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Neurological Review |

New Strategies in the Management of Leptomeningeal Metastases FREE

Morris D. Groves, MD
[+] Author Affiliations

Section Editor: David E. Pleasure, MD
Author Affiliation:Department of Neuro-Oncology, University of Texas MD Anderson Cancer Center, Houston.

More Author Information
Arch Neurol. 2010;67(3):305-312. doi:10.1001/archneurol.2010.18.
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Published online

The management of patients with leptomeningeal metastases (LM) is multifaceted and complex. Even with an aggressive approach, therapeutic outcomes are uniformly disappointing. This is because of the relentless growth of the central nervous system (CNS) and/or the systemic cancers, or their lethal complications. Advances in the understanding of the homing of cancer cells to the CNS, and of cancer metastasis in general, and more effective anticancer drugs that are adequately delivered to the CNS and cerebrospinal fluid (CSF) are needed to improve outcomes for patients with LM. These advances may lead to better treatments for this disease and, ultimately, its prevention.

Despite the passing of nearly 140 years since its original description, little progress has been made in improving survival for patients with LM. Hematologic malignancies can result in LM in up to 24% of patients. The most common solid tumors causing LM are breast cancer, lung cancer, and melanoma,1with incidences ranging between 5% and 23%. Leptomeningeal metastases risk rises with longer cancer survival.

In the United States, standard treatment for LM includes CSF diversion when indicated, radiation, local intrathecal (refers to intraventricular administration, unless otherwise specified) chemotherapy, and systemic chemotherapy. Recent reviews discuss management of LM.2,3With standard interventions, median survival for patients with LM ranges from 8 to 16 weeks. Roughly 24% to 34% die of LM alone, 22% to 25% die of LM simultaneously with progressive systemic cancer, 19% to 44% die of systemic disease progression, and up to 10% die of other causes.46

The incidence of brain metastases (BM) and LM may increase in the near future for at least 2 reasons: (1) longer control of non-CNS cancers may allow for more time for the development of CNS metastases and (2) the use of large-molecule antineoplastic agents with limited CNS and CSF penetration may control systemic disease but leave LM unaffected behind the blood-brain barrier (BBB) and blood-CSF barrier (BCSFB). Paradoxically, the newer large-molecule therapies may improve overall cancer survival while increasing the incidence of CNS metastases. Longer survival and exposure of tumor cells to genotoxic chemotherapy may select for increasingly chemoresistant cell clones, making LM even more resistant to therapy over time.

Once we understand the biology behind LM, we can develop therapies targeting these biological changes. Metastasis is a cascade of events with multiple cellular and molecular changes.7For LM to develop, tumor cells must detach from the primary site, invade a blood or lymphatic vessel, survive vascular transit, adhere to host organ endothelium,8invade the host organ, proliferate, and develop a blood supply.7Molecular factors implicated in CNS metastases and LM include E-cadherin–catenin complexes, plasmin, urokinase-type plasminogen activator, metalloproteinases, tissue inhibitors of metalloproteinases (associated with brain invasion),9and activated integrin αvβ3.10Metalloproteinases can degrade endothelial tight junction proteins at the BBB. Along with vascular endothelial growth factor (VEGF)11and stromal-derived factor 1,12metalloproteinases may allow for transendothelial migration of tumor cells.13Other mechanisms that may contribute to the development of LM include an ectodermal origin of the primary tumor, which may allow for advantageous cell-cell interactions between the metastatic tumor cells and native brain cells.14,15Further, tumor cell surface markers, such as the extracellular domain of the epidermal growth factor receptor 2 protein, are associated with a higher risk of BM in breast cancer16and possibly LM.

The delivery of many anticancer drugs from blood to the brain17,18and from blood to CSF is restricted, for multiple reasons. Drug-related factors include the drug's level of protein binding and its molecular weight, polarity, and lipid solubility.19Physical factors include the architectural properties of the BBB and BCSFB, such as the tight junctions between the endothelial cells of brain capillaries and the epithelial cells of the choroid plexuses, limiting paracellular diffusion of polar compounds. Further, adenosine triphosphate–dependent pumps such as the P-glycoprotein system, multidrug resistance proteins, and organic and inorganic ion transporters can mediate efflux of some anticancer drugs away from the brain.1925

The BBB and BCSFB are not identical. The BCSFB has a more relaxed tight junction architecture that correlates with differential diffusion capacities between it and the BBB.26Recent work has investigated the effect of P-glycoprotein–modulating drugs on the CSF penetration of some chemotherapies. Tamoxifen, a P-glycoprotein inhibitor, decreased the CSF penetration of paclitaxel, supporting the concept that the pumping direction of P-glycoprotein at the choroid plexus is in the opposite direction to the BBB. The P-glycoprotein system appears to direct natural product toxins away from the brain into the CSF, and when inhibited, lower CSF drug levels are found.27Animal models reveal similar findings with the tyrosine kinase inhibitor gefitinib. Its administration results in lower CSF levels and higher brain parenchymal levels of the topoisomerase I inhibitor topotecan.28

Table 1shows the CSF:plasma ratios for some of the drugs studied in humans and rhesus monkeys. A CSF:plasma ratio lower than 0.05 signifies nonspecific leakage of drug. Table 1shows that many drugs normally achieve CSF:plasma ratios lower than 0.05. However, once LM has arisen, or if radiation is directed to the CNS, leakage of the BCSFB develops, and larger molecules can leak from blood into CSF.68Further, some drugs have an intrinsically high CSF:plasma ratio, suggesting their possible utility in treating LM. As the understanding of the BBB and BCSFB advance, we may ultimately be able to facilitate the CNS and CSF penetration of therapeutic molecules, which are now excluded.

Table Graphic Jump LocationTable 1. Cerebrospinal Fluid to Plasma (or Serum) Drug Ratios After Intravenous or Oral Administration in Rhesus Monkeys or Humansa

Intrathecal chemotherapies typically used in LM include methotrexate, cytarabine, liposomal cytarabine, and thiotepa.3Systemic therapies are usually chosen based on tumor histology, drug penetration into the CSF, and a patient's prior drug exposure.

Intrathecal Treatments

Even though intrathecal chemotherapy is widely used in the United States for solid-tumor LM, proof of its benefit has not been established in randomized controlled trials.69Randomized controlled trials do suggest modest improvements with long-acting over standard intrathecal chemotherapies,70,71and some retrospective studies suggest intrathecal chemotherapy prolongs survival,72but there exists contrary evidence.73,74A recently begun randomized controlled trial, European Organization for Research and Treatment of Cancer 26051, is testing intrathecal liposomal cytarabine vs supportive care in solid-tumor LM.

Intraventricular (as opposed to intralumbar) chemotherapy delivery results in improved CSF drug levels and less interpatient variability of drug distribution. This form of regional chemotherapy has led to effective treatment of occult and overt meningeal leukemia in humans, and based on this success, investigators continue its evaluation in patients with solid tumor, hoping for similar outcomes. Pharmacokinetics of commonly used intrathecal anticancer agents shows that high drug concentrations can be achieved in the CSF and leptomeninges but not deep into the brain. Because of this, intrathecal administration is not effective for bulky disease in the meninges.75Further, in solid-tumor LM, intraventricular administration, or the use of sustained-release chemotherapeutic agents if the lumbar route is used, appears to improve treatment outcome.76

Experimental and Newer Agents.The most promising recently tested cytotoxic and radiotherapeutic agents are presented in Table 2. The topoisomerase inhibitors appear as effective as traditionally used intrathecal agents, and both etoposide and topotecan hydrochloride have little toxicity, so may be useful in combination with other agents or as prophylaxis.77,78,87A concentration × time study of intrathecal topotecan is open and accruing patients within the Pediatric Brain Tumor Consortium. Because of pain associated with intrathecal administration, mafosfamide requires slow delivery and premedication with steroids and narcotics but may be useful in childhood CNS malignancies to help delay or avoid radiation exposure.79,80Because of almost no toxicity and some efficacy (29% CSF clearance), sodium iodide I 131 (131I) will be further studied in a phase 2 trial with a higher-dose, multiday schedule.84For similar reasons, phase 2 studies evaluating serial intrathecal injections of the GD2-targeted monoclonal antibody 131I-3F8, are under way.85Early data suggest efficacy in childhood primitive neuroectodermal tumors and neuroblastoma.

Table Graphic Jump LocationTable 2. Promising Intrathecal Cytotoxic and Radiotherapeutic Treatmentsa

Noncytotoxic Intrathecal Therapies.Immunotherapies.The CSF space may be excluded from the benefits of the systemic antitumor effects of the immune system, so immunotherapeutic approaches to the treatment of LM are theoretically attractive. Unfortunately, immune responses are frequently associated with inflammation. Intrathecal administration of interleukin 2 or interferon alfa both resulted in responses in patients with LM but were also fairly toxic, limiting enthusiasm for further development.88,89

Rituximab.Rituximab is a humanized monoclonal antibody against the CD-20 antigen expressed on most B-cell lymphomas. It has been used intravenously since 1997. Cerebrospinal fluid levels of this large molecule (146 kDa) are only 0.1% of the serum level after intravenous administration.57Several case reports demonstrating safety and possible benefits of intrathecal administration of rituximab led to a recently reported phase 1 study.90In this study, the maximum tolerated dose of intrathecal rituximab was 25 mg twice weekly (9 doses total). Mean peak CSF concentration 1 hour postdose rose to 472 μg/mL and estimated half-life averaged 34.9 hours. Cytologic responses were seen in 6 of 10 patients; 4 patients experienced a complete response; 2 patients experienced improvement in intraocular lymphoma; and 1 patient's intraparenchymal lymphoma improved. Toxic reactions were limited. Further studies developing this promising therapy are under way. Additionally, a study of intrathecal rituximab combined with intrathecal methotrexate91for patients with intraocular or LM lymphoma has been initiated.

Trastuzumab.Trastuzumab is a humanized monoclonal antibody that binds to the epidermal growth factor receptor 2 protein, which is overexpressed in 30% of primary breast cancers, as well as some other tumors. Trastuzumab inhibits the growth of tumor cells and mediates antibody-dependent cellular cytotoxicity. A recent study showed that the CSF:serum trastuzumab ratio increased from 0.0023 prior to brain radiotherapy to 0.013 after completion of radiotherapy and was as high as 0.02 with concomitant LM after radiotherapy, revealing that CSF trastuzumab levels are low but can increase if BBB function is impaired.68

Promising results from a pilot study using intrathecal trastuzumab in patients with LM due to breast cancer, medulloblastoma, or glioblastoma were recently presented.92In this report, 16 patients with LM (11 glioblastoma multiforme, 4 breast cancer, 1 medulloblastoma) were treated with intrathecal trastuzumab (20-60 mg per dose, either weekly or every other week) for 4 treatments. Stable patients continued every-other-week therapy until neurologic progression. Two patients with breast cancer, 7 with glioblastoma multiforme, and the one with medulloblastoma responded without reported adverse events; the epidermal growth factor receptor 2 protein status appeared to be predictive of response. Based on these results, further study of intrathecal trastuzumab is warranted.

Systemic Treatments

Numerous reports suggest that systemic therapy improves survival for patients with LM.72,93100Some authors feel systemic therapy is the most important part of the treatment of LM73,74and exclude intrathecal therapy in patients with responsive cancers.94,95,97,101Agents capable of producing adequate CSF concentrations following systemic administration may benefit patients with LM.

Methotrexate.Methotrexate inhibits dihydrofolate reductase and the synthesis of purine nucleotides and thymidylate, interfering with DNA synthesis and repair. At high doses, methotrexate has favorable CSF penetration. A prospective, nonrandomized study comparing intrathecal methotrexate (n = 15) vs high-dose systemic methotrexate (n = 16) in patients with LM produced provocative results. High-dose methotrexate (8 g/m2over 4 hours) resulted in a mean peak concentration of 17.1 μmol/L in the CSF; cytotoxic CSF methotrexate levels remained measurable much longer than with intrathecal dosing. Furthermore, there was higher CSF tumor cell clearance and survival was longer (13.8 months vs 2.3 months, P = .003) in the systemic methotrexate-treated cohort.102Because of the favorable pharmacokinetics of high-dose methotrexate, further studies in patients with LM are warranted, possibly in combination with other agents.

Capecitabine.Capecitabine is a fluoropyrimidine carbamate designed as an oral alternative to 5-fluorouracil. Capecitabine is enzymatically converted to 5-fluorouracil at the tumor site. The increased drug concentration at the tumor site may enhance its antitumor activity and reduce systemic toxicity. Although there is no formal pharmacokinetic data regarding capecitabine's behavior in the CNS, there are empirical observations of responses to the drug in patients with BM and LM.103,104Capecitabine has also resulted in responses in a few patients with recurrent BM or LM even after previous capecitabine exposure.104,105Based on the existing reports, capecitabine is now frequently being used in patients with LM or BM secondary to breast cancer, and further prospective study is under way.

Temozolomide.Temozolomide is an orally bioavailable alkylator that reaches CSF levels roughly 20% of those in the serum.31In a pilot study of oral temozolomide in 10 patients with LM, the drug was well tolerated, although no responses were seen. Two patients had stable disease through 2 courses (6 weeks receiving therapy, 4 weeks not receiving therapy) but progressed while not receiving treatment,106suggesting that continuous treatment might be more efficacious.

Hormonal Therapies

There are several case reports of a beneficial contribution of hormonal therapy for patients with LM with hormone-sensitive tumors (breast and prostate cancer). Responses are reported lasting more than 12 months. For patients with LM from hormone-sensitive cancers, hormonal treatment is reasonable to continue or initiate and may provide some activity against the LM.98100

Experimental Treatment

Pemetrexed.Pemetrexed, a chemotherapeutic molecule similar to methotrexate, is approved for mesothelioma and non–small cell lung cancer and is active in methotrexate-resistant malignancies. The CSF penetration of pemetrexed was low in an animal model50; however, the CSF pharmacokinetics of systemically administered pemetrexed are being evaluated in an ongoing study in patients with LM. The drug is unique from methotrexate in that it is a “multitargeted” antifolate compound acting through several enzyme systems involved in folate metabolism. Pemetrexed gains intracellular access via at least 4 mechanisms, which may increase its activity over methotrexate. Early results demonstrate CSF responses in patients with breast cancer with LM (J. Raizer, MD, written communication, June 22, 2009).

Bevacizumab.Bevacizumab is a systemically administered monoclonal antibody directed against VEGF. Bevacizumab is approved for use in colorectal, breast, and non–small cell lung cancers and glioblastoma multiforme. Recent reports have identified elevated VEGF levels in the CSF of the majority of patients with LM due to melanoma or breast or lung cancer.107109Preliminary data suggest that in LM responders CSF VEGF levels fall and correlate with response.109The degree to which bevacizumab penetrates the CSF is unknown but is likely limited. Testing is under way at MD Anderson Cancer Center in patients with LM due to breast and lung cancer and melanoma to determine if systemically administered bevacizumab can affect CSF VEGF levels or impact tumor cells in the CSF.

Gefitinib.Gefitinib is a small-molecule tyrosine kinase inhibitor with activity against lung cancers that contain mutations of the epidermal growth factor receptor. Case reports have shown responses in patients with LM from non–small cell lung cancer.110,111A prospective study evaluating high-dose gefitinib (up to 1250 mg/d) in patients with LM with non–small cell lung cancer and sensitizing epidermal growth factor receptor mutations was recently closed. High doses of gefitinib were used (standard dose, 250 mg/d) attempting to increase CNS and CSF drug levels and improve anticancer effects.112Early reports of the clinical, CSF, and imaging outcomes were promising; final results are forthcoming (D. Jackman, MD, written communication, June 22, 2009).

Combination and Disease-Specific Treatments

Most reports of intrathecal LM treatments include patients who simultaneously receive systemic agents,5,6,97and many investigators feel combination intrathecal and systemic therapy improves outcomes.72,97Several planned studies will evaluate the concept of combination therapy, prospectively. Some clinical trials in development include a phase 2 study of intrathecal thiotepa for patients with LM due to primary brain tumors, a phase 2 study of lomustine plus cisplatin plus vincristine sulfate and intrathecal liposomal cytarabine for adults with medulloblastoma and CSF positive for tumor cells, and a phase 1/2 study of oral capecitabine plus liposomal cytarabine in patients with breast cancer with LM (R. Soffietti, MD, written communication, June 27, 2009).

Because of a paucity of available patients, LM studies often accrue multiple primary histologies. This heterogeneity obscures potential efficacy signals. Investigators, with respect to rituximab, gefitinib, and bevacizumab, as noted earlier, are beginning to design LM trials with specific histologies in mind.

Prevention strategies similar to those used for children with acute lymphoblastic leukemia113or in patients with aggressive lymphoma114may become feasible if genetic markers identifying tumors with a propensity to invade the CNS can be identified. High positive predictive value plasma or CSF biomarkers could allow for earlier treatment of LM, possibly affording better tumor control. Early studies suggest CSF VEGF may be useful as a biomarker,107but further research is warranted. Until prevention is feasible, or biomarker use is validated, unique clinical scenarios may still hold opportunities for earlier treatment and better outcomes.

Patients with BM may be at increased risk of developing LM, especially if the BM are located in the posterior fossa (BMPF). Among patients undergoing craniotomy for BMPF, estimates of the risk of developing LM are reported as high as 67%.115117Recent reports have begun to dissect out the details on the risk of CSF seeding after craniotomy. In a review of 379 patients with BMPF who were treated with either surgical resection or stereotactic radiation, 8.7% developed LM. But, there was a significantly higher risk of LM (14%; rate ratio, 2.45; P = .02) in those patients having a piecemeal resection of their BMPF when compared with either stereotactic radiation or en bloc resection.118A follow-up study of 827 patients undergoing craniotomy for supratentorial BM found a similar result, with a hazard ratio of 5.8 (P = .002) comparing piecemeal resection vs stereotactic radiation and a hazard ratio of 2.7 (P = .009) comparing piecemeal resection vs en bloc resection.119Patients with BM who undergo piecemeal tumor resection may be a good population in which to test biomarker-based or prophylactic interventions against LM.

Leptomeningeal metastases remain a neurologically devastating and fatal late complication of cancer. The molecular biology underpinning the development of LM is slowly being unraveled. To be effective, new treatments for LM need to reach the meninges and CSF and interact with relevant molecular targets. Since only about one-third of patients with LM die solely of LM, therapies that effectively address the systemic cancer and the LM are necessary for major improvements in survival. Progress is slowly being made with the testing of newer targeted agents and combination treatments, but obviously, there is much work to be done to improve outcomes for patients with LM.

Correspondence:Morris D. Groves, MD, UT MD Anderson Cancer Center, Department of Neuro-Oncology, 1400 Holcombe Blvd, Unit 431, Houston, TX 77030 (mgroves@mdanderson.org).

Accepted for Publication:July 19, 2009.

Financial Disclosure:Dr Groves received research funding from Genentech, Enzon Pharmaceuticals, and Schering-Plough Research Institute and has been on the speakers' bureau or received honoraria from Enzon Pharmaceuticals and Schering-Plough Research Institute.

Posner  JB Neurologic Complications of Cancer.  Philadelphia, PA F. A. Davis Co1995;
Jaeckle  KA Neoplastic meningitis from systemic malignancies: diagnosis, prognosis and treatment. Semin Oncol 2006;33 (3) 312- 323
PubMed
Gleissner  BChamberlain  MC Neoplastic meningitis. Lancet Neurol 2006;5 (5) 443- 452
PubMed
Jaeckle  KAPhuphanich  SBent  MJ  et al.  Intrathecal treatment of neoplastic meningitis due to breast cancer with a slow-release formulation of cytarabine. Br J Cancer 2001;84 (2) 157- 163
PubMed
Chamberlain  MCKormanik  P Carcinoma meningitis secondary to non-small cell lung cancer: combined modality therapy. Arch Neurol 1998;55 (4) 506- 512
PubMed
Chamberlain  MCKormanik  PR Carcinomatous meningitis secondary to breast cancer: predictors of response to combined modality therapy. J Neurooncol 1997;35 (1) 55- 64
PubMed
Nguyen  DXBos  PDMassague  J Metastasis: from dissemination to organ-specific colonization. Nat Rev Cancer 2009;9 (4) 274- 284
PubMed
Fidler  IJYano  SZhang  RDFujimaki  TBucana  CD The seed and soil hypothesis: vascularisation and brain metastases. Lancet Oncol 2002;3 (1) 53- 57
PubMed
Groves  MD The pathogenesis of neoplastic meningitis. Curr Oncol Rep 2003;5 (1) 15- 23
PubMed
Lorger  MKrueger  JSO'Neal  MStaflin  KFelding-Habermann  B Activation of tumor cell integrin {alpha}v{beta}3 controls angiogenesis and metastatic growth in the brain. Proc Natl Acad Sci U S A 2009;106 (26) 10666- 10671
PubMed
Lee  THAvraham  HKJiang  SAvraham  S Vascular endothelial growth factor modulates the transendothelial migration of MDA-MB-231 breast cancer cells through regulation of brain microvascular endothelial cell permeability. J Biol Chem 2003;278 (7) 5277- 5284
PubMed
Lee  BCLee  THAvraham  SAvraham  HK Involvement of the chemokine receptor CXCR4 and its ligand stromal cell-derived factor 1alpha in breast cancer cell migration through human brain microvascular endothelial cells. Mol Cancer Res 2004;2 (6) 327- 338
PubMed
Yang  YEstrada  EYThompson  JFLiu  WRosenberg  GA Matrix metalloproteinase-mediated disruption of tight junction proteins in cerebral vessels is reversed by synthetic matrix metalloproteinase inhibitor in focal ischemia in rat. J Cereb Blood Flow Metab 2007;27 (4) 697- 709
PubMed
Shintani  YHigashiyama  SOhta  M  et al.  Overexpression of ADAM9 in non-small cell lung cancer correlates with brain metastasis. Cancer Res 2004;64 (12) 4190- 4196
PubMed
Schackert  GFidler  IJ Site-specific metastasis of mouse melanomas and a fibrosarcoma in the brain or meninges of syngeneic animals. Cancer Res 1988;48 (12) 3478- 3484
PubMed
Palmieri  DSmith  QRLockman  PR  et al.  Brain metastases of breast cancer. Breast Dis 2006-2007;26139- 147
PubMed
Levin  VAPatlak  CSLandahl  HD Heuristic modeling of drug delivery to malignant brain tumors. J Pharmacokinet Biopharm 1980;8 (3) 257- 296
PubMed
Levin  VA Relationship of octanol/water partition coefficient and molecular weight to rat brain capillary permeability. J Med Chem 1980;23 (6) 682- 684
PubMed
Ghersi-Egea  JFStrazielle  N Brain drug delivery, drug metabolism, and multidrug resistance at the choroid plexus. Microsc Res Tech 2001;52 (1) 83- 88
PubMed
Taylor  EM The impact of efflux transporters in the brain on the development of drugs for CNS disorders. Clin Pharmacokinet 2002;41 (2) 81- 92
PubMed
Deguchi  YYokoyama  YSakamoto  T  et al.  Brain distribution of 6-mercaptopurine is regulated by the efflux transport system in the blood-brain barrier. Life Sci 2000;66 (7) 649- 662
PubMed
Potschka  HFedrowitz  MLoscher  W Multidrug resistance protein MRP2 contributes to blood-brain barrier function and restricts antiepileptic drug activity. J Pharmacol Exp Ther 2003;306 (1) 124- 131
PubMed
Rao  VVDahlheimer  JLBardgett  ME  et al.  Choroid plexus epithelial expression of MDR1 P glycoprotein and multidrug resistance-associated protein contribute to the blood-cerebrospinal-fluid drug-permeability barrier. Proc Natl Acad Sci U S A 1999;96 (7) 3900- 3905
PubMed
Wijnholds  JdeLange  ECScheffer  GL  et al.  Multidrug resistance protein 1 protects the choroid plexus epithelium and contributes to the blood-cerebrospinal fluid barrier. J Clin Invest 2000;105 (3) 279- 285
PubMed
Deeken  JFLoscher  W The blood-brain barrier and cancer: transporters, treatment, and Trojan horses. Clin Cancer Res 2007;13 (6) 1663- 1674
PubMed
Strazielle  NKhuth  STGhersi-Egea  JF Detoxification systems, passive and specific transport for drugs at the blood-CSF barrier in normal and pathological situations. Adv Drug Deliv Rev 2004;56 (12) 1717- 1740
PubMed
Chen  JBalmaceda  CBruce  JN  et al.  Tamoxifen paradoxically decreases paclitaxel deposition into cerebrospinal fluid of brain tumor patients. J Neurooncol 2006;76 (1) 85- 92
PubMed
Zhuang  YFraga  CHHubbard  KE  et al.  Topotecan central nervous system penetration is altered by a tyrosine kinase inhibitor. Cancer Res 2006;66 (23) 11305- 11313
PubMed
Heideman  RLCole  DEBalis  F  et al.  Phase I and pharmacokinetic evaluation of thiotepa in the cerebrospinal fluid and plasma of pediatric patients: evidence for dose-dependent plasma clearance of thiotepa. Cancer Res 1989;49 (3) 736- 741
PubMed
Vassal  GGouyette  AHartmann  OPico  JLLemerle  J Pharmacokinetics of high-dose busulfan in children. Cancer Chemother Pharmacol 1989;24 (6) 386- 390
PubMed
Ostermann  SCsajka  CBuclin  T  et al.  Plasma and cerebrospinal fluid population pharmacokinetics of temozolomide in malignant glioma patients. Clin Cancer Res 2004;10 (11) 3728- 3736
PubMed
Patel  M McCully  CGodwin  KBalis  FM Plasma and cerebrospinal fluid pharmacokinetics of intravenous temozolomide in non-human primates. J Neurooncol 2003;61 (3) 203- 207
PubMed
Berg  SLGerson  SLGodwin  KCole  DELiu  LBalis  FM Plasma and cerebrospinal fluid pharmacokinetics of O6-benzylguanine and time course of peripheral blood mononuclear cell O6-methylguanine-DNA methyltransferase inhibition in the nonhuman primate. Cancer Res 1995;55 (20) 4606- 4610
PubMed
Grygiel  JJBalis  FMCollins  JMLester  CMPoplack  DG Pharmacokinetics of tiazofurin in the plasma and cerebrospinal fluid of rhesus monkeys. Cancer Res 1985;45 (5) 2037- 2039
PubMed
Zimm  SEttinger  LJHolcenberg  JS  et al.  Phase I and clinical pharmacological study of mercaptopurine administered as a prolonged intravenous infusion. Cancer Res 1985;45 (4) 1869- 1873
PubMed
Kerr  IGZimm  SCollins  JMO'Neill  DPoplack  DG Effect of intravenous dose and schedule on cerebrospinal fluid pharmacokinetics of 5-fluorouracil in the monkey. Cancer Res 1984;44 (11) 4929- 4932
PubMed
Heideman  RLBalis  FM McCully  CPoplack  DG Preclinical pharmacology of arabinosyl-5-azacytidine in nonhuman primates. Cancer Res 1988;48 (15) 4294- 4298
PubMed
Balis  FMPoplack  DG Central nervous system pharmacology of antileukemic drugs. Am J Pediatr Hematol Oncol 1989;11 (1) 74- 86
PubMed
Slevin  MLPiall  EMAherne  GWHarvey  VJJohnston  ALister  TA Effect of dose and schedule on pharmacokinetics of high-dose cytosine arabinoside in plasma and cerebrospinal fluid. J Clin Oncol 1983;1 (9) 546- 551
PubMed
Kerr  JZBerg  SLDauser  R  et al.  Plasma and cerebrospinal fluid pharmacokinetics of gemcitabine after intravenous administration in nonhuman primates. Cancer Chemother Pharmacol 2001;47 (5) 411- 414
PubMed
Berg  SLBonate  PLNuchtern  JG  et al.  Plasma and cerebrospinal fluid pharmacokinetics of clofarabine in nonhuman primates. Clin Cancer Res 2005;11 (16) 5981- 5983
PubMed
Kellie  SJBarbaric  DKoopmans  PEarl  JCarr  DJde Graaf  SS Cerebrospinal fluid concentrations of vincristine after bolus intravenous dosing: a surrogate marker of brain penetration. Cancer 2002;94 (6) 1815- 1820
PubMed
Heideman  RLKelley  JAPacker  RJ  et al.  A pediatric phase I and pharmacokinetic study of spirohydantoin mustard. Cancer Res 1988;48 (8) 2292- 2295
PubMed
DeGregorio  MWKing  OYHolleran  WM  et al.  Ultrafiltrate and total platinum in plasma and cerebrospinal fluid in a patient with neuroblastoma. Cancer Treat Rep 1985;69 (12) 1441- 1442
PubMed
Jacobs  SSFox  EDennie  CMorgan  LB McCully  CLBalis  FM Plasma and cerebrospinal fluid pharmacokinetics of intravenous oxaliplatin, cisplatin, and carboplatin in nonhuman primates. Clin Cancer Res 2005;11 (4) 1669- 1674
PubMed
Hande  KRWedlund  PJNoone  RMWilkinson  GRGreco  FAWolff  SN Pharmacokinetics of high-dose etoposide (VP-16-213) administered to cancer patients. Cancer Res 1984;44 (1) 379- 382
PubMed
Relling  MVMahmoud  HHPui  CH  et al.  Etoposide achieves potentially cytotoxic concentrations in CSF of children with acute lymphoblastic leukemia. J Clin Oncol 1996;14 (2) 399- 404
PubMed
Thyss  AMilano  GDeville  AManassero  JRenee  NSchneider  M Effect of dose and repeat intravenous 24 hr infusions of methotrexate on cerebrospinal fluid availability in children with hematological malignancies. Eur J Cancer Clin Oncol 1987;23 (6) 843- 847
PubMed
Balis  FMBlaney  SM McCully  CLBacher  JDMurphy  RFPoplack  DG Methotrexate distribution within the subarachnoid space after intraventricular and intravenous administration. Cancer Chemother Pharmacol 2000;45 (3) 259- 264
PubMed
Stapleton  SLReid  JMThompson  PA  et al.  Plasma and cerebrospinal fluid pharmacokinetics of pemetrexed after intravenous administration in non-human primates. Cancer Chemother Pharmacol 2007;59 (4) 461- 466
PubMed
Habif  DVLipton  RCantell  K Interferon crosses blood-cerebrospinal fluid barrier in monkeys. Proc Soc Exp Biol Med 1975;149 (1) 287- 289
PubMed
Pestalozzi  BCBrignoli  S Trastuzumab in CSF. J Clin Oncol 2000;18 (11) 2349- 2351
PubMed
Stemmler  JSchmitt  MWillems  ABernhard  HHarbeck  NHeinemann  V Brain metastases in HER2-overexpressing metastatic breast cancer: comparative analysis of trastuzumab levels in serum and cerebrospinal fluid [abstract]. J Clin Oncol 2006 ASCO Annual Meeting Proceedings 2006;24 (18S) ((suppl)) 1525
Berg  SLReid  JGodwin  K  et al.  Pharmacokinetics and cerebrospinal fluid penetration of daunorubicin, idarubicin, and their metabolites in the nonhuman primate model. J Pediatr Hematol Oncol 1999;21 (1) 26- 30
PubMed
Baker  SDHeideman  RLCrom  WRKuttesch  JFGajjar  AStewart  CF Cerebrospinal fluid pharmacokinetics and penetration of continuous infusion topotecan in children with central nervous system tumors. Cancer Chemother Pharmacol 1996;37 (3) 195- 202
PubMed
Blaney  SMTakimoto  CMurry  DJ  et al.  Plasma and cerebrospinal fluid pharmacokinetics of 9-aminocamptothecin (9-AC), irinotecan (CPT-11), and SN-38 in nonhuman primates. Cancer Chemother Pharmacol 1998;41 (6) 464- 468
PubMed
Rubenstein  JLCombs  DRosenberg  J  et al.  Rituximab therapy for CNS lymphomas: targeting the leptomeningeal compartment. Blood 2003;101 (2) 466- 468
PubMed
Rubenstein  JLRosenberg  JDamon  L High-dose methotrexate plus rituximab (anti-CD20) monoclonal antibody in the treatment of primary CNS lymphoma.  Paper presented at: Society for Neuro-Oncology Fourth Annual Meeting November 19, 1999 Scottsdale, AZ
Meany  HJFox  E McCully  CTucker  CBalis  FM The plasma and cerebrospinal fluid pharmacokinetics of erlotinib and its active metabolite (OSI-420) after intravenous administration of erlotinib in non-human primates. Cancer Chemother Pharmacol 2008;62 (3) 387- 392
PubMed
Neville  KParise  RAThompson  P  et al.  Plasma and cerebrospinal fluid pharmacokinetics of imatinib after administration to nonhuman primates. Clin Cancer Res 2004;10 (7) 2525- 2529
PubMed
Berg  SLStone  JXiao  JJ  et al.  Plasma and cerebrospinal fluid pharmacokinetics of depsipeptide (FR901228) in nonhuman primates. Cancer Chemother Pharmacol 2004;54 (1) 85- 88
PubMed
Stapleton  SLThompson  PAOu  CN  et al.  Plasma and cerebrospinal fluid pharmacokinetics of valproic acid after oral administration in non-human primates. Cancer Chemother Pharmacol 2008;61 (4) 647- 652
PubMed
Beckloff  GLLerner  HJFrost  DRusso-Alesi  FMGitomer  S Hydroxyurea (NSC-32065) in biologic fluids: dose-concentration relationship. Cancer Chemother Rep 1965;4857- 58
PubMed
Muscal  JAThompson  PAGiranda  VL  et al.  Plasma and cerebrospinal fluid pharmacokinetics of ABT-888 after oral administration in non-human primates. Cancer Chemother Pharmacol 2010;65 (3) 419- 425
PubMed
Kilburn  LBBonate  PLBlaney  SM  et al.  Plasma and cerebrospinal fluid pharmacokinetics of tasidotin (ILX-651) and its metabolites in non-human primates. Cancer Chemother Pharmacol 2009;64 (2) 335- 340
PubMed
Yule  SMPrice  LPearson  ADBoddy  AV Cyclophosphamide and ifosfamide metabolites in the cerebrospinal fluid of children. Clin Cancer Res 1997;3 (11) 1985- 1992
PubMed
Levin  VAGroves  MDForman  AD Intraventricular and intrathecal therapy. Perry  MCThe Chemotherapy Sourcebook 4th ed. Philadelphia, PA Lippincott Williams and Wilkins2008;65- 74
Stemmler  HJSchmitt  MWillems  ABernhard  HHarbeck  NHeinemann  V Ratio of trastuzumab levels in serum and cerebrospinal fluid is altered in HER2-positive breast cancer patients with brain metastases and impairment of blood-brain barrier. Anticancer Drugs 2007;18 (1) 23- 28
PubMed
Rogers  LRChamberlain  MGlantz  M Evidence-based review of intrathecal chemotherapy in outcome of patients with leptomeningeal metastasis [abstract]. J Clin Oncol 2006 ASCO Annual Meeting Proceedings 2006;24 (18S) ((suppl)) 1529
Glantz  MJLaFollette  SJaeckle  KA  et al.  Randomized trial of a slow-release versus a standard formulation of cytarabine for the intrathecal treatment of lymphomatous meningitis. J Clin Oncol 1999;17 (10) 3110- 3116
PubMed
Glantz  MJJaeckle  KAChamberlain  MC  et al.  A randomized controlled trial comparing intrathecal sustained-release cytarabine (DepoCyt) to intrathecal methotrexate in patients with neoplastic meningitis from solid tumors. Clin Cancer Res 1999;5 (11) 3394- 3402
PubMed
Rudnicka  HNiwinska  AMurawska  M Breast cancer leptomeningeal metastasis—the role of multimodality treatment. J Neurooncol 2007;84 (1) 57- 62
PubMed
Boogerd  Wvan den Bent  MJKoehler  PJ  et al.  The relevance of intraventricular chemotherapy for leptomeningeal metastasis in breast cancer: a randomised study. Eur J Cancer 2004;40 (18) 2726- 2733
PubMed
Siegal  T Leptomeningeal metastases: rationale for systemic chemotherapy or what is the role of intra-CSF-chemotherapy? J Neurooncol 1998;38 (2-3) 151- 157
PubMed
Fleischhack  GJaehde  UBode  U Pharmacokinetics following intraventricular administration of chemotherapy in patients with neoplastic meningitis. Clin Pharmacokinet 2005;44 (1) 1- 31
PubMed
Glantz  MJChamberlain  MCBatchelor  TWong  ECavalli  FShapiro  WR Interaction between route of intra-CSF chemotherapy administration and efficacy of therapy in patients with neoplastic meningitis [abstract]. J Clin Oncol 2006 ASCO Annual Meeting Proceedings 2006;24 (18S) ((suppl)) 1530
Chamberlain  MCTsao-Wei  DDGroshen  S Phase II trial of intracerebrospinal fluid etoposide in the treatment of neoplastic meningitis. Cancer 2006;106 (9) 2021- 2027
PubMed
Groves  MDGlantz  MJChamberlain  MC  et al.  A multicenter phase II trial of intrathecal topotecan in patients with meningeal malignancies. Neuro Oncol 2008;10 (2) 208- 215
PubMed
Blaney  SMBalis  FMBerg  S  et al.  Intrathecal mafosfamide: a preclinical pharmacology and phase I trial. J Clin Oncol 2005;23 (7) 1555- 1563
PubMed
Blaney  SMBoyett  JFriedman  H  et al.  Phase I clinical trial of mafosfamide in infants and children aged 3 years or younger with newly diagnosed embryonal tumors: a pediatric brain tumor consortium study (PBTC-001). J Clin Oncol 2005;23 (3) 525- 531
PubMed
Gururangan  SPetros  WPPoussaint  TY  et al.  Phase I trial of intrathecal spartaject busulfan in children with neoplastic meningitis: a Pediatric Brain Tumor Consortium Study (PBTC-004). Clin Cancer Res 2006;12 (5) 1540- 1546
PubMed
Quinn  JAGlantz  MPetros  W  et al.  Intrathecal spartaject busulfan phase I trial for patients with neoplastic meningitis [abstract]. Neuro-oncol 2001;3 (4) 364
Nakagawa  HMiyahara  ESuzuki  TWada  KTamura  MFukushima  Y Continuous intrathecal administration of 5-fluoro-2'-deoxyuridine for the treatment of neoplastic meningitis. Neurosurgery 2005;57 (2) 266- 280
PubMed
Wong  FCGroves  MPapadopoulos  N  et al.  Toxicity and efficacy profiles of intrathecal injection of I-131 NaI via intraventricular (IVent) or intralumbar (Ilumb) route for leptomeningeal metastases (LM) therapy [abstract]. J Clin Oncol 2006 ASCO Annual Meeting Proceedings 2006;24 (18S) ((suppl)) 1549
Kramer  KHumm  JLSouweidane  MM  et al.  Phase I study of targeted radioimmunotherapy for leptomeningeal cancers using intra-Ommaya 131-I-3F8. J Clin Oncol 2007;25 (34) 5465- 5470
PubMed
Groves  MD Leptomeningeal Metastases: Still a Challenge.  Alexandria, VA American Society of Clinical Oncology2008;80- 87
Blaney  SMHeideman  RBerg  S  et al.  Phase I clinical trial of intrathecal topotecan in patients with neoplastic meningitis. J Clin Oncol 2003;21 (1) 143- 147
PubMed
Herrlinger  UWeller  MSchabet  M New aspects of immunotherapy of leptomeningeal metastasis. J Neurooncol 1998;38 (2-3) 233- 239
PubMed
Chamberlain  MC A phase II trial of intra-cerebrospinal fluid alpha interferon in the treatment of neoplastic meningitis. Cancer 2002;94 (10) 2675- 2680
PubMed
Rubenstein  JLFridlyand  JAbrey  L  et al.  Phase I study of intraventricular administration of rituximab in patients with recurrent CNS and intraocular lymphoma. J Clin Oncol 2007;25 (11) 1350- 1356
PubMed
Chamberlain  MCGlantz  MJ Intra-CSF rituximab for lymhomatous meningitis. J Clin Oncol 2007;25 (28) 4508- 4509
PubMed
Allison  DLGlantz  MWerner  TLKirkegaard  SLMurdock  KJensen  RL Intra-CSF trastuzumab in patients with neoplastic meningitis from breast cancer or primary brain tumors [abstract]. J Clin Oncol 2009 ASCO Annual Meeting Proceedings 2009;27 (15S) ((suppl)) 2006
Herrlinger  UForschler  HKuker  W  et al.  Leptomeningeal metastasis: survival and prognostic factors in 155 patients. J Neurol Sci 2004;223 (2) 167- 178
PubMed
Siegal  TLossos  APfeffer  MR Leptomeningeal metastases: analysis of 31 patients with sustained off-therapy response following combined-modality therapy. Neurology 1994;44 (8) 1463- 1469
PubMed
Grant  RNaylor  BGreenberg  HSJunck  L Clinical outcome in aggressively treated meningeal carcinomatosis. Arch Neurol 1994;51 (5) 457- 461
PubMed
de Wit  MLange-Brock  VKruell  ABokemeter  C Leptomeningeal metastases: results of different therapeutic approaches [abstract]. J Clin Oncol 2007 ASCO Annual Meeting Proceedings 2007;25 (18S) ((suppl)) 2047
Fizazi  KAsselain  BVincent-Salomon  A  et al.  Meningeal carcinomatosis in patients with breast carcinoma: clinical features, prognostic factors, and results of a high-dose intrathecal methotrexate regimen. Cancer 1996;77 (7) 1315- 1323
PubMed
Mencel  PJDeAngelis  LMMotzer  RJ Hormonal ablation as effective therapy for carcinomatous meningitis from prostatic carcinoma. Cancer 1994;73 (7) 1892- 1894
PubMed
Boogerd  WDorresteijn  LDvan Der Sande  JJde Gast  GCBruning  PF Response of leptomeningeal metastases from breast cancer to hormonal therapy. Neurology 2000;55 (1) 117- 119
PubMed
Ozdogan  MSamur  MBozcuk  HS  et al.  Durable remission of leptomeningeal metastasis of breast cancer with letrozole: a case report and implications of biomarkers on treatment selection. Jpn J Clin Oncol 2003;33 (5) 229- 231
PubMed
Boogerd  WHart  AAvan der Sande  JJEngelsman  E Meningeal carcinomatosis in breast cancer: prognostic factors and influence of treatment. Cancer 1991;67 (6) 1685- 1695
PubMed
Glantz  MJCole  BFRecht  L  et al.  High-dose intravenous methotrexate for patients with nonleukemic leptomeningeal cancer: is intrathecal chemotherapy necessary? J Clin Oncol 1998;16 (4) 1561- 1567
PubMed
Giglio  PTremont-Lukats  IWGroves  MD Response of neoplastic meningitis from solid tumors to oral capecitabine. J Neurooncol 2003;65 (2) 167- 172
PubMed
Ekenel  MHormigo  AMPeak  SDeAngelis  LMAbrey  LE Capecitabine therapy of central nervous system metastases from breast cancer. J Neurooncol 2007;85 (2) 223- 227
PubMed
Tham  YLHinckley  LTeh  BSElledge  R Long-term clinical response in leptomeningeal metastases from breast cancer treated with capecitabine monotherapy: a case report. Clin Breast Cancer 2006;7 (2) 164- 166
PubMed
Davis  THFadul  CEGlantz  MJ  et al.  Pilot phase II trial of temozolomide for leptomeningeal metastases: preliminary report [abstract]. J Clin Oncol 2003 ASCO Annual Meeting Proceedings 2003;22 (115a) ((suppl)) 460
Groves  MDHess  KRPuduvalli  VK  et al.  Biomarkers of disease: cerebrospinal fluid vascular endothelial growth factor (VEGF) and stromal cell derived factor (SDF)-1 levels in patients with neoplastic meningitis (NM) due to breast cancer, lung cancer and melanoma. J Neurooncol 2009;94 (2) 229- 234
PubMed
Stockhammer  GPoewe  WFBurgstaller  SF  et al.  Vascular endothelial growth factor in CSF: a biological marker for carcinomatous meningitis. Neurology 2000;54 (8) 1670- 1676
PubMed
Herrlinger  UWiendl  HRenninger  MForschler  HDichgans  JWeller  M Vascular endothelial growth factor (VEGF) in leptomeningeal metastasis: diagnostic and prognostic value. Br J Cancer 2004;91 (2) 219- 224
PubMed
Choong  NWDietrich  SSeiwert  TY  et al.  Gefitinib response of erlotinib-refractory lung cancer involving meninges—role of EGFR mutation. Nat Clin Pract Oncol 2006;3 (1) 50- 57
PubMed
Kanaji  NBandoh  SNagamura  NKushida  YHaba  RIshida  T Significance of an epidermal growth factor receptor mutation in cerebrospinal fluid for carcinomatous meningitis. Intern Med 2007;46 (19) 1651- 1655
PubMed
 High dose gefitinib for the treatment of carcinomatous meningitis in adult patients with non-small cell lung cancer and known or suspected EGFR mutations. Clinicaltrials.gov Web site. http://clinicaltrials.gov/ct2/show/NCT00372515. Accessed July 1, 2009
Hill  FGRichards  SGibson  B  et al. UK Medical Research Council Working Party on Childhood Leukaemia, Successful treatment without cranial radiotherapy of children receiving intensified chemotherapy for acute lymphoblastic leukaemia: results of the risk-stratified randomized central nervous system treatment trial MRC UKALL XI (ISRC TN 16757172). Br J Haematol 2004;124 (1) 33- 46
PubMed
Hill  QAOwen  RG CNS prophylaxis in lymphoma: who to target and what therapy to use. Blood Rev 2006;20 (6) 319- 332
PubMed
Norris  LKFGrossman  SAFOlivi  A Neoplastic meningitis following surgical resection of isolated cerebellar metastasis: a potentially preventable complication. J Neurooncol 1997;32 (3) 215- 223
PubMed
Siomin  VEVogelbaum  MAKanner  AALee  SYSuh  JHBarnett  GH Posterior fossa metastases: risk of leptomeningeal disease when treated with stereotactic radiosurgery compared to surgery. J Neurooncol 2004;67 (1-2) 115- 121
PubMed
van der Ree  TCDippel  DWAvezaat  CJSillevis Smitt  PAVecht  CJvan den Bent  MJ Leptomeningeal metastasis after surgical resection of brain metastases. J Neurol Neurosurg Psychiatry 1999;66 (2) 225- 227
PubMed
Suki  DAbouassi  HPatel  AJSawaya  RWeinberg  JSGroves  MD Comparative risk of leptomeningeal disease after resection or stereotactic radiosurgery for solid tumor metastasis to the posterior fossa. J Neurosurg 2008;108 (2) 248- 257
PubMed
Suki  DHatiboglu  MAPatel  AJ  et al.  Comparative risk of leptomeningeal dissemination of cancer after surgery or stereotactic radiosurgery for a single supratentorial solid tumor metastasis. Neurosurgery 2009;64 (4) 664- 674
PubMed

Figures

Tables

Table Graphic Jump LocationTable 1. Cerebrospinal Fluid to Plasma (or Serum) Drug Ratios After Intravenous or Oral Administration in Rhesus Monkeys or Humansa
Table Graphic Jump LocationTable 2. Promising Intrathecal Cytotoxic and Radiotherapeutic Treatmentsa

References

Posner  JB Neurologic Complications of Cancer.  Philadelphia, PA F. A. Davis Co1995;
Jaeckle  KA Neoplastic meningitis from systemic malignancies: diagnosis, prognosis and treatment. Semin Oncol 2006;33 (3) 312- 323
PubMed
Gleissner  BChamberlain  MC Neoplastic meningitis. Lancet Neurol 2006;5 (5) 443- 452
PubMed
Jaeckle  KAPhuphanich  SBent  MJ  et al.  Intrathecal treatment of neoplastic meningitis due to breast cancer with a slow-release formulation of cytarabine. Br J Cancer 2001;84 (2) 157- 163
PubMed
Chamberlain  MCKormanik  P Carcinoma meningitis secondary to non-small cell lung cancer: combined modality therapy. Arch Neurol 1998;55 (4) 506- 512
PubMed
Chamberlain  MCKormanik  PR Carcinomatous meningitis secondary to breast cancer: predictors of response to combined modality therapy. J Neurooncol 1997;35 (1) 55- 64
PubMed
Nguyen  DXBos  PDMassague  J Metastasis: from dissemination to organ-specific colonization. Nat Rev Cancer 2009;9 (4) 274- 284
PubMed
Fidler  IJYano  SZhang  RDFujimaki  TBucana  CD The seed and soil hypothesis: vascularisation and brain metastases. Lancet Oncol 2002;3 (1) 53- 57
PubMed
Groves  MD The pathogenesis of neoplastic meningitis. Curr Oncol Rep 2003;5 (1) 15- 23
PubMed
Lorger  MKrueger  JSO'Neal  MStaflin  KFelding-Habermann  B Activation of tumor cell integrin {alpha}v{beta}3 controls angiogenesis and metastatic growth in the brain. Proc Natl Acad Sci U S A 2009;106 (26) 10666- 10671
PubMed
Lee  THAvraham  HKJiang  SAvraham  S Vascular endothelial growth factor modulates the transendothelial migration of MDA-MB-231 breast cancer cells through regulation of brain microvascular endothelial cell permeability. J Biol Chem 2003;278 (7) 5277- 5284
PubMed
Lee  BCLee  THAvraham  SAvraham  HK Involvement of the chemokine receptor CXCR4 and its ligand stromal cell-derived factor 1alpha in breast cancer cell migration through human brain microvascular endothelial cells. Mol Cancer Res 2004;2 (6) 327- 338
PubMed
Yang  YEstrada  EYThompson  JFLiu  WRosenberg  GA Matrix metalloproteinase-mediated disruption of tight junction proteins in cerebral vessels is reversed by synthetic matrix metalloproteinase inhibitor in focal ischemia in rat. J Cereb Blood Flow Metab 2007;27 (4) 697- 709
PubMed
Shintani  YHigashiyama  SOhta  M  et al.  Overexpression of ADAM9 in non-small cell lung cancer correlates with brain metastasis. Cancer Res 2004;64 (12) 4190- 4196
PubMed
Schackert  GFidler  IJ Site-specific metastasis of mouse melanomas and a fibrosarcoma in the brain or meninges of syngeneic animals. Cancer Res 1988;48 (12) 3478- 3484
PubMed
Palmieri  DSmith  QRLockman  PR  et al.  Brain metastases of breast cancer. Breast Dis 2006-2007;26139- 147
PubMed
Levin  VAPatlak  CSLandahl  HD Heuristic modeling of drug delivery to malignant brain tumors. J Pharmacokinet Biopharm 1980;8 (3) 257- 296
PubMed
Levin  VA Relationship of octanol/water partition coefficient and molecular weight to rat brain capillary permeability. J Med Chem 1980;23 (6) 682- 684
PubMed
Ghersi-Egea  JFStrazielle  N Brain drug delivery, drug metabolism, and multidrug resistance at the choroid plexus. Microsc Res Tech 2001;52 (1) 83- 88
PubMed
Taylor  EM The impact of efflux transporters in the brain on the development of drugs for CNS disorders. Clin Pharmacokinet 2002;41 (2) 81- 92
PubMed
Deguchi  YYokoyama  YSakamoto  T  et al.  Brain distribution of 6-mercaptopurine is regulated by the efflux transport system in the blood-brain barrier. Life Sci 2000;66 (7) 649- 662
PubMed
Potschka  HFedrowitz  MLoscher  W Multidrug resistance protein MRP2 contributes to blood-brain barrier function and restricts antiepileptic drug activity. J Pharmacol Exp Ther 2003;306 (1) 124- 131
PubMed
Rao  VVDahlheimer  JLBardgett  ME  et al.  Choroid plexus epithelial expression of MDR1 P glycoprotein and multidrug resistance-associated protein contribute to the blood-cerebrospinal-fluid drug-permeability barrier. Proc Natl Acad Sci U S A 1999;96 (7) 3900- 3905
PubMed
Wijnholds  JdeLange  ECScheffer  GL  et al.  Multidrug resistance protein 1 protects the choroid plexus epithelium and contributes to the blood-cerebrospinal fluid barrier. J Clin Invest 2000;105 (3) 279- 285
PubMed
Deeken  JFLoscher  W The blood-brain barrier and cancer: transporters, treatment, and Trojan horses. Clin Cancer Res 2007;13 (6) 1663- 1674
PubMed
Strazielle  NKhuth  STGhersi-Egea  JF Detoxification systems, passive and specific transport for drugs at the blood-CSF barrier in normal and pathological situations. Adv Drug Deliv Rev 2004;56 (12) 1717- 1740
PubMed
Chen  JBalmaceda  CBruce  JN  et al.  Tamoxifen paradoxically decreases paclitaxel deposition into cerebrospinal fluid of brain tumor patients. J Neurooncol 2006;76 (1) 85- 92
PubMed
Zhuang  YFraga  CHHubbard  KE  et al.  Topotecan central nervous system penetration is altered by a tyrosine kinase inhibitor. Cancer Res 2006;66 (23) 11305- 11313
PubMed
Heideman  RLCole  DEBalis  F  et al.  Phase I and pharmacokinetic evaluation of thiotepa in the cerebrospinal fluid and plasma of pediatric patients: evidence for dose-dependent plasma clearance of thiotepa. Cancer Res 1989;49 (3) 736- 741
PubMed
Vassal  GGouyette  AHartmann  OPico  JLLemerle  J Pharmacokinetics of high-dose busulfan in children. Cancer Chemother Pharmacol 1989;24 (6) 386- 390
PubMed
Ostermann  SCsajka  CBuclin  T  et al.  Plasma and cerebrospinal fluid population pharmacokinetics of temozolomide in malignant glioma patients. Clin Cancer Res 2004;10 (11) 3728- 3736
PubMed
Patel  M McCully  CGodwin  KBalis  FM Plasma and cerebrospinal fluid pharmacokinetics of intravenous temozolomide in non-human primates. J Neurooncol 2003;61 (3) 203- 207
PubMed
Berg  SLGerson  SLGodwin  KCole  DELiu  LBalis  FM Plasma and cerebrospinal fluid pharmacokinetics of O6-benzylguanine and time course of peripheral blood mononuclear cell O6-methylguanine-DNA methyltransferase inhibition in the nonhuman primate. Cancer Res 1995;55 (20) 4606- 4610
PubMed
Grygiel  JJBalis  FMCollins  JMLester  CMPoplack  DG Pharmacokinetics of tiazofurin in the plasma and cerebrospinal fluid of rhesus monkeys. Cancer Res 1985;45 (5) 2037- 2039
PubMed
Zimm  SEttinger  LJHolcenberg  JS  et al.  Phase I and clinical pharmacological study of mercaptopurine administered as a prolonged intravenous infusion. Cancer Res 1985;45 (4) 1869- 1873
PubMed
Kerr  IGZimm  SCollins  JMO'Neill  DPoplack  DG Effect of intravenous dose and schedule on cerebrospinal fluid pharmacokinetics of 5-fluorouracil in the monkey. Cancer Res 1984;44 (11) 4929- 4932
PubMed
Heideman  RLBalis  FM McCully  CPoplack  DG Preclinical pharmacology of arabinosyl-5-azacytidine in nonhuman primates. Cancer Res 1988;48 (15) 4294- 4298
PubMed
Balis  FMPoplack  DG Central nervous system pharmacology of antileukemic drugs. Am J Pediatr Hematol Oncol 1989;11 (1) 74- 86
PubMed
Slevin  MLPiall  EMAherne  GWHarvey  VJJohnston  ALister  TA Effect of dose and schedule on pharmacokinetics of high-dose cytosine arabinoside in plasma and cerebrospinal fluid. J Clin Oncol 1983;1 (9) 546- 551
PubMed
Kerr  JZBerg  SLDauser  R  et al.  Plasma and cerebrospinal fluid pharmacokinetics of gemcitabine after intravenous administration in nonhuman primates. Cancer Chemother Pharmacol 2001;47 (5) 411- 414
PubMed
Berg  SLBonate  PLNuchtern  JG  et al.  Plasma and cerebrospinal fluid pharmacokinetics of clofarabine in nonhuman primates. Clin Cancer Res 2005;11 (16) 5981- 5983
PubMed
Kellie  SJBarbaric  DKoopmans  PEarl  JCarr  DJde Graaf  SS Cerebrospinal fluid concentrations of vincristine after bolus intravenous dosing: a surrogate marker of brain penetration. Cancer 2002;94 (6) 1815- 1820
PubMed
Heideman  RLKelley  JAPacker  RJ  et al.  A pediatric phase I and pharmacokinetic study of spirohydantoin mustard. Cancer Res 1988;48 (8) 2292- 2295
PubMed
DeGregorio  MWKing  OYHolleran  WM  et al.  Ultrafiltrate and total platinum in plasma and cerebrospinal fluid in a patient with neuroblastoma. Cancer Treat Rep 1985;69 (12) 1441- 1442
PubMed
Jacobs  SSFox  EDennie  CMorgan  LB McCully  CLBalis  FM Plasma and cerebrospinal fluid pharmacokinetics of intravenous oxaliplatin, cisplatin, and carboplatin in nonhuman primates. Clin Cancer Res 2005;11 (4) 1669- 1674
PubMed
Hande  KRWedlund  PJNoone  RMWilkinson  GRGreco  FAWolff  SN Pharmacokinetics of high-dose etoposide (VP-16-213) administered to cancer patients. Cancer Res 1984;44 (1) 379- 382
PubMed
Relling  MVMahmoud  HHPui  CH  et al.  Etoposide achieves potentially cytotoxic concentrations in CSF of children with acute lymphoblastic leukemia. J Clin Oncol 1996;14 (2) 399- 404
PubMed
Thyss  AMilano  GDeville  AManassero  JRenee  NSchneider  M Effect of dose and repeat intravenous 24 hr infusions of methotrexate on cerebrospinal fluid availability in children with hematological malignancies. Eur J Cancer Clin Oncol 1987;23 (6) 843- 847
PubMed
Balis  FMBlaney  SM McCully  CLBacher  JDMurphy  RFPoplack  DG Methotrexate distribution within the subarachnoid space after intraventricular and intravenous administration. Cancer Chemother Pharmacol 2000;45 (3) 259- 264
PubMed
Stapleton  SLReid  JMThompson  PA  et al.  Plasma and cerebrospinal fluid pharmacokinetics of pemetrexed after intravenous administration in non-human primates. Cancer Chemother Pharmacol 2007;59 (4) 461- 466
PubMed
Habif  DVLipton  RCantell  K Interferon crosses blood-cerebrospinal fluid barrier in monkeys. Proc Soc Exp Biol Med 1975;149 (1) 287- 289
PubMed
Pestalozzi  BCBrignoli  S Trastuzumab in CSF. J Clin Oncol 2000;18 (11) 2349- 2351
PubMed
Stemmler  JSchmitt  MWillems  ABernhard  HHarbeck  NHeinemann  V Brain metastases in HER2-overexpressing metastatic breast cancer: comparative analysis of trastuzumab levels in serum and cerebrospinal fluid [abstract]. J Clin Oncol 2006 ASCO Annual Meeting Proceedings 2006;24 (18S) ((suppl)) 1525
Berg  SLReid  JGodwin  K  et al.  Pharmacokinetics and cerebrospinal fluid penetration of daunorubicin, idarubicin, and their metabolites in the nonhuman primate model. J Pediatr Hematol Oncol 1999;21 (1) 26- 30
PubMed
Baker  SDHeideman  RLCrom  WRKuttesch  JFGajjar  AStewart  CF Cerebrospinal fluid pharmacokinetics and penetration of continuous infusion topotecan in children with central nervous system tumors. Cancer Chemother Pharmacol 1996;37 (3) 195- 202
PubMed
Blaney  SMTakimoto  CMurry  DJ  et al.  Plasma and cerebrospinal fluid pharmacokinetics of 9-aminocamptothecin (9-AC), irinotecan (CPT-11), and SN-38 in nonhuman primates. Cancer Chemother Pharmacol 1998;41 (6) 464- 468
PubMed
Rubenstein  JLCombs  DRosenberg  J  et al.  Rituximab therapy for CNS lymphomas: targeting the leptomeningeal compartment. Blood 2003;101 (2) 466- 468
PubMed
Rubenstein  JLRosenberg  JDamon  L High-dose methotrexate plus rituximab (anti-CD20) monoclonal antibody in the treatment of primary CNS lymphoma.  Paper presented at: Society for Neuro-Oncology Fourth Annual Meeting November 19, 1999 Scottsdale, AZ
Meany  HJFox  E McCully  CTucker  CBalis  FM The plasma and cerebrospinal fluid pharmacokinetics of erlotinib and its active metabolite (OSI-420) after intravenous administration of erlotinib in non-human primates. Cancer Chemother Pharmacol 2008;62 (3) 387- 392
PubMed
Neville  KParise  RAThompson  P  et al.  Plasma and cerebrospinal fluid pharmacokinetics of imatinib after administration to nonhuman primates. Clin Cancer Res 2004;10 (7) 2525- 2529
PubMed
Berg  SLStone  JXiao  JJ  et al.  Plasma and cerebrospinal fluid pharmacokinetics of depsipeptide (FR901228) in nonhuman primates. Cancer Chemother Pharmacol 2004;54 (1) 85- 88
PubMed
Stapleton  SLThompson  PAOu  CN  et al.  Plasma and cerebrospinal fluid pharmacokinetics of valproic acid after oral administration in non-human primates. Cancer Chemother Pharmacol 2008;61 (4) 647- 652
PubMed
Beckloff  GLLerner  HJFrost  DRusso-Alesi  FMGitomer  S Hydroxyurea (NSC-32065) in biologic fluids: dose-concentration relationship. Cancer Chemother Rep 1965;4857- 58
PubMed
Muscal  JAThompson  PAGiranda  VL  et al.  Plasma and cerebrospinal fluid pharmacokinetics of ABT-888 after oral administration in non-human primates. Cancer Chemother Pharmacol 2010;65 (3) 419- 425
PubMed
Kilburn  LBBonate  PLBlaney  SM  et al.  Plasma and cerebrospinal fluid pharmacokinetics of tasidotin (ILX-651) and its metabolites in non-human primates. Cancer Chemother Pharmacol 2009;64 (2) 335- 340
PubMed
Yule  SMPrice  LPearson  ADBoddy  AV Cyclophosphamide and ifosfamide metabolites in the cerebrospinal fluid of children. Clin Cancer Res 1997;3 (11) 1985- 1992
PubMed
Levin  VAGroves  MDForman  AD Intraventricular and intrathecal therapy. Perry  MCThe Chemotherapy Sourcebook 4th ed. Philadelphia, PA Lippincott Williams and Wilkins2008;65- 74
Stemmler  HJSchmitt  MWillems  ABernhard  HHarbeck  NHeinemann  V Ratio of trastuzumab levels in serum and cerebrospinal fluid is altered in HER2-positive breast cancer patients with brain metastases and impairment of blood-brain barrier. Anticancer Drugs 2007;18 (1) 23- 28
PubMed
Rogers  LRChamberlain  MGlantz  M Evidence-based review of intrathecal chemotherapy in outcome of patients with leptomeningeal metastasis [abstract]. J Clin Oncol 2006 ASCO Annual Meeting Proceedings 2006;24 (18S) ((suppl)) 1529
Glantz  MJLaFollette  SJaeckle  KA  et al.  Randomized trial of a slow-release versus a standard formulation of cytarabine for the intrathecal treatment of lymphomatous meningitis. J Clin Oncol 1999;17 (10) 3110- 3116
PubMed
Glantz  MJJaeckle  KAChamberlain  MC  et al.  A randomized controlled trial comparing intrathecal sustained-release cytarabine (DepoCyt) to intrathecal methotrexate in patients with neoplastic meningitis from solid tumors. Clin Cancer Res 1999;5 (11) 3394- 3402
PubMed
Rudnicka  HNiwinska  AMurawska  M Breast cancer leptomeningeal metastasis—the role of multimodality treatment. J Neurooncol 2007;84 (1) 57- 62
PubMed
Boogerd  Wvan den Bent  MJKoehler  PJ  et al.  The relevance of intraventricular chemotherapy for leptomeningeal metastasis in breast cancer: a randomised study. Eur J Cancer 2004;40 (18) 2726- 2733
PubMed
Siegal  T Leptomeningeal metastases: rationale for systemic chemotherapy or what is the role of intra-CSF-chemotherapy? J Neurooncol 1998;38 (2-3) 151- 157
PubMed
Fleischhack  GJaehde  UBode  U Pharmacokinetics following intraventricular administration of chemotherapy in patients with neoplastic meningitis. Clin Pharmacokinet 2005;44 (1) 1- 31
PubMed
Glantz  MJChamberlain  MCBatchelor  TWong  ECavalli  FShapiro  WR Interaction between route of intra-CSF chemotherapy administration and efficacy of therapy in patients with neoplastic meningitis [abstract]. J Clin Oncol 2006 ASCO Annual Meeting Proceedings 2006;24 (18S) ((suppl)) 1530
Chamberlain  MCTsao-Wei  DDGroshen  S Phase II trial of intracerebrospinal fluid etoposide in the treatment of neoplastic meningitis. Cancer 2006;106 (9) 2021- 2027
PubMed
Groves  MDGlantz  MJChamberlain  MC  et al.  A multicenter phase II trial of intrathecal topotecan in patients with meningeal malignancies. Neuro Oncol 2008;10 (2) 208- 215
PubMed
Blaney  SMBalis  FMBerg  S  et al.  Intrathecal mafosfamide: a preclinical pharmacology and phase I trial. J Clin Oncol 2005;23 (7) 1555- 1563
PubMed
Blaney  SMBoyett  JFriedman  H  et al.  Phase I clinical trial of mafosfamide in infants and children aged 3 years or younger with newly diagnosed embryonal tumors: a pediatric brain tumor consortium study (PBTC-001). J Clin Oncol 2005;23 (3) 525- 531
PubMed
Gururangan  SPetros  WPPoussaint  TY  et al.  Phase I trial of intrathecal spartaject busulfan in children with neoplastic meningitis: a Pediatric Brain Tumor Consortium Study (PBTC-004). Clin Cancer Res 2006;12 (5) 1540- 1546
PubMed
Quinn  JAGlantz  MPetros  W  et al.  Intrathecal spartaject busulfan phase I trial for patients with neoplastic meningitis [abstract]. Neuro-oncol 2001;3 (4) 364
Nakagawa  HMiyahara  ESuzuki  TWada  KTamura  MFukushima  Y Continuous intrathecal administration of 5-fluoro-2'-deoxyuridine for the treatment of neoplastic meningitis. Neurosurgery 2005;57 (2) 266- 280
PubMed
Wong  FCGroves  MPapadopoulos  N  et al.  Toxicity and efficacy profiles of intrathecal injection of I-131 NaI via intraventricular (IVent) or intralumbar (Ilumb) route for leptomeningeal metastases (LM) therapy [abstract]. J Clin Oncol 2006 ASCO Annual Meeting Proceedings 2006;24 (18S) ((suppl)) 1549
Kramer  KHumm  JLSouweidane  MM  et al.  Phase I study of targeted radioimmunotherapy for leptomeningeal cancers using intra-Ommaya 131-I-3F8. J Clin Oncol 2007;25 (34) 5465- 5470
PubMed
Groves  MD Leptomeningeal Metastases: Still a Challenge.  Alexandria, VA American Society of Clinical Oncology2008;80- 87
Blaney  SMHeideman  RBerg  S  et al.  Phase I clinical trial of intrathecal topotecan in patients with neoplastic meningitis. J Clin Oncol 2003;21 (1) 143- 147
PubMed
Herrlinger  UWeller  MSchabet  M New aspects of immunotherapy of leptomeningeal metastasis. J Neurooncol 1998;38 (2-3) 233- 239
PubMed
Chamberlain  MC A phase II trial of intra-cerebrospinal fluid alpha interferon in the treatment of neoplastic meningitis. Cancer 2002;94 (10) 2675- 2680
PubMed
Rubenstein  JLFridlyand  JAbrey  L  et al.  Phase I study of intraventricular administration of rituximab in patients with recurrent CNS and intraocular lymphoma. J Clin Oncol 2007;25 (11) 1350- 1356
PubMed
Chamberlain  MCGlantz  MJ Intra-CSF rituximab for lymhomatous meningitis. J Clin Oncol 2007;25 (28) 4508- 4509
PubMed
Allison  DLGlantz  MWerner  TLKirkegaard  SLMurdock  KJensen  RL Intra-CSF trastuzumab in patients with neoplastic meningitis from breast cancer or primary brain tumors [abstract]. J Clin Oncol 2009 ASCO Annual Meeting Proceedings 2009;27 (15S) ((suppl)) 2006
Herrlinger  UForschler  HKuker  W  et al.  Leptomeningeal metastasis: survival and prognostic factors in 155 patients. J Neurol Sci 2004;223 (2) 167- 178
PubMed
Siegal  TLossos  APfeffer  MR Leptomeningeal metastases: analysis of 31 patients with sustained off-therapy response following combined-modality therapy. Neurology 1994;44 (8) 1463- 1469
PubMed
Grant  RNaylor  BGreenberg  HSJunck  L Clinical outcome in aggressively treated meningeal carcinomatosis. Arch Neurol 1994;51 (5) 457- 461
PubMed
de Wit  MLange-Brock  VKruell  ABokemeter  C Leptomeningeal metastases: results of different therapeutic approaches [abstract]. J Clin Oncol 2007 ASCO Annual Meeting Proceedings 2007;25 (18S) ((suppl)) 2047
Fizazi  KAsselain  BVincent-Salomon  A  et al.  Meningeal carcinomatosis in patients with breast carcinoma: clinical features, prognostic factors, and results of a high-dose intrathecal methotrexate regimen. Cancer 1996;77 (7) 1315- 1323
PubMed
Mencel  PJDeAngelis  LMMotzer  RJ Hormonal ablation as effective therapy for carcinomatous meningitis from prostatic carcinoma. Cancer 1994;73 (7) 1892- 1894
PubMed
Boogerd  WDorresteijn  LDvan Der Sande  JJde Gast  GCBruning  PF Response of leptomeningeal metastases from breast cancer to hormonal therapy. Neurology 2000;55 (1) 117- 119
PubMed
Ozdogan  MSamur  MBozcuk  HS  et al.  Durable remission of leptomeningeal metastasis of breast cancer with letrozole: a case report and implications of biomarkers on treatment selection. Jpn J Clin Oncol 2003;33 (5) 229- 231
PubMed
Boogerd  WHart  AAvan der Sande  JJEngelsman  E Meningeal carcinomatosis in breast cancer: prognostic factors and influence of treatment. Cancer 1991;67 (6) 1685- 1695
PubMed
Glantz  MJCole  BFRecht  L  et al.  High-dose intravenous methotrexate for patients with nonleukemic leptomeningeal cancer: is intrathecal chemotherapy necessary? J Clin Oncol 1998;16 (4) 1561- 1567
PubMed
Giglio  PTremont-Lukats  IWGroves  MD Response of neoplastic meningitis from solid tumors to oral capecitabine. J Neurooncol 2003;65 (2) 167- 172
PubMed
Ekenel  MHormigo  AMPeak  SDeAngelis  LMAbrey  LE Capecitabine therapy of central nervous system metastases from breast cancer. J Neurooncol 2007;85 (2) 223- 227
PubMed
Tham  YLHinckley  LTeh  BSElledge  R Long-term clinical response in leptomeningeal metastases from breast cancer treated with capecitabine monotherapy: a case report. Clin Breast Cancer 2006;7 (2) 164- 166
PubMed
Davis  THFadul  CEGlantz  MJ  et al.  Pilot phase II trial of temozolomide for leptomeningeal metastases: preliminary report [abstract]. J Clin Oncol 2003 ASCO Annual Meeting Proceedings 2003;22 (115a) ((suppl)) 460
Groves  MDHess  KRPuduvalli  VK  et al.  Biomarkers of disease: cerebrospinal fluid vascular endothelial growth factor (VEGF) and stromal cell derived factor (SDF)-1 levels in patients with neoplastic meningitis (NM) due to breast cancer, lung cancer and melanoma. J Neurooncol 2009;94 (2) 229- 234
PubMed
Stockhammer  GPoewe  WFBurgstaller  SF  et al.  Vascular endothelial growth factor in CSF: a biological marker for carcinomatous meningitis. Neurology 2000;54 (8) 1670- 1676
PubMed
Herrlinger  UWiendl  HRenninger  MForschler  HDichgans  JWeller  M Vascular endothelial growth factor (VEGF) in leptomeningeal metastasis: diagnostic and prognostic value. Br J Cancer 2004;91 (2) 219- 224
PubMed
Choong  NWDietrich  SSeiwert  TY  et al.  Gefitinib response of erlotinib-refractory lung cancer involving meninges—role of EGFR mutation. Nat Clin Pract Oncol 2006;3 (1) 50- 57
PubMed
Kanaji  NBandoh  SNagamura  NKushida  YHaba  RIshida  T Significance of an epidermal growth factor receptor mutation in cerebrospinal fluid for carcinomatous meningitis. Intern Med 2007;46 (19) 1651- 1655
PubMed
 High dose gefitinib for the treatment of carcinomatous meningitis in adult patients with non-small cell lung cancer and known or suspected EGFR mutations. Clinicaltrials.gov Web site. http://clinicaltrials.gov/ct2/show/NCT00372515. Accessed July 1, 2009
Hill  FGRichards  SGibson  B  et al. UK Medical Research Council Working Party on Childhood Leukaemia, Successful treatment without cranial radiotherapy of children receiving intensified chemotherapy for acute lymphoblastic leukaemia: results of the risk-stratified randomized central nervous system treatment trial MRC UKALL XI (ISRC TN 16757172). Br J Haematol 2004;124 (1) 33- 46
PubMed
Hill  QAOwen  RG CNS prophylaxis in lymphoma: who to target and what therapy to use. Blood Rev 2006;20 (6) 319- 332
PubMed
Norris  LKFGrossman  SAFOlivi  A Neoplastic meningitis following surgical resection of isolated cerebellar metastasis: a potentially preventable complication. J Neurooncol 1997;32 (3) 215- 223
PubMed
Siomin  VEVogelbaum  MAKanner  AALee  SYSuh  JHBarnett  GH Posterior fossa metastases: risk of leptomeningeal disease when treated with stereotactic radiosurgery compared to surgery. J Neurooncol 2004;67 (1-2) 115- 121
PubMed
van der Ree  TCDippel  DWAvezaat  CJSillevis Smitt  PAVecht  CJvan den Bent  MJ Leptomeningeal metastasis after surgical resection of brain metastases. J Neurol Neurosurg Psychiatry 1999;66 (2) 225- 227
PubMed
Suki  DAbouassi  HPatel  AJSawaya  RWeinberg  JSGroves  MD Comparative risk of leptomeningeal disease after resection or stereotactic radiosurgery for solid tumor metastasis to the posterior fossa. J Neurosurg 2008;108 (2) 248- 257
PubMed
Suki  DHatiboglu  MAPatel  AJ  et al.  Comparative risk of leptomeningeal dissemination of cancer after surgery or stereotactic radiosurgery for a single supratentorial solid tumor metastasis. Neurosurgery 2009;64 (4) 664- 674
PubMed

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