Leptomeningeal carcinomatosis (LC) is a rare complication of cancer in which the disease spreads to the membranes (meninges) surrounding the brain and spinal cord. LC occurs in approximately 5% of people with cancer and is usually terminal. If left untreated, median survival is 4-6 weeks; if treated, median survival is 2-3 months.
Essential update: Impact of leptomeningeal carcinomatosis on survival in non-small-cell lung cancer patients
Due to improvements in treatment and survival, an increasing number of patients with metastatic non-small-cell lung cancer (NSCLC) are diagnosed with leptomeningeal carcinomatosis (LC). A retrospective review of 149 NSCLC patients with cytologically proven LC found that although prognosis of LC from NSCLC is poor, some patients do have improved median overall survival. According to researchers, intrathecal chemotherapy (ITC), whole-brain radiotherapy (WBRT), systemic therapy with epidermal growth factor receptor tyrosine kinase inhibitors, and ventriculoperitoneal (VP) shunt operations to treat LC might improve clinical outcomes in NSCLC patients.
In this study, the median follow-up duration was 34 months, and median overall survival was 14 weeks following diagnosis of LC. Treatment numbers were as follows: ITC alone in 44 patients, ITC plus systemic therapy in 18 patients, ITC plus radiotherapy in 29 patients, all 3 treatments in 18 patients, other treatments without ITC in 20 patients, and only supportive care in 20 patients.
Signs and symptoms
Meningeal symptoms are the first manifestations in some patients (pain and seizures are the most common presenting complaints) and can include the following:
Headaches (usually associated with nausea, vomiting, light-headedness)
Gait difficulties from weakness or ataxia
CNS symptoms are divided into the following 3 anatomic groups:
Cerebral involvement: Headache, lethargy, papilledema, behavioral changes, and gait disturbance.
Cranial-nerve involvement: Impaired vision, diplopia, hearing loss, and sensory deficits, including vertigo; cranial-nerve palsies commonly involve CN III, IV, VI, VII, and VIII
Spinal-root involvement: Nuchal rigidity and neck and back pain, or invasion of the spinal roots.
See Clinical Presentation for more detail.
Diagnosis of LC is made with positive CSF cytologic results, subarachnoid metastases identified on radiologic studies, or a history and physical examination suggestive of LC along with abnormal CSF findings.
The standard diagnostic procedure
Positive CSF cytology is found on the initial lumbar puncture in 50-70% and in nearly all cases after 3 attempts
Increased CSF pressure and elevated CSF protein are also commonly found.
Gadolinium-enhanced multiplanar MRI is the preferred imaging modality over CT because of its sensitivity and specificity
MRI findings considered diagnostic of LC include leptomeningeal enhancement of the brain, spinal cord, cauda equina, or subependymal areas, which extend into the sulci of the cerebrum or folia of the cerebellum
MRI of the spinal cord can show nerve-root thickening, cord enlargement, intraparenchymal and subarachnoid nodules, or epidural compression
See Workup for more detail.
Leptomeningeal carcinomatosis is incurable and difficult to treat. Treatment goals include improvement or stabilization of the patient's neurologic status, prolongation of survival, and palliation. Most patients require a combination of surgery, radiation, and chemotherapy.
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.
Intrathecal chemotherapy treats subclinical leptomeningeal deposits and tumor cells floating in the CSF, preventing further seeding. Cytarabine (Ara-C), methotrexate (MTX), and thiotepa are 3 agents routinely administered.
Supportive care for patients includes analgesia with opioids, anticonvulsants for seizures, antidepressants, and anxiolytics. Attention problems and somnolence from whole-brain radiation can be treated with psychostimulants or modafinil.
Leptomeningeal carcinomatosis (LC), also termed neoplastic meningitis, is a serious complication of cancer that carries substantial rates of morbidity and mortality. It may occur at any stage in the neoplastic disease, either as the presenting sign or as a late complication, though it is associated frequently with relapse of cancer elsewhere in the body.
LC occurs with invasion to and subsequent proliferation of neoplastic cells in the subarachnoid space. Intra-axial CNS tumors of diverse origins and hematologic cancers may spread to this space, which is bound by the leptomeninges.
The leptomeninges consist of the arachnoid and the pia mater; the space between the 2 contains the CSF. When tumor cells enter the CSF (either by direct extension, as in primary brain tumors, or by hematogenous dissemination, as in leukemia), they are transported throughout the nervous system by CSF flow, causing either multifocal or diffuse infiltration of the leptomeninges in a sheetlike fashion along the surface of the brain and spinal cord. This multifocal seeding of the leptomeninges by malignant cells is called leptomeningeal carcinomatosis if the primary is a solid tumor, and lymphomatous meningitis or leukemic meningitis if the primary is not a solid tumor.
Lymphomatous or leukemic meningitis is somewhat of a misnomer, as meningitis implies an inflammatory response that may or may not be present. First recognized by Eberth in 1870, LC remains underdiagnosed even today. Nevertheless, it has been recognized more frequently in the last 3 decades than before because of improved diagnostic tools, therapy, and awareness. It is not a single entity pathologically; it can occur concurrently with CNS invasion or wide dissemination in the intraventricular spaces, or in association with CNS metastases, with the clinical picture differing somewhat in each case.
Metastatic seeding of the leptomeninges may be explained by the following 6 postulated mechanisms: (1) hematogenous spread to choroid plexus and then to leptomeninges, (2) primary hematogenous metastases through the leptomeningeal vessels, (3) metastasis via the Batson venous plexus, (4) retrograde dissemination along perineural lymphatics and sheaths, (5) centripetal extension along perivascular and perineural lymphatics from axial lymphatic nodes and vessels through the intervertebral and possibly from the cranial foramina to the leptomeninges, and (6) direct extension from contiguous tumor deposits. CSF flow then seeds the tumor cells widely, with infiltration greatest at the basilar cisterns and dorsal surface of the spinal cord, particularly the cauda equina.
Signs and symptoms are usually attributable to obstruction of CSF flow by tumor adhesions that leads to one of the following:
Increased intracranial pressure (ICP) or hydrocephalus
Local tumor infiltration in the brain or spinal cord that causes cranial-nerve palsies or radiculopathies
Alterations in the metabolism of nervous tissue that cause seizures, encephalopathy, or focal deficits
Occlusion of blood vessels as they cross the subarachnoid, leading to infarcts
Approximately 1-8% of patients with cancer are diagnosed with LC, and it is present in 19% of those with cancer and neurologic signs and symptoms on autopsy, usually in those with disseminated systemic disease. LC is present in 1-5% of patients with solid tumors, 5-15% of patients with leukemia, and 1-2% of patients with primary brain tumors. LC can be the presenting symptom 5-10% of the time; however, the exact incidence is difficult to determine. Gross inspection at autopsy may miss LC, and microscopic pathologic examination findings may be normal if the seeding is multifocal or if an unaffected area of the CNS is examined.
Adenocarcinomas are the most common tumors to metastasize to the leptomeninges, although any systemic cancer can do so. Small-cell lung cancers spread to the leptomeninges in 9-25% of cases; melanomas, in 23%; and breast cancers, in 5%. However, because of the different relative frequencies of these cancers, most patients with LC have breast cancer.
Uncommon neoplasms, such as embryonal rhabdomyosarcoma and retinoblastoma, also tend to spread to leptomeninges, but sarcomas rarely do. Medulloblastomas are among those tumors that spread to the CSF, as do ependymomas and glioblastomas on occasion. Squamous cell carcinomas of head and neck can spread to the meninges along cranial-nerve paths. Although LC is uncommon in children, it can be seen in those with acute lymphocytic leukemia (ALL) and primary brain tumors, particularly ependymomas, medulloblastomas, and germ-cell tumors.
The incidence of LC increases the longer a patient has the primary cancer; LC is accompanied by other intracranial metastases in 98% of patients with a nonleukemic primary cancer.
The median survival is 7 months for patients with LC from breast cancers, 4 months for patients with LC from small-cell lung carcinomas, and 3.6 months for patients with LC from melanomas.
Without therapy, most patients survive 4-6 weeks, with death occurring because of progressive neurologic dysfunction.
With therapy, most patients die from the systemic complications of their cancer rather than the neurologic complications of LC.
Fixed focal neurologic deficits (eg, cranial-nerve palsies) generally do not improve, but encephalopathies can improve dramatically with treatment.
There is no evidence that races are differentially affected.
Men and women are equally affected.
The incidence of most forms of cancer that lead to LC increases with age.
Involvement of the CNS is divided into the following 3 broad anatomical groups:
Cerebral involvement results in headache, lethargy, papilledema, behavior changes, and gait disturbance (the latter can be due to either cerebellar or cauda equina involvement). Major dysfunction, such as hemiparesis and hemisensory loss or visual field defects, is rare and more indicative of parenchymal metastasis.
Cranial-nerve involvement presents with impaired vision, diplopia (most common), hearing loss, and sensory deficits, including vertigo. Palsies of cranial nerves III, V, and VI are most common; palsy of nerve VII is less common. Solid tumor-derived LC has a higher affinity for the optic and extraocular nerves, while leukemic meningitis preferentially affects the facial nerve. Involvement of multiple cranial nerves is the rule rather than the exception.
Spinal-root involvement is caused by either meningeal irritation, presenting with nuchal rigidity (15%) and neck and back pain (rare), or invasion of the spinal roots. The latter can cause leg weakness, radiculopathy (usually lumbar, mimicking a herniated disk), reflex asymmetry or loss (most common, noted in 70% of patients), sphincter incontinence (less common), positive Babinski reflexes, paresthesias, and numbness. Asymptomatic bladder enlargement can occur from spinal cord compression. Spinal-root symptoms are usually followed by cranial-nerve symptoms. Nuchal rigidity, positive results on the straight-leg raising test, and decreased rectal tone are rare.
Over the course of the disease, cranial-nerve deficits are the most frequent signs, occurring in 94% of patients. Although these are seldom the presenting complaint (30% of patients), mild cranial-nerve abnormalities are usually present on physical examination; the abnormalities typically include diplopia, dysphagia, dysarthria, and hearing loss. However, most patients do not have isolated cranial-nerve deficits; rather, they have a combination of cranial-nerve, cerebral, and spinal signs.
The diagnosis is made with positive CSF cytologic results (the most useful test), subarachnoid metastases identified on radiologic studies, or a history and physical examination suggestive of LC along with abnormal CSF findings. Order a workup for LC in patients presenting with the following:
Neurologic signs and symptoms at more than 1 level of the neuraxis (present in 75% of patients with LC).
Neurologic signs and symptoms consistent with a single lesion but with no mass evident on imaging.
Neurologic signs and symptoms consistent with inflammatory meningitis but without fever.
Imaging showing leptomeningeal enhancement or CSF-flow obstruction.
Elevated CSF protein level in a patient with cancer but without known cerebral metastases.
The first step in the diagnostic workup should be gadolinium-enhanced MRI of the area of maximal symptomatology, followed by a lumbar puncture (LP) if the patient has no evidence of increased ICP, repeated as many as 3 times or until findings are positive.
In general, imaging findings are consistent with or suggestive rather than diagnostic of LC, and they are most useful in detecting secondary complications of LC, such as hydrocephalus, periventricular edema, and gyral effacement.
About 50% of patients with LC have abnormal imaging findings, most commonly contrast enhancement of the basilar cisterns, cortical convexities, cauda equina, or hydrocephalus without a mass legion. However, this enhancement usually follows positive cytologic findings by 6 months.
MRI of the spinal cord involvement can show nerve-root thickening, cord enlargement, intraparenchymal and subarachnoid nodules, or epidural compression.
Meningeal enhancement, which reflects either a blood supply outside the blood-brain barrier or a disturbed blood-brain barrier, is also seen in infections, inflammatory diseases, trauma, or subdural hematomas; after craniotomy; and sometimes after LP. Nevertheless, delineation of the extent of leptomeningeal disease through imaging is important because radiotherapy then can be effectively targeted to these regions rather than to the entire neuraxis.
Perform contrast-enhanced brain CT or gadolinium-enhanced MRI of the entire CNS in patients with cancer and neurologic symptoms to look for metastases and to determine the risk of herniation from LP. However, these tests are relatively insensitive for LC itself. The sensitivity of MRI for LC is nearly 70% while that of CT is around 30%; both have a false-negative rate of 60%, however, so normal imaging does not exclude the diagnosis.
CT, although usually normal, may reveal unexplained communicating hydrocephalus or abnormal enhancement of the tentorium, sylvian fissures and basal cisterns, cortical subarachnoid space, and ventricular walls.
Although seldom indicated, myelography may show nodularities or thickening of the nerve roots in approximately 25% of patients with LC, with similar findings apparent on MRI. Myelography can show intra-arachnoid nodular filling defects, longitudinal striations, prominent and crowded nerve roots of the cauda equina, or scalloping of the subarachnoid space.
Radionuclide studies using either111 indium-diethylenetriamine penta-acetic acid or99 Tc macroaggregated albumin can be used to assess CSF flow, which is abnormal in 30-40% of patients with LC. Abnormal CSF flow must be addressed prior to the administration of intrathecal chemotherapy, as it can prevent homogenous delivery.
Myelography, cerebral arteriography, and other tests, such as EEG, seldom are indicated.
Electromyography (EMG) can assist with diagnosis, but it is rarely necessary.
Monoclonal antibodies can be useful in diagnosing CSF lymphoma, particularly if cytologic examination cannot distinguish between reactive lymphocytes and malignant lymphocytes.
Analysis of CSF obtained is more accurate than that obtained by using a ventricular catheter, as ventricular fluid usually has higher glucose and lower protein levels and is less likely to yield positive cytologic findings. For this reason, periodic LP is recommended, even in patients with catheters.
Measure the opening pressure (elevated in 50% of patients) and send the CSF for an analysis of cytology, cell counts, and protein and glucose levels.
Carcinoma cells in the CSF are diagnostic, with the exception of a few false-positive results in patients who have reactive lymphocytes (which are difficult to distinguish from malignant lymphomatous cells) because of an infectious or inflammatory process in the CSF. However, negative cytologic findings do not rule out the diagnosis, as 50% of patients with LC have a negative cytologic result on the first LP. This percentage drops to 20% after 2 high-volume LPs and 15% after 3.
Cytologic findings are more likely to be positive in patients with extensive leptomeningeal involvement than in patients with focal involvement because CSF obtained from a site distant to the pathology is more likely to yield negative pathology.
Other causes of false negatives can include not obtaining CSF from a site of symptomatic or radiographically demonstrated disease, withdrawing < 10.5 mL CSF, delayed processing of samples, and obtaining only 1 sample.
CSF pleocytosis and modest protein elevations are consistent with but not indicative of the diagnosis, but reduced glucose levels usually are seen only with LC (ie, abnormal glucose transport) or infection (ie, increased glucose utilization).
The lymphocyte count is elevated in more than 50% of patients with LC, and the presence of eosinophils should raise the suspicion of lymphomatous infiltration (except patients who are given ibuprofen).
Xanthochromia can occur from leptomeningeal bleeding, which is most likely in LC from a melanoma.
Most biochemical markers in CSF have poor sensitivity and specificity, but when present, levels decline with successful therapy. Their reelevation can thus signal a relapse before any other findings become apparent. Useful markers include carcinoembryonic antigen (CEA) from adenocarcinomas, alpha-fetoprotein and beta-human chorionic gonadotropin from testicular cancers, 5-hydroxyindoleacetic acid (5-HIAA) from carcinoid tumors, and immunoglobulins from multiple myeloma; their presence in CSF is virtually diagnostic. Nonspecific markers such as endothelial growth factor can be strong indirect indicators of LC, but none are sensitive enough to improve th e cytological diagnosis.
Epithelial-associated glycoprotein (HMFGI antigen) is present in 90% of LCs.
Cytokeratins measured by tissue polypeptide antigen (TPA) and tissue polypeptide-specific antigen (TPS) have 80% sensitivity to LC from breast cancer.
Neither CEA nor beta-glucuronidase is helpful in detecting solid tumors or metastases, nor are they useful in detecting leptomeningeal lymphomatosis. However, if their levels are elevated, a return to normal levels of both markers signifies successful treatment.
Elevated CSF CEA is specific, unless serum levels are unusually high (ie, >100 ng/mL).
CSF beta-glucuronidase values are frequently elevated, but wide fluctuations make it unreliable as a marker, and elevations also occur with bacterial, viral, fungal, or tubercular meningitis. In association with elevated lactate dehydrogenase (LDH), however, high CSF beta-glucuronidase levels can indicate LC from a breast primary tumor with a high sensitivity and specificity.
CSF fibronectin values are elevated in LC but also in bacterial meningitis and tick-borne encephalitis.
Myelin basic protein can indicate disease activity, particularly if values are measured longitudinally.
CSF vascular growth factor has recently been suggested as a useful biomarker.
Antithrombin III has been suggested as a useful biomarker in patients with primary CNS lymphoma but has not been evaluated in patients with LC.
For lymphoma and leukemia, the weight of the evidence (as well as recent National Comprehensive Cancer Network guidelines) suggests that flow cytometry is more sensitive than cytology and should be used instead.[6, 7]
Monoclonal antibodies are not more sensitive than cytology but can be used to distinguish between reactive and neoplastic lymphocytes in the case of LC from lymphoma.
Creatine-kinase BB isoenzyme (CK-BB), tissue polypeptide antigen (TPA), b2- microglobulin, β -glucuronidase, LDH isoenzyme-5, and vascular endothelial growth factor (VEGF) are strong indirect indicators of LC, but are not sensitive enough to improve on cytology.
LDH concentrations are elevated in cases of stroke, bacterial meningitis, CSF pleocytosis, head injury, primary CNS tumors, and some metastases. Levels are also elevated in 80% of LCs; therefore, they can be useful in confirming the diagnosis. LDH isoenzyme-5 levels are elevated in LCs from breast or lung primary tumors and melanoma, as well as bacterial meningitis, but they are sometimes normal even when cytologic findings are positive
Levels of CSF β 2 -microglobulin may be useful in detecting LC caused by hematologic spread but not in LC from solid tumors. levels may be elevated after treatment with intrathecal methotrexate (MTX).
Ferritin levels are sensitive to inflammatory changes in the CSF, but they are nonspecific for early LC.
CSF alkaline phosphatase levels may be elevated in an LC from a lung primary tumor.
CSF prostate-specific antigen (PSA) may be elevated in an LC from a prostate primary tumor.
PCR is not useful as the precise genetic alteration of the neoplasia is usually not known.
Leptomeningeal biopsy may be necessary if the patient has no evidence of a primary tumor. The findings can be diagnostic if results of all other tests are negative, especially if taken from an enhancing region identified on MRI. Macroscopic pathology shows diffuse fibrotic thickening of the brain and spinal cord, as well as layering of the nerve roots with tumor tissue. Microscopic examination shows local fibrosis with tumor cells covering the blood vessels and nerves, either as a single layer or as aggregates.
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.
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).
Trastuzumab has been given intrathecally to treat LC from breast cancer.
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.
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.
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.
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.
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.
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.
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.
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.
Once intrathecal chemotherapy has been initiated for leptomeningeal carcinomatosis (LC), check CSF cytology every 4 weeks.
If the cytologic result is negative, continue chemotherapy at the same rate of twice a week for 2 more weeks, then decrease the frequency to twice a week for 1 week a month, followed by further CSF monitoring every two months.
If the CSF cytologic results remain positive, continue the chemotherapy at the same rate, change the chemotherapeutic agent, or reclassify patient as poor risk and administer palliative treatment.
Supportive care should include anticonvulsants for seizure control, adequate analgesia with opioids, and antidepressants and anxiolytics as needed. Corticosteroids may help vasogenic edema associated with metastases (although they have limited effect on neurologic symptoms associated with LC), and may be combined with antiemetics for treatment of chemical meningitis. Psychostimulants can help with inattention and somnolence secondary to whole-brain radiation.
The most common complication is hydrocephalus, which results when tumor occludes the CSF outflow foramina of the fourth ventricle and the inflammatory response decreases CSF reabsorption.
A rapidly developing hydrocephalus causes increased ICP, occasionally leading to herniation of the tentorium and cerebellum, while a slowly developing hydrocephalus can cause dilatation of the ventricles without an increase in ICP, confusing the diagnostician if this is the presenting sign.
Even in the absence of hydrocephalus, flow abnormalities are present in 70% of patients with LC, adversely affecting the distribution of intrathecal chemotherapy.
Other complications are frequent.
LC may cause seizures or other neurologic dysfunction by invading the parenchyma of the brain or Virchow-Robin spaces or cause areas of ischemia or infarction by interfering with blood supply.
Competition for glucose between malignant cells and neurons can lead to hypofunction in affected areas. For example, in hypothalamic leukemia, weight gain in patients in leukemic remission can signify relapse because hypothalamic hypoglycorrhachia is induced by local competition for glucose by metastatic tumor cells.
LC also causes partial disruption of the blood-brain barrier once the tumor size has increased enough to stimulate growth of its own vasculature.
Treatment-related complications can result from catheter placement, chemotherapy, or radiation.
Catheter placement causes perioperative complications (1% of patients), and after placement, the catheter tip can migrate into the brain tissue, obstruct the shunt, or, more commonly, cause infection (usually Staphylococcus epidermidis, in 5% of patients).
MTX administration can cause acute arachnoiditis (nausea, vomiting, mental status changes), seizures, mucositis, or myelosuppression (mitigated with folinic acid coadministration, 10 mg q6h for 24 h).
Meningeal irritation, characterized by headache, fever, stiff neck (sometimes), confusion, and disorientation, often develops several hours following intrathecal MTX administration but is self-limiting and resolves within 24-72 hours. This can be treated on an outpatient basis with antipyretics, antiemetics, and corticosteroids.
Transverse myelitis is a rare idiosyncratic reaction to MTX that begins 30 min to 48 h after intrathecal treatment and presents with paraplegia, leg pains, and development of a sensory level and bladder dysfunction; it should be distinguished from traumatic spinal subdural hematoma. Again, no specific treatment is available but some improvement can occur over days to months.
Leukoencephalopathy is the most serious complication; it appears a year after treatment and is more likely in those who have also undergone cranial radiation. It presents as a progressive encephalopathy, often with ataxia, dysarthria, and focal findings.
Cytarabine, like MTX, also may cause meningism, headache, and fever.
Thiotepa causes less neurologic toxicity than MTX; the most common effect is transient limb paresthesias. Unlike MTX, there is no way of mitigating the resultant myelosuppression.
Radiation can cause myelosuppression and increase the neurotoxicity of intrathecal chemotherapy. Necrotizing leukoencephalopathy is most common after a combination of MTX and cranial irradiation. Initial findings are changes in the white matter on neuroimaging after 6 months of therapy; progressive dementia and other neurologic complications develop later. Other complications are delayed cerebral radiation necrosis, acute transverse myelopathy, chronic progressive myelopathy, and acute brachial plexus lesions.
The prognosis is generally poor because LC usually signifies the presence of metastases elsewhere, and the course of the systemic cancer is the major determinant of the patient's survival. Untreated, median survival is 4-6 weeks; treated, median survival is 2-3 months . The exception is leukemic or lymphomatous meningitis, which is sensitive to both MTX and Ara-C and often can be eradicated completely from the CNS. Poor prognostic indicators include the following:
Poor (Karnofsky) performance status
Multiple, serious neurologic deficits
Extensive systemic disease with few treatment options
Coexistent carcinomatous encephalopathy
CSF flow abnormalities on radionuclide ventriculography
Bulky CNS disease
Among patients with LC from solid tumors, the best response to chemotherapy and radiation occurs in those with LC from breast cancer, with 60% improving or stabilizing and a median survival of 7 months; 15% survive for a year, a survival rate rare in patients with LC with a primary tumor other than breast.
Only 40% of LCs from small-cell lung carcinoma improve or stabilize, and patients with this disease have a median survival of only 4 months.
Melanoma-derived LC carries a 3.6-month median survival, and only 20% of these patients stabilize or improve with treatment.
Nonresponders to chemotherapy seldom survive longer than a month. This prognosis has not improved measurably in the last 20 years despite an increase in incidence and diagnosis.
The most useful prognostic indicator is the Karnofsky scale (KS) score. Patients with a KS score of 70 or higher survive for a mean of 313 days, whereas those with a score of 60 or lower survive for a mean of only 36 days.
Tumor response 2 weeks after the initiation of treatment is a good portent.
Progressive multilevel involvement or rapid progression in 1 or more CNS lesions is ominous.
Michael J Schneck, MD, Vice Chair and Professor, Departments of Neurology and Neurosurgery, Loyola University, Chicago Stritch School of Medicine; Associate Director, Stroke Program, Director, Neurology Intensive Care Program, Medical Director, Neurosciences ICU, Loyola University Medical Center
Disclosure: Boehringer-Ingelheim Honoraria Speaking and teaching; Sanofi/BMS Honoraria Speaking and teaching; Pfizer Honoraria Speaking and teaching; UCB Pharma Honoraria Speaking and teaching; Talecris Consulting fee Other; NMT Medical Grant/research funds Independent contractor; NIH Independent contractor; Sanofi Grant/research funds Independent contractor; Boehringer-Ingelheim Grant/research funds Independent contractor; Baxter Labs Consulting fee Consulting
Frederick M Vincent Sr, MD, Clinical Professor, Department of Neurology and Ophthalmology, Michigan State University Colleges of Human and Osteopathic Medicine
Disclosure: Nothing to disclose.
Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Medscape Salary Employment
Jorge C Kattah, MD, Head, Associate Program Director, Professor, Department of Neurology, University of Illinois College of Medicine at Peoria
Stephen A Berman, MD, PhD, MBA, Professor of Neurology, University of Central Florida College of Medicine
Disclosure: Nothing to disclose.
Lawrence D Recht, MD Professor of Neurology and Neurosurgery, Department of Neurology and Clinical Neurosciences, Stanford University Medical School
Lawrence D Recht, MD is a member of the following medical societies: American Academy of Neurology, American Association for Cancer Research, American Neurological Association, and Society for Neuroscience
Disclosure: Nothing to disclose.
R Andrew Sewell, MD Associate Research Scientist in Psychiatry and Mental Illness Research, Education,Veterans Affairs Connecticut Health Care System, Yale University School of Medicine
R Andrew Sewell, MD is a member of the following medical societies: American Academy of Neurology, American Headache Society, American Pain Society, and American Psychiatric Association