Cerebrospinal Fluid Dissemination and Neoplastic Meningitis in Primary Brain Tumors Sajeel Chowdhary, MD, Sherri Damlo, and Marc C

Special Report

Cerebrospinal Fluid Dissemination and Neoplastic Meningitis in Primary Brain Tumors Sajeel Chowdhary, MD, Sherri Damlo, and Marc C. Chamberlain, MD

Background: Neoplastic meningitis, also known as leptomeningeal disease, affects the entire neuraxis. The clinical manifestations of the disease may affect the cranial nerves, cerebral hemispheres, or the spine. Because of the extent of disease involvement, treatment options and disease staging should involve all compartments of the cerebrospinal fluid (CSF) and subarachnoid space. Few studies of patients with primary brain tumors have specifically addressed treatment for the secondary complication of neoplastic meningitis. Therapy for neoplastic meningitis is palliative in nature and, rarely, may have a curative intent. Methods: A review of the medical literature pertinent to neoplastic meningitis in primary brain tumors was performed. The complication of neoplastic meningitis is described in detail for the various types of primary brain tumors. Results: Treatment of neoplastic meningitis is complicated because determining who should receive aggressive, central nervous system (CNS)–directed therapy is difficult. In general, the therapeutic response of neoplastic meningitis is a function of CSF cytology and, secondarily, of the clinical improvement in neurological manifestations related to the disease. CSF cytology may manifest a rostrocaudal disassociation; thus, consecutive, negative findings require that both lumbar and ventricular cytological testing are performed to confirm the complete response. Based on data from several prospective, randomized trials extrapolated to primary brain tumors, the median rate of survival for neoplastic meningitis is several months. Oftentimes, therapy directed at palliation may improve quality of life by protecting patients from experiencing continued neurological deterioration. Conclusions: Neoplastic meningitis is a complicated disease in which response to therapy varies by histology. Thus, survival rates after CNS-directed therapy will differ by the underlying primary tumor. Optimal therapy of neoplastic meningitis is poorly defined, and few guidelines exist to guide clinicians on the most appropriate choice of therapy.

Introduction methotrexate, rituximab, thiotepa, and trastuzumab. Neoplastic meningitis is a disease that affects the ce- Chamberlain et al1 proposed an evaluation for as- rebral hemispheres, the spine, and the cranial nerves. sessing response in neoplastic meningitis that includes All cerebrospinal fluid (CSF) compartments (ventricles, CSF cytology/flow cytometry, radiographic evaluation, basal cisterns, cerebral and spinal subarachnoid space) and a standardized neurological examination. The need to be assessed during staging and considered with proposal (Response Assessment in Neuro-Oncology) respect to treatment. Most often, treatment involves ra- recommended that CSF analysis be performed for all diotherapy and the intra-CSF administration of chemo- patients, as well as complete, contrast-enhanced neur- therapy. For many patients, concomitant, systemic axis magnetic resonance imaging (MRI), and, when therapy is required because of systemic tumor recur- the intra-CSF administration of therapy is planned, rence. Therapeutic agents for intra-CSF administration radioisotope CSF flow studies should be obtained.1 A include cytosine arabinoside, liposomal cytarabine, standardized instrument was created to assess a neurological examination that does not require neurological 1 From the Lynn Cancer Institute (SC), Marcus Neuroscience Institute, consultation. Because the majority of radiographic le- Boca Raton, Florida, Damlo Does (SD), and Seattle Cancer Care Alli- sions that occur in the setting of neoplastic meningitis ance (MCC), Cascadian Therapeutics, Seattle, Washington. cannot be measured, the working group proposed that Submitted January 30, 2017; accepted April 26, 2017. clinicians use a novel, radiological response scorecard Address correspondence to Sajeel Chowdhary, MD, Marcus Neuro- science Institute, 800 Meadows Road, First Floor, Boca Raton, to grade neuroimaging as improved, stable, or progres- FL 33486. E-mail: [email protected]. sive. Isolated progression based on radiographic evi- Dr Chamberlain has received funding for research, is a consultant dence was defined as sufficient to determine disease for, and holds stock in Pharmaco-Kinesis, Nativis, Roche, and progression of neoplastic meningitis.1 The proposal by Tocagen. No significant relationships exist between the remaining 1 authors and the companies/organizations whose products or ser- Chamberlain et al recognizes these instruments are vices may be referenced in this article. novel and will require validation in prospective clinical

January 2017, Vol. 24, No. 1 Cancer Control S1 trials of neoplastic meningitis. Nearly one-half of patients with positive CSF cy- A paucity of literature exists relating to the treat- tology will have cytologically negative findings on an ment of primary brain tumors and the co-occurrence of initial CSF examination.7-11 That number increases to neoplastic meningitis. However, general principles have 80% when repeat CSF examination is performed; how- been established regarding neoplastic meningitis. Ther- ever, little benefit is achieved from more than 2 lumbar apy for neoplastic meningitis is palliative in nature with punctures.8-20 rare curative intent. Few guidelines exist for the treat- Wasserstrom et al3 reported on 90 patients with ment and response evaluation of neoplastic meningitis. carcinomatous meningitis, 5% of whom had positive The current effort reviewed the medical literature perti- results on CSF cytology from either the cisterna magna nent to neoplastic meningitis in primary brain tumors to or ventricles. Chamberlain et al10 found that positive assist clinicians in understanding existing therapies for findings on lumbar CSF cytology at diagnosis, absent and the evaluation of neoplastic meningitis. CSF flow obstruction, and simultaneously obtained ventricular and lumbar cytology samples were dis- Clinical Presentation cordant in 30% of cases. When spinal manifestations The classic presentation of neoplastic meningitis in- were present, the authors discovered that lumbar CSF cludes pleomorphic clinical manifestations relating to cytology was more likely to be positive; alternatively, neurological function in the spinal cord and its exiting ventricular CSF cytology was more likely to be positive nerve roots, the cerebral hemispheres, and the cranial when cranial signs or symptoms were present.10 Not nerves.2-7 Typically, a neurological examination will un- obtaining CSF from a site of radiographically demon- cover additional signs and symptoms beyond what pa- strable or symptomatic disease was associated with tients have reported. false-negative results on cytology in their prospective Changes in mental status and headache are the evaluation of 39 patients, as did withdrawing less than most common manifestations of dysfunction in the 10.6 mL of CSF, taking fewer than 2 samples, and de- cerebral hemisphere, although confusion, dementia, laying the processing of specimens.11 After the authors hemiparesis, and seizure can occur. Dysfunction of the corrected for these factors, they discovered several of cranial nerves, the most common being cranial nerve their study patients with neoplastic meningitis still had VI, can manifest as diplopia or trigeminal sensory or persistently negative findings on CSF cytology.11 motor loss; optic neuropathy and cochlear dysfunction Nearly 40% of cases with clinically suspected neo- are also common. Spinal manifestations can include plastic meningitis proven at the time of autopsy are lower- and upper-extremity weakness, segmental/der- cytologically negative, according to a study by Glass matomal sensory loss, pain, and nuchal rigidity.2-7 et al.9 This number was higher than 50% in patients Clinicians should have a high index of suspicion to with focal neoplastic meningitis.9 make the diagnosis of neoplastic meningitis. Discovery Low sensitivity rates of CSF cytology make diag- of multifocal neuraxis disease in a patient with malig- nosing neoplastic meningitis and assessing treatment nancy is suggestive of neoplastic meningitis; however, response difficult. Immunohistochemistry, molecular patients with neoplastic meningitis also commonly biology techniques, and several biochemical mark- present with isolated syndromes, including cranial ers have been explored to discern a reliable biologi- neuropathy and cauda equina syndrome. cal marker of disease; however, in general, use of bio- New manifestations of a neurological nature may markers has been limited by poor rates of specificity represent disease progression; however, the clinician and sensitivity.8-20 Using monoclonal antibodies for the must distinguish these from the signs and symptoms analysis of immunohistochemistry in the setting of of parenchymal disease and treatment-related ad- neoplastic meningitis does not significantly increase verse events.2-7 the sensitivity rate of cytology alone.8-20 However, for cases of leukemia and lymphoma, antibodies against Diagnosis surface markers can distinguish between neoplastic Examination of the Cerebrospinal Fluid and reactive lymphocytes in the CSF.8-20 Examination of the CSF is considered the most use- Researchers have studied the use of cytogenetics ful laboratory study to aid in the diagnosis of neoplas- to help improve the rate of diagnostic accuracy for neo- tic meningitis.8-20 Abnormalities that clinicians should plastic meningitis. Additional diagnostic information consider on the examination of CSF include increased may be gained through the use of flow/DNA single-cell leukocyte count, elevated opening pressure, decreased cytometry, chromosomal measurements, and fluores- glucose level, or elevated protein level; however, such cence in situ hybridization, which can detect numeri- values are only suggestive and are not diagnostic of neo- cal and structural genetic aberrations as signs of malig- plastic meningitis. Although the presence of malignant nancy; however, these methods still have low rates of cells in the CSF is diagnostic for the disease, determina- sensitivity.15-20 When results from cytology are incon- tion of specific histology is currently not possible.8-20 clusive, the clinician may consider use of polymerase

S2 Cancer Control January 2017, Vol. 24, No. 1 chain reaction to help establish the diagnosis, but an- analyses could help determine the mechanisms tumor other piece of information must already be identified: cells use to metastasize to the central nervous system the genetic alteration of the neoplasia. Typically, this (CNS). Lv et al25 also reported on detecting tumor cells information is unknown, and this is especially true in in the CSF through combined immunofluorescence in cases of solid tumors.15-20 situ hybridization. The study involved 24 patients Milojkovic Kerklaan et al21,22 reported on the di- (n = 16 with neoplastic meningitis from lung can- agnostic value of flow cytometry using epithelial cell- cer, n = 8 without CNS malignancy). The researchers adhesion molecule (EpCAM) and compared it with compared the CTCs in the CSF between these 2 patient CSF cytology for diagnosing neoplastic meningitis in groups. Rates of diagnostic sensitivity, specificity, and patients with epithelial tumors, which constitute the effectiveness were 75%, 100%, and 83%, respectively.25 majority of solid tumors in adults. The researchers de- Negative and positive predictive values were 67% tected tumor cells in the CSF and whole blood by mul- and 100%, respectively.25 Findings from Lv et al25 tiparameter flow cytometry using an EpCAM antibody. suggest that value may exist in detecting CTCs in the They reported sensitivity and specify rates of 100% CSF via combined immunofluorescence in situ hy- each for the flow cytometry assay when diagnosing bridization for diagnosing meningeal metastasis in neoplastic meningitis, whereas the sensitivity rate was select primary cancers. 62% for CSF cytology.21,22 Biochemical parameters and Pentsova et al26 reported on sequencing 341 genes cell counts in the CSF were abnormal in all patients associated with cancer in cell-free DNA from CSF. The studied with neoplastic meningitis. The results suggest researchers obtained CSF samples through routine that CSF cytology is inferior to EpCAM-based flow cy- lumbar puncture in 53 patients with cancer and known tometry assay for diagnosing neoplastic meningitis in or suspected CNS involvement. They detected somatic patients with an epithelial tumor who have clinically alterations in 50% of patients with primary brain tu- suspicious neoplastic meningitis and inconclusive find- mors, 63% of patients who had CNS metastases of solid ings on MRI.22 tumors, and in 0% of cases without CNS involvement. Nayak et al23 reported on using rare cell-cap- The researchers reported that, among the patients ture technology for diagnosing neoplastic meningi- studied with glioma, which is the most common malig- tis from solid tumors by identifying circulating tu- nant primary brain tumor in adults, their examination mor cells (CTCs) in the CSF. The researchers found of cell-free DNA revealed patterns of tumor evolution, CTCs in 16 patients.23 A false-positive result was re- including mutations associated with temozolomide.26 ported in 1 patient; however, lumbar puncture was Thus, they concluded that CSF can harbor clinically rel- performed 6 months later in that patient, who then evant genomic alterations in patients with CNS-associ- met the criteria for neoplastic meningitis.23 The re- ated cancers. They also suggest that “liquid biopsies” searchers reported that CSF CTCs were absent in the could be used to monitor tumor evolution and treat- entire control population. Sensitivity rates for rare ment response.26 cell-capture technology, conventional cytology, and In cases for whom no evidence exists of systemic MRI were 100%, 67%, and 73%, respectively.23 Thus, cancer and findings on CSF examination are inconclu- these results suggest that rare cell-capture technolo- sive, meningeal biopsy may be diagnostic. The yield gy is an accurate, novel method that can detect neo- of this test increases if the biopsy specimen is ob- plastic meningitis in solid tumors. The authors sug- tained from an enhancing region seen on MRI. Most gest that this method could provide clinicians with often a posterior fossa or pterional surgical approach earlier diagnostic confirmation, thereby sparing pa- is utilized.27,28 tients from undergoing repeat lumbar punctures.23 Magbanua et al24 isolated CTCs derived from the Neuroradiographical Data CSF in 15 study patients with metastatic breast can- Gadolinium-enhanced MRI is the technique of choice cer who were also diagnosed with neoplastic men- for the evaluation of suspected leptomeningeal me- ingitis. The researchers performed genomic profil- tastasis.28-30 Neoplastic meningitis involves the entire ing in 87% of the patients.24 Results of copy number neuraxis; therefore, the clinician is required to obtain analysis in CTCs revealed the presence of CTCs con- imaging of the entire CNS in patients who are candi- sistent with their malignant origin and genomic al- dates for treatment. T1-weighted sequences, with and terations commonly observed in primary breast can- without contrast, in combination with fat-suppression, cer.24 In 6 patients, the researchers compared CTCs and T2-weighted sequences are considered the stan- with corresponding, archival primary tumors and dard imaging modalities in this clinical setting.28-30 MRI discovered divergence in the clonal relationships. has been shown to have higher rates of sensitivity than This type of isolation methodology and molecular cranial, contrast-enhanced computed tomography; its CTC analysis added to our understanding of these sensitivity is also similar to computed tomographic my- malignant cells.24 Future functional and genomic elography for evaluating the spine, but it is a logistical-

January 2017, Vol. 24, No. 1 Cancer Control S3 ly simpler and better tolerated modality.28-30 diagnosed with and who received treatment for ana- Tumors involving the leptomeninges can be visu- plastic astrocytoma or glioblastoma, therapy directed alized on enhanced MRI as a fine, signal-intense layer at leptomeningeal gliomatosis had little effect.46 In pa- following the superficial sulci and gyri. Subependymal tients with high-grade glioma, evidence of leptomen- ventricular involvement can also result in ventricular ingeal gliomatosis on autopsy is far more likely than enhancement. Several changes seen on MRI, includ- clinically evident leptomeningeal gliomatosis, possibly ing enhancement of cranial nerves and intradural ex- because discrepancies in antemortem and postmortem tramedullary enhancing nodules, may be diagnostic of diagnoses are difficult to interpret.44-50 neoplastic meningitis in patients with cancer.31-33 Rare- Witham et al47 reported on 14 patients with lep- ly, lumbar puncture can cause a meningeal reaction, tomeningeal gliomatosis (n = 5 anaplastic astrocy- which can then lead to dural-arachnoidal enhance- toma, n = 9 glioblastoma) who were treated with the ment; thus, it is preferred that imaging be obtained pri- intra-CSF administration of thiotepa. Of those with or to performing lumbar pucture.33-35 Gadolinium-en- high-grade glioma, leptomeningeal gliomatosis was hanced MRI has a 30% rate of false-negative findings, the presenting symptom in 3.47 Five patients had clini- so normal imaging findings cannot exclude the diag- cal manifestations associated with leptomeningeal gli- nosis of neoplastic meningitis. Alternatively, in patients omatosis.47 Among the 8 patients for whom CSF sam- with typical clinical presentations, abnormal findings ples were obtained and examined, CSF cytology was seen on gadolinium-enhanced MRI are adequate to es- not obtained in 6 and the results were positive in 2.47 tablish the diagnosis.33-35 Subependymal disease was sufficient to diagnose leptomeningeal gliomatosis per the neuroradiographical Types of Primary Brain Tumors criteria used in the study.47 Glioma Overall median survival rates have been reported The management of leptomeningeal gliomatosis and to be 19 months for patients with anaplastic astrocy- gliomas can be challenging to the clinician because toma and 10 months for those with glioblastoma.48-50 neurological function will be compromised in most Patients with high-grade glioma and leptomeningeal cases as a result of treatment and of the topography of gliomatosis defined by clinical manifestations, positive the primary tumor.36-40 neuroradiographical findings, and positive results on Most epidemiological research on leptomeningeal CSF cytology reportedly respond poorly to aggressive, gliomatosis is based on autopsy reports.41-43 Erlich and multimodal therapy.48-50 Median survival after the diag- Davis41 reviewed the autopsy results of 25 patients with nosis of leptomeningeal gliomatosis is made has been glioblastoma; of those, examination of the spinal cord reported to be similar to that of neoplastic meningitis was performed in 20 cases. Five cases had evidence of secondary to systemic solid cancers.48-50 With regard to leptomeningeal gliomatosis.41 Yung et al42 reviewed the neoplastic meningitis, a paucity of evidence suggests autopsy findings of 52 patients with high-grade glio- that one intra-CSF chemotherapy agent is superior to ma; of those, evidence of leptomeningeal gliomatosis another or even when used in combination.48-50 Fur- was seen in 11 patients. Eight cases were diagnosed thermore, many patients may succumb to complica- antemortem by positive CSF cytology.42 In an ante- tions secondary to leptomeningeal gliomatosis, not as mortem series, Vertosick and Selker43 reviewed cases a result of primary cancer progression.48-50 in which leptomeningeal gliomatosis was diagnosed Therapy for neoplastic meningitis is multimodal, based on neuroradiographical imaging findings, not as approximately two-thirds of patients require radio- on CSF cytology. They found that leptomeningeal glio- therapy for symptomatic or neuroradiographical bulky matosis occurred in 2% of cases.42 subarachnoid disease, and approximately one-third Awad et al44 reported on 13 patients with lepto- require systemic chemotherapy for the progression of meningeal gliomatosis and high-grade glioma, 8 of their primary tumor.48-50 Therefore, standard manage- whom had symptoms prior to their death that were ment options for carcinomatous meningitis involve consistent with leptomeningeal gliomatosis. Lepto- treatments such as radiotherapy, systemic chemothera- meningeal gliomatosis was a preterminal event in all py, and the intra-CSF administration of chemotherapy. patients studied. Reporting on 51 autopsies performed Because neoplastic meningitis variably and pleomor- on patients with glioblastoma, Onda et al45 demon- phically affects the entire neuraxis, combination thera- strated evidence of leptomeningeal gliomatosis in 27% pies are used and, thus, it becomes difficult to ascer- of cases. A report of 11 patients with high-grade gli- tain benefit to any specific therapy.48-50 oma and leptomeningeal gliomatosis was published Even though modest rates of treatment-related by Grant et al,46 who reported that the diagnoses were toxicity have been observed in several studies, limited made antemortem. In 3 cases, leptomeningeal glioma- survival rates and poor therapeutic responses suggest tosis was found at the time of initial tumor presenta- that a less-aggressive approach may be justified in pa- tion. They also found that, among patients previously tients with leptomeningeal gliomatosis and high-grade

S4 Cancer Control January 2017, Vol. 24, No. 1 glioma.51-62 Combining palliative care involving radio- overall incidence has been increasing, and this is par- therapy directed to the symptomatic disease site and ticularly true among the elderly and those with com- simple systemic chemotherapy regimens could be, in promised immune systems.76 Optimal treatment is rel- theory, less invasive and as effective as an aggressive, atively unknown because of too few adequately sized multimodal approach. However, such patients may still trials. Initially, most patients receive high-dose, meth- benefit from enrolling in clinical trials designed to ex- otrexate-based chemotherapy alone, because whole- plore novel treatment approaches to leptomeningeal brain radiotherapy given at standard doses is associat- gliomatosis.51-62 ed with neurological toxicity in these patients and does not have a survival benefit.76 Meningioma Approximately 10% of patients with PCNSL have Meningiomas mostly occur in middle- or older-aged positive findings by CSF cytology, and an additional adults and have a female predominance; most menin- 15% have neuropathology or demonstrable disease giomas are benign, whereas few cases are atypical or by neuroradiography consistent with leptomeninge- malignant (6%–15% and 2%, respectively).63-66 Many pa- al spread. In either of these instances, these findings tients diagnosed with this extra-axial brain tumor elect complement positive findings by CSF cytopathology to undergo surgery for its removal and are advised to and are indicative of lymphomatous meningitis.77-86 A do so based on the presence of neurological symp- large series by Ferreri et al75 reported that the preva- toms.63-66 Often complete surgical resection is curative; lence rate was 16%, whereas Balmaceda et al81 report- for cases of incomplete resection or in patients with re- ed on data that supported a rate of 26%. Other studies current tumors not previously irradiated, radiotherapy indicate an even lower prevalence rate of 13%.78-80,82-85 is appropriate.63-66 Conventional external beam radio- These rates suggest that many patients have combined therapy or stereotactic radiotherapy may be consid- brain and leptomeningeal disease and that PCNSL is ered, with stereotactic radiotherapy being increasingly frequently associated with lymphomatous meningi- utilized. In unresectable cases or when the disease has tis.75,77-86 Fischer et al87 examined the CSF samples from failed to respond to surgery or radiotherapy, immuno- 116 patients with compromised immune systems and chemotherapy may be considered. Rarely, meningio- newly diagnosed PCNSL. In this prospective, multi- mas may metastasize, most often to extraneural sites center study, lymphoma cells were found in 18% of the such as the cervical lymph nodes or lungs.63-66 samples, CSF pleocytosis in 36%, and elevated levels of Metastasis is commonly associated with World protein in 65%.94 The researchers reported that pleo- Health Organization grade 2 (aggressive) or 3 (malig- cytosis correlated with positive findings on cytology, nant) disease, occurring at a rate of up to 25%; howev- whereas an elevated protein level in the CSF did not.87 er, the risk of dissemination into the CSF is unclear.67-70 Lymphomatous meningitis is not rare in cases of Aside from angiogenic inhibitors, few chemotherapy PCNSL, so leptomeningeal and CSF-directed compart- agents have demonstrated activity against recurrent mental therapy (craniospinal irradiation, high-dose meningiomas, thus complicating therapeutic options systemic chemotherapy [methotrexate, cytarabine, for these already complex cases. Some authors have thiotepa], intrathecal chemotherapy) can be adminis- reported on patients being treated with multimodal tered in select patients with newly diagnosed PCNSL. therapy, including systemic and regional chemotherapy Methotrexate given at high doses is the most effective and involved-field radiotherapy to sites of symptomatic drug for newly diagnosed PCNSL. When methotrexate disease within the spine; however, despite such an ap- is administered at high levels, cytotoxic CSF levels can proach, median survival has been reported to be ap- be achieved. proximately 6 months.70-72 Meningiomas mostly metas- In the large, multicenter study of 370 patients with tasize by the hematological route, with only occasional PCNSL conducted by Ferreri et al,75 the benefit of ad- CSF dissemination. Multifocal meningiomas may reflect juvant high-dose methotrexate in combination with or an instance of CSF dissemination. No agents are ap- without intrathecal chemotherapy was studied. How- proved for the treatment of refractory meningioma, so ever, no survival benefit was demonstrated with the effective chemotherapy agents are an unmet need.72-74 addition of the intra-CSF administration of chemotherapy. Furthermore, the study reported that intrathecal Primary Central Nervous System Lymphoma chemotherapy had no impact on the recurrence rate or Primary CNS lymphoma (PCNSL) is a disease that meningeal relapse. These findings were also true for largely involves the brain.75 The leptomeninges may be patients with positive CSF cytology findings at diag- involved in the initial presentation and during disease nosis.75 Thus, the study results suggest that high-dose recurrence, although isolated leptomeningeal disease methotrexate systemic regimens obviate the need for is rare in patients with PCNSL.75 intra-CSF administration of chemotherapy in patients Korfel et al76 described PCNSL as a rare, diffuse with leptomeningeal disease.78-85 large B-cell lymphoma originating within the CNS. Its Glantz et al88 reported on 16 patients with solid

January 2017, Vol. 24, No. 1 Cancer Control S5 tumors and leptomeningeal metastases. Patients were brain requiring treatment with radiotherapy has been given intravenous methotrexate 8 g/m2 within 4 hours, controversial. Notwithstanding the initial enthusiasm after which serial sampling of their CSF and blood was for craniospinal irradiation, several study authors have performed. These patients were compared with a par- suggested that use of limited-field radiotherapy for M0 allel group, who were administered intra-CSF metho- disease may be appropriate, thereby reserving cranio- trexate according to its standard dosing schedule. In spinal irradiation for M1+ disease regardless of tumor the patients who received the drug intravenously, 1.0 histology and, according to others, for anaplastic epen- μM and 0.1 μM levels of methotrexate were maintained dymomas in the infratentorial compartment.96-108 in the CSF for approximately 48 and 93 hours, respec- Robertson et al96 studied the role of adjuvant che- tively. In those receiving a single intrathecal dose, 1.0 motherapy after surgery and craniospinal irradiation μM and 0.1 μM levels of methotrexate were main- in a prospective trial of 32 children. The study patients tained for approximately 48 and 57 hours, respec- were newly diagnosed with intracranial ependymoma. tively. 88 Therefore, the authors concluded that the dura- They found that the volume of residential disease and tion of cytotoxic drug exposure in the CSF was similar extent of surgical resection predicted the rate of PFS, among the 2 groups. but that chemotherapy, regardless of the regimen, did not impact PFS. They reported that overall survival and Ependymoma 5-year PFS rates were 64% and 50%, respectively.96 A CSF dissemination occurs in up to 12% of all cases of total of 71% of relapses observed were related to fail- intracranial ependymomas, with its highest frequen- ures of local treatment and 21% to concurrent distant cy occurring in infratentorial anaplastic ependymo- and local metastasis to the CNS.96 Approximately 7% mas.89-94 Albeit a small but measurable risk, CSF dis- were related to isolated metastatic relapse but occurred semination may occur in any patient newly diagnosed only in cases of metastatic disease at diagnosis.96 Simi- with ependymoma; thus, patients should be evaluated lar outcomes were seen among patients receiving cra- for extent of the disease. Such an examination occurs niospinal irradiation or involved-field radiotherapy. most often after surgery and should include obtaining Robertson et al96 concluded that craniospinal irradia- CSF cytology and craniospinal MRI. Staging can be uti- tion should be confined to patients with documented lized to stratify patients into those with (stage M1) or disseminated neuraxis disease. Whether the intra-CSF without CSF metastasis (stage M0) as well as those with administration chemotherapy will replace craniospi- residual disease or without following surgery. Metasta- nal irradiation in patients who present with metastatic sis and residual disease are the most important clinical disease seems unlikely because rates of survival have parameters that affect patient outcomes.89-94 not improved with the use of adjuvant chemotherapy, In a retrospective review, Fangusaro et al95 evalu- nor have enough study data been compiled to compare ated the incidence rate of metastatic disease, prognos- craniospinal irradiation with the intra-CSF administra- tic factors, and survival outcomes in 61 patients with tion of chemotherapy.109-116 intracranial ependymoma. Bulky metastatic disease Regarding the management of recurrent epen- observed on postcontrast spine MRI occurred in 10% dymomas, consensus exists on the extent of the dis- of the study population.95 They found that none of the ease evaluation. In the recurrent setting, evaluation patients whose findings on spine MRI were negative should include contrast-enhanced neuraxis MRI and had positive findings on lumbarCSF cytology, thus CSF cytology for all patients. When disseminated highlighting the rarity of microscopic metastatic dis- disease is demonstrated, the treatment is altered. In ease observed on lumbar CSF cytology alone.95 These one study of 36 patients with recurrent intracranial results suggest that lumbar CSF cytology may not be ependymoma by Goldwein et al,92 12 received con- useful when negative findings are observed on post- ventional radiotherapy, 33 underwent repeat surgery, contrast spine MRI. and all received chemotherapy. They reported that The first treatment of choice for ependymomas is the median time to recurrence was nearly 3 years. surgical resection because it is the most important co- When relapse occurred (which happened in the ma- variant affecting rates of overall and progression-free jority of the study population), 78% of cases were survival (PFS).96-108 Following surgery, the second most determined to be local and 14% were considered to frequently used adjuvant treatment is radiotherapy, be local with concomitant distant metastasis.92 Most even with the general medical consensus that epen- patients experienced repeat relapse (79%); of those, dymomas are resistant to radiotherapy and in the ab- 80% were determined to have had a local component sence of randomized clinical trials suggesting any ben- to the relapse.92 Two-year PFS and overall survival efit for completely resected tumors. Furthermore, no rates were low at 23% and 29%, respectively.92 Median data indicate whether a dose-response relationship PFS was 12 months, and the median duration of re- exists in ependymomas; thus, total tumor dose varies. sponse in patients with stable or responsive disease CSF spread is theoretically possible and the volume of was 9 months.92 Based on these results, Goldwein et

S6 Cancer Control January 2017, Vol. 24, No. 1 al92 proposed the intra-CSF administration of chemo- rospectively reviewed the records of 112 patients with therapy to patients with metastatic ependymoma who medulloblastoma who underwent surgical resection. had not received craniospinal irradiation. The rate of sensitivity for spine MRI was 83% for its ability to detect disseminated tumor; by contrast, the Primitive Neuroectodermal Tumor rate of sensitivity of contemporaneous CSF cytology Primitive neuroectodermal tumors (PNETs) are made was 60%.132 When multiple samples were subsequently up of undifferentiated (medulloblastoma) and differ- obtained, the sensitivity rate increased to 78% for CSF entiated tumors (cerebral neuroblastoma, olfactory cytology analysis.132 However, compared with CSF cy- neuroblastoma, pineoblastoma, retinoblastoma). Be- tology analysis, spine MRI still had a higher overall cause PNETs, specifically medulloblastoma, are associ- rate of diagnostic accuracy for detecting early dissemi- ated with CSF dissemination, standard initial care for nated medulloblastoma. If both CSF analysis and spine patients with PNETs includes craniospinal irradiation MRI were performed less than 2 weeks preoperatively, regardless of the extent of disease. Currently, there is then false-positive results were more likely to occur. no role for intra-CSF administration of chemotherapy The researchers also reported that CSF cytology find- in patients with CSF-disseminated PNET. Furthermore, ings were, at times, positive for disseminated tumor no adjuvant studies have suggested that craniospinal even in cases in which negative results on spine MRI irradiation should be provided in combination with the were found.132 Thus, a delay of more than 2 weeks intra-CSF administration of chemotherapy in patients following surgery could reduce the likelihood of false 132 with M+ disease. However, administration of intra-CSF positives. chemotherapy may allow for further dose reductions One group of researchers concluded that death of craniospinal irradiation, according to some au- caused by medulloblastoma is mainly associated with thors.117-131 In addition, the intra-CSF administration of the recurrence of leptomeningeal dissemination.133 chemotherapy can be considered in patients with posi- Yang et al133 studied the miRNA-expression profiles of tive findings on CSF cytology after receiving craniospi- 29 cases of medulloblastomas according to whether nal irradiation, although the rate of this occurrence is CSF seeding was present. They discovered reduced lev- not defined. By contrast, the results of several studies els of expression of miR-192, a microRNA precursor, in have shown that M1 disease defined as positive find- the CSF-seeding group. Their findings suggested that, ings on CSF cytology in metastatic microscopic disease by modulating cell proliferation and anchoring ability, alone does not correlate with reduced rates of survival, miR-192 expression could suppress the leptomeningeal suggesting a very limited role for intra-CSF administra- dissemination of medulloblastoma.133 tion of chemotherapy in the initial management of me- To study whether metastasis influences prognosis, dulloblastoma. Among children with medulloblastoma Miralbell et al134 retrospectively reviewed data from who had an average-level risk, data suggest that reduc- 86 children with medulloblastoma. For M0, Mx, M1, ing the craniospinal irradiation dose in conjunction and M2/3 disease, they found that the 5- and 10-year with systemic chemotherapy can result in an excellent rates of overall survival were 76% and 54%, 68% and 5-year event-free survival rate of 79% and without an 50%, 36% and 25%, and 22% and 22%, respectively.134 increased risk of neuraxis failure.117-131 Among patients with M1 and M2/3 disease, the re- Anaplastic/large cell medulloblastoma is charac- searchers did not observe any significant differences in terized by frequent CSF dissemination, and the disease survival. Seven of the 26 patients had positive findings often manifests in an aggressive way.117-131 A report by on CSF cytology performed postoperatively. Outcomes Leonard et al117 evaluated the genetic and clinicopatho- were reportedly similar among the 6 patients with logical features of 7 patients with anaplastic/large cell stage M1 disease and significantly different from those medulloblastoma at their institution. Metastasis to the with M0 disease. Nineteen of the studied patients had lymph nodes was observed in 1 case, isochromosome M2/3 disease, and, of these, 8 had positive findings on 17q was discovered in 5 cases, and CSF dissemination CSF cytology, 5 had negative findings on CSF cytology, was discovered in all 7 cases.117 Aneuploidy, which was and 6 had findings that were unknown.134 A positive defined as evidence of chromosomal gains or losses, finding on CSF cytology, either before or after surgery, was present in 3 of the tumors studied, and MYC am- predicted poor outcomes, although the researchers plification was observed in 3.117 The authors concluded noted that postoperative cytology findings were more that, based on their findings, the morphological char- likely to be concordant with CSF analysis performed acteristics of this type of medulloblastoma suggest a prior to surgery and appeared to be reflective of similar more advanced stage of tumor than that found in the prognostic significance.134 classical presentation of medulloblastoma. Perioperative neuraxis MRI and intracranial/lum- Because tumor dissemination frequently occurs bar CSF cytology can be used in a complementary along CSF pathways, MRI after surgery is routinely per- manner to help decrease the rates of dissemination formed to stage medulloblastoma. Meyers et al132 ret- that go diagnostically undetected. Terterov et al135 stud-

January 2017, Vol. 24, No. 1 Cancer Control S7 ied records from 150 children with PNETs to examine use (localized, whole ventricle, whole brain, craniospi- whether a role exists for intracranial CSF cytology in nal irradiation).150-164 This is like the controversial ra- detecting early dissemination. Their data led them to diotherapy proposed for ependymoma. The extent of conclude that discordance exists between results ob- disease is increasingly used to determine the volume tained by intracranial lumbar CSF cytology and neur- of brain irradiated, as is tumor histology. Typically, cra- axis MRI for the perioperative detection of dissemina- niospinal irradiation is used in cases of disseminated tion in cases of ependymoma, medulloblastoma, and disease, whereas whole ventricle or involved-field ra- supratentorial PNET in children.135 When they ana- diotherapy is used for cases of localized disease. Inter- lyzed the survival data, they found that findings on est is also increasing for the use of multimodal ther- perioperative neuraxis MRI correlated with survival; apy that includes platinum-based chemotherapy and by contrast, findings on perioperative lumbar/intracra- radiotherapy, thereby reducing the dose and volume nial CSF cytology did not.135 of radiation needed. It is unclear whether a role ex- Data are robust on the patterns of relapse in me- ists for the intra-CSF administration of chemotherapy dulloblastoma, with local, local plus disseminated, and to manage disseminated germ cell tumors because the metastatic only making up one-third each.129-138 Nearly trials performed to date have studied only systemic 20% of cases that metastasize will manifest extraneu- chemotherapy with radiotherapy. Cases of isolated, ral metastases, with a predominance for bone.129-138 CSF-disseminated disease rarely occur. Similar to dis- CSF dissemination, which is defined as a positive find- seminated PNET, it is unclear whether to recommend ing on CSF cytology or the presence of subarachnoid the intra-CSF administration of chemotherapy for man- nodules (intracranial or spinal) on neuroradiography, aging disseminated germ cell tumors, although it could occurs in one-half of patients with recurrent medul- be argued when extrapolating data from studies of car- loblastoma.129-138 In general, however, disseminated, cinomatous meningitis.150-164 recurrent medulloblastoma is managed with sys- Cheng et al164 retrospectively analyzed therapies temic chemotherapy regardless of CSF spread of dis- and outcomes in a cohort of patients with intracranial ease.129-138 One exception is isolated CSF dissemination germinoma who were consecutively given multiagent and medulloblastoma managed with the intra-CSF ad- chemotherapy followed by ventricular radiotherapy ministration of chemotherapy. Exactly how to extrapo- with or without boost and focal, whole brain, or cra- late information from the limited available data on the niospinal radiotherapy.165 Rates of 5-year overall sur- intra-CSF administration of chemotherapy for the treat- vival and PFS were 100% and 96%, respectively.165 The ment of PNET is unclear, and all recommendations for excellent rates of 5-year overall survival observed in treatment should be considered in this context.129-138 this study were achieved in the patients who received chemotherapy and reduced whole ventricular radio- Germ Cell Tumor therapy, regardless of whether the primary tumor re- Germ cell tumors make up less than 1% of all primary ceived a radiotherapy boost.165 brain tumors; germ cell tumors have a male predomi- C-kit expression in CSF and its clinical signifi- nance (~ 75%) and up to 70% of cases occur in the first cance in germ cell tumors was examined by Miyano- 2 decades of life.139-149 Similar to ependymoma and hara et al.166 C-kit was diffusely expressed on the cell PCNSL, germ cell tumors have a proclivity for CSF dis- surface of the germinoma cells in all 18 specimens that semination. Thus, staging of the disease, which in- contained germinomas. Only some mature compo- cludes CSF cytology, oncofetal protein analysis, and nents had immunoreactivity to c-kit in the immature contrast-enhanced neuraxis MRI, should be performed teratoma specimens. Negative findings were seen in when the patient is first diagnosed.139-149 CSF-dissem- syncytiotrophoblastic giant cells, a finding that sug- inated disease occurs in 35% of nonseminomatous gested germinoma cells primarily express c-kit.166 germ cell tumors and 20% of germinomas.139-149 The researchers also used a sandwich enzyme-linked Combination treatment with platinum-based che- immunosorbent assay to analyze 47 CSF samples ob- motherapy and radiotherapy or radiotherapy alone is tained from 32 germ cell tumors, and they found that often curative in patients with germinoma, also called the level of s-kit was significantly higher in samples seminoma. Mature teratomas have the potential for cure that included syncytiotrophoblastic giant-cell germi- with surgery only. Although nonseminomatous germ nomas compared with control samples or samples that cell tumors frequently recur, approximately 65% of cas- contained teratomas or non–germ-cell brain tumors.166 es can be cured with either high-dose, thiotepa-based Miyanohara et al166 also found that s-kit concentrations chemotherapy in combination with autologous stem cell were much higher in the pretreatment samples com- transplantation, radiotherapy alone, or combination ra- pared with the samples retrieved at the time of tumor diotherapy and platinum-based chemotherapy.139-149 recurrence and those retrieved during tumor remis- Treatment of germ cell tumors is somewhat con- sion. S-kit concentration in the CSF was associated troversial regarding the appropriate radiation field to with the clinical course of the disease. These results in-

S8 Cancer Control January 2017, Vol. 24, No. 1 dicate that the level of s-kit concentration in CSF could (eg, ataxia, confusion, cranial nerve deficits, segmental be used as a clinical marker in germinomas to detect weakness) only stabilize or minimally improve follow- possible recurrence.166 ing treatment.179-190

Treatment Surgery Lack of standardized diagnostic methods, difficulties Surgery is utilized to place a ventriculoperitoneal shunt determining treatment response, and lack of large, in cases of symptomatic hydrocephalus and an intra- randomized controlled trials complicate the evalua- ventricular catheter and subgaleal reservoir are placed tion and management of neoplastic meningitis.167-178 for the administration of cytotoxic agents.191-198 Access Those issues notwithstanding, evidence suggests that to the subarachnoid space by lumbar puncture or via palliative therapies for neoplastic meningitis are ef- an intraventricular reservoir system can be used for fective and, in certain patients, can prolong survival. the administration of medications. The intraventricular Typically, treatment is multimodal and involves a reservoir system is the preferred approach because it is combination of surgery, radiotherapy, and chemo- more comfortable for the patient, is safer than repeat therapy. The Figure outlines a treatment algorithm for lumbar puncture, is simpler to perform, and it results neoplastic meningitis.167-178 in a more uniform distribution of the cytotoxic agent In general, the only neurological manifestations into the CSF space, thus producing more consistent of neoplastic meningitis that improve with treatment CSF levels.191-198 In up to 10% of lumbar punctures, drug are related to pain. Neurological signs and symptoms delivery occurs in the epidural space, even if CSF re-

Diagnosis

Supportive care Treatment

CNS imaging

Bulky disease or symptomatic site(s) No bulky disease

Ommaya placement Supportive care Radiotherapy

Ommaya placement

CSF flow study

CSF flow block Normal CSF flow

Radiation to site of block Intra-CSF chemotherapy

CSF flow study

CSF flow block

Supportive care See Table

Fig. — Treatment algorithm for neoplastic meningitis. CNS = central nervous system, CSF = cerebrospinal fluid. Adapted from references 189 and 190.

January 2017, Vol. 24, No. 1 Cancer Control S9 turn is observed following needle placement; in addi- diotherapy used to treat neoplastic meningitis from tion, distribution is enhanced after medication is deliv- solid tumors because of its association with significant ered through a reservoir.191-198 levels of systemic toxicity (eg, severe myelosuppres- Communicating hydrocephalus, a condition as- sion, mucositis) and because it is not curative.199-210 sociated with increased intracranial pressure, can be caused by neoplastic meningitis. Whole-brain radio- Chemotherapy therapy may alleviate elevated intracranial pressure Among all of the therapies used to manage neoplastic presumably by relief from obstructed sites of CSF flow, meningitis, chemotherapy is the single treatment modal- thereby obviating the need for CSF shunting. Alter- ity used to treat the whole neuraxis, administered either natively, if hydrocephalus is present, then placing a intrathecally or systemically.199-210 In patients with solid ventriculoperitoneal shunt often relieves intracranial tumors, the intra-CSF administration of chemotherapy is hypertension with attendant clinical improvement. If the mainstay of neoplastic meningitis management, and available, the use of an inline, on/off valve and reser- several groups suggest that administering chemothera- voir to aid in the intra-CSF administration of chemo- py to the CSF improves outcomes in these patients.211-220 therapy can be installed in parallel with the ventriculo- However, most studies exclude patients who are too ill to peritoneal shunt. Importantly, however, not all patients receive any treatment — a number that could approach can tolerate the shunt being turned off to allow for the one-third of patients with neoplastic meningitis.211-220 intra–CSF-administered drug to circulate.191-198 Cytarabine and its liposome formulation, metho- In persistent cases of ventricular CSF blockage, a trexate, and thiotepa are typical chemotherapeutic lumbar catheter and reservoir, as well as a ventricular agents used in the management of neoplastic meningi- catheter, may be used to provide intrathecal chemo- tis. In randomized trials of adult patients with neoplas- therapy to the spine. However, persistent cases of CSF tic meningitis and solid tumors, no response differences flow blocks following radiotherapy may be more ap- were reported between comparisons of single-agent propriately managed with supportive care only. On oc- methotrexate and thiotepa or between multiple agents casion, meningeal biopsy may be required to confirm (methotrexate/thiotepa/cytarabine or methotrexate/ neoplastic meningitis on pathology; however, these bi- cytarabine) and single-agent methotrexate.211-220 The opsies are rarely performed today because, in general, Table outlines common regimens for these drugs. Intra- leptomeningeal abnormalities can be determined by CSF, sustained-release cytarabine liposome administra- MRI, an abnormal CSF profile, or clinical examination tion has been shown to result in cytotoxic cytarabine findings consistent with neoplastic meningitis.191-198 levels in the CSF for at least 10 days.49-52,55,56,162,163,168,169 When comparing patients with neoplastic meningitis Radiotherapy and solid tumors receiving bimonthly cytarabine lipo- Radiotherapy is used in cases of neoplastic meningitis some injection and in those receiving biweekly metho- as a means to correct abnormal CSF flow (demonstra- trexate, the cytarabine regimen was shown to result in ble on radionuclide ventriculography), to relieve dis- a longer time to neurological progression and better ease-related symptoms (eg, cauda equina syndrome), quality of life.49-52,55,56,162,163,168,169 These findings were and to decrease the radiographic-identified bulky dis- later confirmed in studies of lymphomatous meningitis, ease (eg, co-existent parenchymal brain metastases). suggesting that the injection formulation of cytarabine Even without evidence on radiography of bulky dis- should be considered first-line treatment for neoplastic ease, patients with a symptomatic site of disease may meningitis when investigational agents are not avail- benefit from radiotherapy. As an example, radiothera- able.49-52,55,56,162,163,168,169 py to the lumbosacral spine in patients who experience The intra-CSF administration of chemotherapy is symptoms of cauda equina syndrome (back pain and based on the suggestion that, when these same drugs lower-extremity weakness and sensory disturbance) are systemically administered, all have poor penetra- is often employed and improves associated pain and tion into the CSF. As a consequence, therapeutic levels halts the imminent progression of symptoms. Similar- in the CSF are generally not achieved. Exceptions are ly, whole-brain or skull-base radiotherapy is often ad- systemic high-dose methotrexate, thiotepa, and cyta- ministered to patients with cranial neuropathies.199-210 rabine, all of which can result in cytotoxic levels in the Radiotherapy is indicated for patients with bulky CSF.211-220 However, systemic administration of these radiographic disease because the intra-CSF administra- agents is limited by the challenge of incorporating tion of chemotherapy is limited by diffusion to 2 to 3 them with other chemotherapy regimens being used mm of penetration into the tumor nodules. In addition, to manage the primary disease and their associated involved-field radiotherapy should be employed to cor- systemic toxicity. Several groups suggest that intra-CSF rect abnormalities in CSF flow because normalizing chemotherapy does not improve treatment outcomes, CSF flow obstruction is associated with improvements because systemic therapy can reach the subarachnoid in patient outcomes.199-210 Rarely is whole-neuraxis ra- deposits through their vascular supply.211-220

S10 Cancer Control January 2017, Vol. 24, No. 1 Table. — Common Regional Chemotherapy Options for Neoplastic Meningitis Drug Regimen Induction Consolidation Maintenance Bolus Concentration Bolus Concentration Bolus Concentration × Time × Time × Time Cytarabine 25–100 mg 25 mg/d for 25–100 mg 25 mg/d × 3 d 25–100 mg 25 mg/d × 3 d BIW or TIW × 4 wk TIW × 4 wk QW × 4 wk EOW × 4 wk QM QM Cytarabine liposome 50 mg — 50 mg — — — injection Q2W × 8 wk Q4W × 24 wk Etoposide 0.5 mg — 0.5 mg — 0.5 mg — BIW × 6 wk QW × 6 wk QM Interferon α 1 × 106 U — 1 × 106 U — 1 × 106 U — TIW × 4 wk TIW EOW × 4 wk TIW QM Methotrexate 10–15 mg 2 mg/d × 5 d 10–15 mg 2 mg/d for 5 d 10–15 mg 2 mg/d × 5 d BIW × 4 wk EOW × 8 wk QW × 4 wk EOW × 4 wk QM QM Rituximab 25–40 mg QW or — 25–40 mg OW or — 25–40 mg QW or — BIW × 4 wk EOW × 4 wk BIW × 4 wk Thiotepa 10 mg BIW or 10 mg/d 10 mg 10 mg/d for 3 d 10 mg 10 mg/d for 3 TIW × 4 wk TIW × 4 wk QW × 4 wk EOW × 4 wk QM d QM Topotecan 400 mg — 400 mg — 400 mg — BIW × 6 wk QW × 6 wk QM Trastuzumab 150 mg — EOW × 4 wk — QM — QW × 4 wk (2 doses total) BIW = twice weekly, EOW = every other week, QM = once monthly, Q2W = every 2 weeks, Q4W = every 4 weeks, QW = once weekly, TIW = thrice weekly.

Bokstein et al164 published a retrospective com- Supportive Care parison of patients who received systemic chemother- Aggressive treatment is not appropriate for every pa- apy and radiotherapy to involved areas in combination tient with neoplastic meningitis. Therapy using a mul- with or without intrathecal chemotherapy. Between timodal approach should be offered to patients with the 2 groups of patients, no significant differences in a Karnofsky performance status score higher than rates of median survival, response, and long-term sur- 60 (ie, independent in activities of daily living) and vival were observed. Glantz et al167 published the data for those whose life expectancy will be more than from 16 patients who were treated with intravenous, 3 months. Supportive care should be offered to every high-dose methotrexate. Outcomes were compared patient, regardless of whether disease-directed thera- with a control group (n = 15) who received intra-CSF py is provided. Such options, if necessary, can include administration of methotrexate. Rates of survival and antidepressants, anxiolytics, opioids for adequate an- response were significantly higher in the group receiv- algesia, and anticonvulsants for seizure control (inci- ing methotrexate via the intravenous route of adminsi- dence rate of 10%–15% in patients with neoplastic men- tration.167 Another report was published on 2 patients ingitis). Although corticosteroids have a limited role in with breast cancer who were receiving systemic hor- the management of neurological symptoms related to monal therapy to manage their neoplastic meningi- neoplastic meningitis, they may be useful for control of tis,168 and findings from anecdotal reports have sug- nausea/vomiting (along with added routine antiemet- gested that systemic chemotherapy is effective for ics) and the management of vasogenic edema associat- managing meningeal gliomatosis.211-220 ed with epidural or intraparenchymal metastases. Psy- Nonetheless, intra-CSF administration is still the chostimulants may also have a role in the management preferred route of administration for chemotherapy to of decreased attention and for the treatment of somno- manage neoplastic meningitis. Other agents, such as lence secondary to whole-brain radiotherapy.179-190 diaziquone, gemcitabine, interferon a, mafosfamide, temozolomide, and topotecan, have been evaluated Conclusions in an attempt to improve therapeutic efficacy.179-190 Im- Neoplastic meningitis is a difficult disease to treat. munotherapy utilizing interleukin 2 and interferon a, Most reports of neoplastic meningitis treat all tumors gene therapy, and iodine I 131-radiolabeled monoclo- as a single histology notwithstanding differences with nal antibodies are among several other therapeutic op- respect to options for treatment and expected out- tions being explored in clinical trials.179-190 comes. Because clinical trials in oncology use specific

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