clinical trials using currently available CNS chemotherapeutic agents, median survival in carefully selected patients was only three to four months

Delayed diagnosis, irreversible neurologic deficits at the time of diagnosis, and extensive disease outside the CNS all can contribute to the observed poor outcome.

Tumor histology may be an important factor influencing prognosis. As an example, the median survival is six to seven months for women with breast cancer who are treated aggressively . In contrast, patients with leptomeningeal spread of high-grade gliomas do particularly poorly; median survival is approximately three months even with aggressive treatment , while those with secondary gliomatosis from low-grade astrocytomas appear to have a longer survival and may benefit from chemotherapy

Performance status and systemic disease burden are important prognostic factors. Prognosis generally is better for younger patients with a good Karnofsky performance status (KPS)  long duration of pretreatment symptoms, and well-controlled extraneural disease compared to those with adverse prognostic factors (eg, advanced age, poor KPS, rapidly progressive neurologic or cognitive deficits, bulky subarachnoid disease on neuroimaging studies)

Despite the poor prognosis in the majority of patients with LM, sustained tumor control is reported in a small subset with favorable characteristics. Such observations provide the primary rationale for aggressive treatment of good-risk patients with low tumor burden (ie, minimal bulky disease in the brain or subarachnoid space).

SUMMARY AND RECOMMENDATIONS — The goals of treatment include symptom palliation, improving or stabilizing neurologic function, and prolonging survival. The prognosis varies considerably, depending upon the extent of both neurologic and systemic disease. The appropriate therapeutic approach for an individual patient is dependent upon these risk factors

Treatment of good-risk patients — For patients with a good performance status, no or modest fixed neurologic deficits, and minimal systemic disease burden or a cancer for which there are reasonable treatment options, we suggest an aggressive approach that includes control of increased intracranial pressure, radiation therapy (RT) to areas of bulky disease and/or obstructed CSF flow, and intrathecal or high-dose chemotherapy.

Specific recommendations include the following:

Increased intracranial pressure — We recommend dexamethasone beginning with a dose of 8 mg twice a day to control increased intracranial pressure. A ventriculoperitoneal shunt should be avoided unless increased intracranial pressure cannot be controlled with corticosteroids.

Radiation therapy — We recommend RT (30 to 36 Gy in 10 to 12 fractions) for the initial management of areas of bulky disease and to treat any obstructions to CSF flow

  • CSF flow study — Prior to beginning RT, a CSF flow study via a radionuclide cisternogram should be done to define any areas of obstruction to CSF flow

IT chemotherapy in patients without bulky LM — For patients without bulky LM, as evidenced by a negative MRI or linear enhancement only, we recommend IT chemotherapy with either methotrexate or DepoCyt

  • Ommaya reservoir — We recommend that IT chemotherapy be administered via an Ommaya reservoir, rather than by lumbar puncture, whenever possible. Meticulous attention to the technique of chemotherapy administration is required
  • Intrathecal methotrexate — We recommend IT methotrexate (10 to 12 mg twice a week) as the preferred agent for patients with LM from solid tumors. After four weeks, the frequency of treatment is tapered to weekly and then every other week in responding patients (

We administer oral leucovorin (10 mg orally twice daily for three days) in all patients receiving IT methotrexate to prevent systemic methotrexate toxicity

  • Liposomal cytarabine (DepoCyt) — DepoCyt (50 mg every two weeks) is an appropriate alternative for patients in whom a less frequent administration schedule for IT chemotherapy is an important consideration

Systemic chemotherapy in patients with bulky LM — For patients with bulky disease, we recommend systemic high-dose methotrexate (MTX, 3 to 8 g/m2 ) with aggressive hydration and leucovorin rescue, rather than IT chemotherapy. This approach is also an alternative when placement of an Ommaya reservoir is difficult or impossible

Evaluation of response — Clinical signs and symptoms, CSF cytology, and radiographic studies should be monitored closely during treatment. Failure to clear malignant cells from the CSF within four to eight weeks after initiating chemotherapy or worsening clinical parameters indicates a need to alter therapy or reconsider therapeutic objectives.

Treatment of poor-risk patients — For poor-risk patients (ie, a poor performance status, significant fixed neurologic deficits, and/or the presence of advanced systemic disease without good therapeutic options), we recommend supportive care to minimize symptoms.