Volume=20 36, Supplement=20 2, Pages S46-S54 (August = 2009)

8 of 10

ABSTRACT

FULL=20 TEXT

FULL-TEXT PDF (462=20 KB)

Treatment Modalities for = Leptomeningeal=20 Metastases

William=20 R. Shapiroa 3D"Corresponding

, Conrad=20 E. Johansonb, = Willem Boogerdc

Secondary involvement of the=20 leptomeninges represents an infrequent but devastating (and = nearly=20 always fatal) complication of solid tumors, hematologic = malignancies=20 (both leukemia and lymphoma), and primary brain tumors. = Clinical=20 suspicion of neoplastic meningitis (NM) may be raised by the = appearance of multivariate neurological symptoms; however, a = definitive diagnosis is often difficult to obtain. Improved=20 treatments for primary malignancies and advances in = diagnostic=20 imaging technology have led to an apparent increase in the = number of=20 patients diagnosed with NM. Unfortunately, therapeutic = options=20 remain limited, particularly for patients with = chemoresistant=20 tumors. Optimized treatment remains controversial and may = rely upon=20 a combination of chemotherapy (intrathecal and/or = intravenous) and=20 concurrent focal radiotherapy. This review discusses the = advantages=20 and disadvantages of intra-cerebrospinal fluid (CSF) versus = systemic=20 strategies for treating NM. Clinical trial evidence is = presented for=20 the different treatment modalities. In addition, the = therapeutic=20 potential of intra-CSF therapy for cancer prophylaxis is = discussed.=20 Earlier diagnosis and more aggressive preventive treatment = regimens=20 may provide substantial increases in survival and favorably = affect=20 quality of life. Additional data from large-scale, = well-controlled=20 trials are required to more accurately assess the efficacy = of=20 intra-CSF versus systemic treatment in NM. Future treatment = options=20 using novel targets for intra-CSF therapy will be addressed = as=20 well.

Article Outline

=E2=80=A2 Abstract

=E2=80=A2 Intra-CSF=20 Chemotherapy: Routes of Delivery

=E2=80=A2 Intra-CSF=20 Prophylaxis

=E2=80=A2 Solid-Tumor=20 NM: Therapeutic Potential of Intra-CSF Drug Delivery

=E2=80=A2 Novel=20 Modalities for Intra-CSF Cancer Therapy and = Prevention=E2=80=94Exploiting=20 the Choroid Plexus

=E2=80=A2 Conclusion

=E2=80=A2 References

=E2=80=A2 Copyright

Metastatic spread of tumor cells to = the=20 leptomeninges of the central nervous system (CNS) is a = severe=20 complication of cancer that is usually associated with late = stages=20 of disease progression.1 = Malignant cells=20 are disseminated within the cerebrospinal fluid (CSF) and = replicate=20 at various sites within the CNS. CSF is contained in the = cerebral=20 ventricles and in the subarachnoid space found between the = pia mater=20 and arachnoid leptomeningeal membranes, enveloping the brain = and=20 spinal cord. Cancer cells that penetrate into the CSF can = form=20 secondary deposits in the leptomeninges throughout the = neuroaxis.2, 3 = Neoplastic=20 meningitis (NM) is estimated to occur in 3% to 8% of all = patients=20 with cancer; however, as therapies improve and enable = patients with=20 cancer to live longer, this incidence appears to be = increasing.1 Due = to the rapid=20 pace of diagnostic and therapeutic advancements, malignant=20 infiltration of the leptomeninges by systemic cancer is = being=20 recognized with increasing frequency.

Leptomeningeal metastasis of = malignant cells=20 is associated with high morbidity and mortality rates. The = median=20 survival of patients with untreated cancer with NM is 4 to 6 = weeks.=20 For these patients, death generally occurs because of = progressive=20 neurologic dysfunction.1 = Treatment is=20 intended to improve or stabilize neurologic status, maintain = neurologic quality of life (QoL), and prolong survival.4 = Although fixed=20 neurologic defects are rarely improved with treatment, the=20 progression of neurologic deterioration may be halted in = some=20 patients, and median survival can be increased to 4 to 6 = months.=20 Numerous prognostic factors for survival and response have = been=20 suggested, but many remain controversial. It is commonly = accepted=20 that poor prognosis is associated with low performance = status (using=20 validated QoL assessment instruments such as the Karnofsky=20 Performance Scale [KPS]), multiple fixed neurologic = deficits, the=20 presence of bulky CNS disease, coexistent encephalopathy, = and CSF=20 flow abnormalities demonstrated by radionuclide = ventriculography.=20 Ideally, CNS cancers should be diagnosed in the early stages = of=20 disease to prevent progression of disabling neurologic = deficits.1

Current treatment strategies for=20 leptomeningeal metastasis include radiation therapy (RT), = systemic=20 therapy, intra-CSF therapy (ie, intrathecal), and = combination=20 therapy. Systemic chemotherapy often is associated with = difficulties=20 in achieving and maintaining cytotoxic CSF concentrations.4 = However, the use=20 of high doses has, to a certain extent, resulted in = cytotoxic=20 concentrations in the CSF. Intra-CSF therapy has shown = efficacy in=20 the treatment of CNS cancers and may have potential for the=20 prophylactic treatment of such cancers.4 Four = main agents=20 are currently used for intra-CSF therapy: methotrexate = (MTX),=20 thiotepa, cytarabine, and liposomal cytarabine.4 This = review will=20 discuss the efficacy and safety of the various treatment = modalities=20 and compare their advantages and disadvantages. Future = medications=20 may exploit novel points of entry to the CSF. A final = discussion=20 will highlight how the choroid plexus may represent a new = transport=20 interface for CNS cancer treatment and how it may enhance = our=20 prospects for targeted CSF drug delivery.5

Intra-CSF = Chemotherapy: Routes=20 of Delivery

Chemotherapies are required to = achieve and=20 maintain a therapeutic concentration at the target site for = a=20 sufficient amount of time in order to be efficacious.6 Most = chemotherapies produce a pharmacologic response in a = dose-dependent=20 manner. Historically, chemotherapy has been delivered to the = CNS via=20 systemic intravenous (IV) routes or via direct intra-CSF = injection.=20 A major challenge associated with systemic therapy, which = relies on=20 the circulatory system for drug delivery to the CNS, lies in = the=20 ability to penetrate the blood-brain barrier (BBB) and = blood-CSF=20 barrier.7 = Collectively,=20 these barrier systems serve to maintain brain homeostasis by = restricting the uncontrolled diffusion of blood-borne = chemicals into=20 the CNS parenchyma. Only a few chemotherapeutic agents have = achieved=20 cytotoxic intra-CSF concentrations after IV administration = without=20 reaching toxic levels systemically. High-dose IV deliveries = of MTX,=20 thiotepa, and cytarabine have been used effectively to treat = CNS=20 cancers; however, systemic toxicity remains an important = concern.8, 9, 10, = 11

The therapeutic or cytotoxic = concentration=20 required for MTX efficacy has been estimated at 3 =C3=97 = 10=E2=88=926 mol/L; however, = considerable debate=20 persists regarding the absolute effective concentration.12 = Concentrations=20 as low as 1 =C3=97 10=E2=88=928 mol/L have been=20 shown to produce substantial tumor-cell death, depending on = the=20 duration of exposure.13 A = study by=20 Shapiro et al10 = found that IV=20 injection of 50 mg MTX resulted in sub-cytotoxic = concentrations of=20 drug in the ventricular CSF (peak serum concentration 2 = =C3=97 10=E2=88=925 mol/L; peak = ventricular concentration=20 =E2=89=A40.06% of serum). IV infusion over 24 hours with a = 10-fold higher=20 dose (0.5 g/m2) achieved = greater CSF=20 penetration but still did not achieve cytotoxic = concentrations (mean=20 serum concentration 2 =C3=97 10=E2=88=925 mol/L;=20 mean ventricular concentration 6 =C3=97 10=E2=88=927 mol/L). This study = confirmed that CNS=20 permeability is limited following single-dose systemic IV=20 administration of MTX; even with higher dose infusions, = therapeutic=20 concentrations in the CSF are rarely achieved. However, this = early=20 study used a lower dose of MTX than has been reported more = recently,=20 and concentrations were quantified following a single IV = bolus. The=20 precise amount of MTX that constitutes high-dose delivery is = not=20 clearly defined in the literature.14 = Doses greater=20 than 3 g/m2 are used most = often with=20 the intent of delivering high-dose systemic therapy.

In a study by Glantz et al9 = investigating=20 the efficacy of high-dose IV MTX therapy (delivered by = 4-hour=20 continuous IV infusion at a dose of 8 g/m2) for patients (N =3D 16) with = nonleukemic=20 leptomeningeal cancer, MTX concentrations in the CSF on = average=20 remained greater than 1 =C3=97 10=E2=88=926 mol/L=20 for 48 hours and greater than 1 =C3=97 10=E2=88=927 mol/L for 93.3 hours. = A retrospective=20 comparison of cytologic and clinical response was made with = a=20 reference group of 15 patients who were treated with = standard=20 intrathecal MTX therapy during the same time interval = (results=20 compiled from Shapiro et al,10 = Strother et=20 al,15 = and Bleyer et=20 al16). = Intrathecal=20 MTX was administered at a dose of 12 mg, two doses per week = during a=20 4-week period. Cytologic response was considered to be = complete=20 clearing of tumor cells from the CSF 1 month after = initiation of=20 treatment. Clinical response was assessed through neurologic = examination at 1 month using the KPS (improved =3D improved = KPS score=20 and improvement in disease-related signs and symptoms; = stable =3D=20 unchanged or improved KPS score and no change in signs and = symptoms;=20 all other patients were considered to have progressed). = Improved and=20 stable patients were considered clinical responders. = Cytologic and=20 clinical responses were seen in 81% of patients treated with = high-dose MTX. These response rates compared favorably with = the=20 rates of cytologic and clinical response (60% and 47%, = respectively)=20 seen in the group of patients who received intrathecal MTX = therapy=20 in the study by Glantz et al.9

Several studies also have = demonstrated that=20 therapeutic levels in the CSF may be achieved following = systemic=20 administration of high-dose unencapsulated cytarabine.17, = 18, = 19, = 20 = However, the=20 measurement of unencapsulated cytarabine in the CSF is = complicated=20 by its rapid elimination and metabolism.21 = Overall,=20 systemic chemotherapy offers several potential advantages = over=20 direct CSF delivery methods. In particular, the necessity of = lumbar=20 punctures and surgery (eg, Ommaya reservoir) and their = associated=20 complications are avoided.22 In = addition,=20 patients with an obstruction to normal CSF flow can be = treated=20 without correction of the flow abnormality and more uniform = drug=20 distribution may be achieved. Furthermore, because the drug = reaches=20 leptomeningeal tumor deposits through their systemic = vascular=20 supply, bulky disease may respond to treatment.22

Direct intra-CSF injection of = chemotherapeutic=20 agents by either lumbar puncture or intraventricular Ommaya=20 reservoir offers an alternative to systemic administration = with the=20 advantages of selective compartmentalized delivery and a = lower=20 propensity for systemic toxicity.4, 6 The = efficacy of=20 intra-CSF therapy is limited by the ability of drug to = penetrate=20 surrounding parenchyma. Preclinical evidence demonstrated = that=20 tritiated (3H) MTX = administered into=20 the ventricles (of New Zealand white rabbits) via an Ommaya=20 reservoir penetrates tissue in the grey matter adjacent to = the=20 CSF.23 = Similar=20 distribution patterns have been reported following both = lumbar and=20 ventricular administration of cytarabine and MTX.24 = Mathematical=20 modeling studies in various brain compartments following = intra-CSF=20 administration via lumbar puncture injection or Ommaya = reservoir=20 have expanded our understanding of drug flow dynamics and=20 penetration.25, = 26, = 27 = These models=20 may offer some predictive guidelines for drug diffusion=20 characteristics and can be useful in helping clinicians = understand=20 potential parameters limiting CSF drug distribution. They = also may=20 guide future drug design strategies.

Blasberg et al26 = constructed a=20 model of MTX flow dynamics following intraventricular = administration=20 and found that movement of drug to the basal cistern and = ventricle=20 is very rapid, while movement to the lumbar sac is much = slower. This=20 model suggested that MTX concentrations continued to rise in = periventricular tissues at 48 hours following = administration. When=20 the additive effects of capillary permeability and drug = metabolism=20 were incorporated into the model (half-life was set at = =E2=89=A46 hours),=20 the rise of MTX at 48 hours was no longer predicted, and the = duration of cytotoxic levels in the tissue was reduced from = 48 hours=20 to 24 hours.26 = The authors=20 postulated that MTX most likely reaches the subarachnoid = space,=20 producing a =E2=80=9Csecond source=E2=80=9D of drug after it = returns to the=20 ventricle. When the 6-hour estimated half-life was included = in the=20 modeling, MTX at 8, 24, and 48 hours did not penetrate = tissue or=20 produce adequate cytotoxic tissue levels. On the basis of = these=20 results, the authors suggest six primary limiting factors of = CSF=20 drug delivery to CNS tissue (Table 1).

Table 1.

Factors Limiting Drug = Delivery to=20 Brain Tissue After Intrathecal Drug Administration26

	1.Drug=20 distribution between CSF compartments, where the = lumbar sac=20 has a longer delay than the cistern and=20 ventricle 2.CSF=20 clearance of drug 3.Apparent=20 diffusion constant of drug through brain=20 ECF 4.Distance=20 between opposing CSF surfaces 5.Half-lives of drug in brain ECF: = metabolism=20 and transcapillary drug loss 6.CNS and=20 systemic toxicity of = drug

Abbreviations: CNS, = central=20 nervous system; CSF, cerebrospinal fluid; ECF, = extracellular=20 fluid.

The method by which drugs are = administered=20 directly into the CNS may affect distribution. For example, = Shapiro=20 et al10 = compared the=20 kinetics and distribution of MTX when administered via = lumbar=20 puncture or Ommaya reservoir. The authors concluded that = intra-CSF=20 therapy via Ommaya reservoir produced the most consistent = and=20 durable cytotoxic levels of MTX in the CSF. In this study, = MTX=20 injection via lumbar puncture did not produce reliable CSF = drug=20 levels and occasionally resulted in epidural and subdural = leakage.10 = Similarly,=20 another study concluded that intraventricular MTX is = significantly=20 more effective against CNS leukemia than identical therapy = given via=20 lumbar puncture.28 In = contrast,=20 evidence suggests that liposomal cytarabine achieves uniform = distribution throughout the neuroaxis when given either via = lumbar=20 puncture or Ommaya reservoir.29, = 30, = 31 = Liposomal=20 cytarabine has a unique pharmacokinetic profile with a = ventricle=20 half-life of 130 hours (administered via lumbar puncture) to = 141=20 hours (administered intraventricularly), which was = considerably=20 longer than unencapsulated cytarabine (2 hours) or MTX (8 to = 15=20 hours).32, = 33, = 34 In = general,=20 the preferred route of intra-CSF chemotherapy is through the = intraventricular Ommaya reservoir, which exploits CSF bulk = flow for=20 more reliable and uniform delivery of drug throughout the=20 neuroaxis.35

A number of early- and late-stage = risk factors=20 and potential complications associated with intra-CSF = therapy exist.=20 Early complications may include surgical complications (eg,=20 misplacement of intraventricular catheters, mechanical = dysfunction,=20 risk of hemorrhage or CSF leaks into the peritoneum) and=20 inflammatory reactions (eg, transient chemical meningitis = that is=20 manifested by fever, headache, nausea, vomiting, and = photophobia).36 = Late=20 complications may include necrotizing leukoencephalopathy = that may=20 be progressive and fatal.37, = 38 = Clinical=20 sequelae of leukoencephalopathy include confusion, = somnolence or=20 irritability, ataxia, dementia, and tremor.23 An = important=20 risk factor for intra-CSF therapy complications is CSF flow=20 obstruction.35, = 39

Abnormal CSF flow is commonly = reported in=20 patients with bulky leptomeningeal cancer.35, = 40, = 41 = Among patients=20 with NM from solid tumors, CSF flow obstructions have been = reported=20 to occur in =E2=89=A530% of patients.35, = 40, = 42 = CSF flow=20 abnormalities can impede adequate distribution of intra-CSF = drugs to=20 all disease areas and may therefore constitute one reason = for=20 treatment failure.35 = Non-uniform=20 drug distribution secondary to CSF flow obstruction has = important=20 implications for the evaluation of therapeutic approaches, = as it may=20 confound proper and realistic evaluation of a medication's=20 efficacy.40, = 42 = CSF blocks=20 occur most commonly at the base of the skull, in the spinal = canal,=20 and over the cerebral convexities.35 = Neurotoxicity=20 also may result due to a high drug accumulation in unimpeded = CSF=20 compartments.35=20 Radionucleotide studies using either indium 111=E2=80=93DTPA = or technetium=20 99m macro-aggregated albumin are routinely used to assess = CSF flow=20 dynamics.40, = 43, = 44 = Involved-field=20 radiotherapy is currently the treatment of choice for = patients with=20 a CSF flow block and is effective in 50% of patients with=20 intracranial CSF obstruction and in 35% of patients with = spinal=20 subarachnoid CSF obstruction.4, 44 = Correction of=20 CSF flow obstruction by radiotherapy has been shown to = result in=20 significant improvements in response and survival.35, = 42

Intra-CSF=20 Prophylaxis

There is a genuine need for = prospective trials=20 investigating novel therapeutic strategies and interventions = for=20 patients with CNS metastases. Early diagnosis is critically=20 important, because patients who present with few or no = neurological=20 deficits and a low CNS tumor burden commonly achieve = improved=20 treatment response and survival rates.4 = Patients at high=20 risk for NM may be ideal candidates for prophylactic = intervention.=20 Factors that put patients with lymphoma at high risk include = a=20 raised lactate dehydrogenase level; a low serum albumin = level; age=20 <60 years; involvement of the testis, breast, or bone = marrow; and=20 more than two extranodal disease sites.44 = Optimally, NM=20 should be diagnosed in the early stages of disease to = prevent=20 progression of disabling neurologic deficits and to increase = the=20 potential for successful prophylactic intervention. = Potential=20 advantages of prophylaxis for solid tumor metastases to the=20 leptomeninges needs to include: minimal disease setting, = minimal CSF=20 flow abnormalities, and the absence of acquired drug = resistance.=20 Conversely, obstacles to effective prophylaxis include the = high risk=20 of associated toxicity and the fact that intervention often = occurs=20 in late-stage, widely disseminated systemic cancer. = Furthermore, CNS=20 metastases are rarely the single site of relapse, and = patients with=20 late-stage cancer often possess a higher degree of = chemoresistance=20 because of prior exposure to treatment regimens.39, = 45

There are currently no randomized = studies=20 investigating chemotherapeutic drug delivery for established = NM in=20 patients with solid tumors. The lack of controlled data for = the=20 successful treatment of leptomeningeal disease has impeded = the=20 implementation of prophylactic measures. However, = prophylaxis offers=20 significant potential advantages and has been used = successfully in=20 other disease settings. For example, antibiotics have been = used in=20 the prophylaxis of infection of postoperative wounds and = surgical=20 site infections.46 = Clear=20 guidelines have been established for the prophylactic use of = antibiotics.46, = 47 = Antibiotic=20 prophylaxis is indicated in situations where the risk of = infection=20 substantially outweighs the risk of potential adverse events = from=20 antibiotic use.46 = Guidelines=20 taken from prophylaxis in other disease models could form = the basis=20 for a new model of intra-CSF prophylaxis in patients with=20 solid-tumor NM.

Solid-Tumor NM: = Therapeutic=20 Potential of Intra-CSF Drug Delivery

The availability of safe and = effective=20 chemotherapies with sustained intra-CSF pharmacokinetics is = an=20 obvious prerequisite for the initiation of prophylactic = therapy.=20 Currently, there is no high-level evidence that intra-CSF=20 chemotherapy provides clear benefit to patients with NM from = solid=20 tumors. Intra-CSF therapy and local radiotherapy have become = the=20 standard of care on the basis of success with the treatment = of=20 specific cancers (not necessarily solid tumors), including = leukemia,=20 lymphoma, and breast cancer.48, = 49, = 50, = 51 = Shapiro et=20 al48 = conducted a=20 study in patients receiving intraventricular MTX and/or = cytarabine=20 via Ommaya reservoir, either with or without CNS = irradiation. The=20 longest median survival among patients with solid tumors was = 5=20 months for patients with breast cancer with CNS metastases. = The=20 majority of these patients received combined MTX/cytarabine = therapy=20 with additional focal CNS irradiation. Other studies have = reported=20 variable mean survival times ranging from 5 weeks to 3 = months.8, 52, = 53 = Prognosis and=20 survival time depend upon a variety of factors, including = primary=20 tumor type, disease stage, and patient characteristics (eg, = age).=20 Disease- and patient-related factors may figure more = prominently in=20 prognosis and survival than specific factors related to the = mode of=20 therapeutic intervention.

Several studies suggest that there = may not be=20 any added benefit, in terms of prognosis or survival, to = intra-CSF=20 versus systemic therapy for NM from solid tumors.29, = 37, = 54, = 55, = 56, = 57, = 58 It = bears=20 noting that several of these studies suffer from limitations = such=20 as: being under-powered to detect significant differences = between=20 groups, the failure to randomize patients to = intraventricular or=20 lumbar puncture administration, not choosing clinically = meaningful=20 end points, and the appropriateness of intrathecal dosing = and=20 frequency.

There are many factors that may = account for a=20 poor response to intra-CSF chemotherapy in NM from solid = tumors.=20 These include a low degree of chemosensitivity of solid = tumors, a=20 small spectrum of available therapies,45 = poor diffusion=20 of chemotherapeutic drugs, inadequate penetration into the = bulky=20 tumor,23, = 24 = and a high=20 degree of tumor chemoresistance.45 = Enhanced=20 penetration through systemic drug delivery is partially = supported by=20 the outcome of several non-randomized studies.8, 54, = 55=20 Chemotherapeutic response (measured by clinical assessment = and=20 survival) was improved with combined systemic and intra-CSF = therapy=20 versus no systemic therapy in two separate studies.8, 54 In = addition,=20 two retrospective studies of patients with breast cancer = showed=20 similar survival but reduced toxicity with systemic versus = intra-CSF=20 therapy.54, = 55 In = contrast, a=20 more recent retrospective study of patients with breast = cancer=20 highlighted the importance of CSF clearance in clinical = outcome in=20 these patients.59 = This study=20 reported significant improvements in median survival = (P=20 <.003) and clinical improvement in patients receiving = intrathecal=20 MTX whose CSF was clear of abnormal cells compared with = those=20 patients whose CSF did not stabilize.

A randomized study conducted by = Boogerd et=20 al58 = also provides=20 support for the concept that standard systemic chemotherapy = with RT,=20 in the absence of intra-CSF therapy, may be a feasible = treatment=20 option for NM secondary to breast cancer. In this study, = treatment=20 differed only in the inclusion or exclusion of = intraventricular=20 chemotherapy. Patients with breast cancer were randomized to = receive=20 either intra-CSF MTX with appropriate systemic chemotherapy = (not=20 defined but based on previous treatment, hormone receptor = status,=20 and patient condition), and, if necessary, radiation therapy = to=20 relevant sites (n =3D 17), or they received essentially the = same=20 therapeutic regimen but without intra-CSF MTX (n =3D 18). = Analysis of=20 the intent-to-treat population revealed that a higher = proportion of=20 patients receiving systemic therapy without intra-CSF = therapy=20 exhibited neurological improvement and/or stabilization (67% = [12/18]=20 v 59% [10/17]; P =3D not significant [NS]) and = slower=20 time to neurologic progression compared with patients = receiving=20 intra-CSF therapy (overall median 24 weeks v 23 = weeks,=20 respectively; P =3D NS). The median survival was not=20 significantly different between groups (18 v 30 = weeks,=20 respectively; P =3D .32). Likewise, the 1-year = survival did not=20 differ significantly between groups (18% v 32%, = respectively;=20 P =3D NS) (Figure 1).58 = Overall,=20 treatment-related neurologic complications and toxicities = (including=20 headache, lethargy, cognitive impairment, and delayed=20 leukoencephalopathy) were significantly higher for the group = that=20 received intra-CSF therapy (47% v 6%; P =3D = .0072). This=20 study concluded that the addition of intraventricular = chemotherapy=20 to systemic therapy and involved field radiotherapy in = patients with=20 NM from breast cancer does not lead to improved neurological = response or survival but instead may be associated with = increased=20 treatment-related toxicity.58

Figure=20 1. The effect of intrathecal chemotherapy = on the=20 survival of patients with leptomeningeal metastasis = from=20 breast cancer. Survival curves are given for the=20 intraventricular treatment (IT) group versus the no-IT = group.=20 At 1 year, estimated survival was 18% (=C2=B19% [SE]) = for the IT=20 arm and 32% (=C2=B112%) for the no-IT arm (P = =3D .32, log-rank=20 test). Median survival was 18.3 weeks (=C2=B16.7) in = the IT arm and=20 30.3 weeks (=C2=B110.9) weeks in the no-IT arm = (P =3D NS).=20 Reprinted with permission.58=20 Copyright =C2=A9 2004 Elsevier Ltd.

Large-scale, randomized studies are = warranted=20 to provide further evidence of the benefit, or lack thereof, = of=20 intra-CSF treatment in NM from solid tumors. In an attempt = to=20 address this important issue, the European Organization for = Research=20 and Treatment of Cancer (EORTC) 26051 trial is investigating = the=20 benefit of intra-CSF liposomal cytarabine in patients with = NM from=20 breast cancer and lung cancer. Liposomal cytarabine was = chosen, as=20 it confers a number of benefits over unencapsulated = cytarabine and=20 MTX, including sustained release of cytarabine and therefore = a less=20 frequent dosing schedule;60 = even=20 distribution of cytotoxic concentrations throughout the = neuroaxis=20 when delivered via lumbar puncture or Ommaya reservoir;61 = and prolonged=20 progression-free survival.29 = Patients=20 diagnosed by cytologic examination and/or magnetic resonance = imaging=20 and without CSF flow blockade are randomized to receive a=20 combination of both radiation therapy and appropriate = primary=20 chemotherapy (n =3D 47) or radiation therapy, chemotherapy, = and=20 intra-CSF liposomal cytarabine (n =3D 47). Patients are = stratified=20 according to tumor type (eg, breast cancer or lung cancer), = KPS=20 score, and institution. The primary end points are = neurological=20 progression-free survival and overall safety profile. = Secondary end=20 points include survival, improvement of signs and symptoms, = and QoL=20 (assessed using the EORTC QLQ-C30 and the Brain Module = 20).

A number of potentially confounding = variables=20 associated with evaluating the efficacy of intra-CSF = therapies=20 warrant careful consideration. Apart from CSF flow = abnormalities or=20 obstructions,35 = the=20 differential chemosensitivity of various types of solid = tumors also=20 can complicate analysis of the results.45 As = discussed=20 above, abnormal flow affects the distribution of drug and,=20 consequently, restricts access of the drug to the tumor = tissue.35 To = alleviate=20 any doubt that intra-CSF therapy has the opportunity to be=20 effective, it is recommended to include patients with flow=20 abnormalities but to provide radiation therapy to remove the = abnormality before randomization. To avoid a potentially = spurious=20 evaluation, it also is recommended that solid-tumor NM with = a high=20 propensity for developing treatment resistance over time = (eg,=20 melanoma) be excluded from analyses. In addition, the method = chosen=20 for quantifying outcome measures must be carefully = considered. For=20 example, the EORTC 26051 trial uses neurologic = progression-free=20 survival as a primary end point and allows clinicians to = measure=20 this outcome in an unblinded manner. Because this = methodology may=20 introduce unintended bias, an outside masked source for = measuring=20 clinical outcome and the use of prospectively defined = objective=20 criteria are recommended to govern the quantification=20 process.

Novel Modalities for = Intra-CSF=20 Cancer Therapy and Prevention=E2=80=94Exploiting the Choroid = Plexus

CSF flow has a profound impact on = cerebral=20 metabolism.5, 62 = CSF flow,=20 volume, and pressure are regulated and maintained by = transport=20 processes at barrier interfaces.5 = There are two=20 principal interfaces that act in this capacity: the BBB and = the=20 blood-CSF barrier. The cells forming these virtually = impenetrable=20 barriers are endothelial and epithelial, respectively, which = are=20 joined by tight junctions that restrict free passage of=20 water-soluble molecules and cells.5 The = BBB=20 interface transports glucose, amino acids, free fatty acids, = and=20 peptides, whereas the blood-CSF epithelial interface = transports=20 growth factors, vitamins, and hormones.63

The blood-CSF barrier is widely = distributed=20 and, with its wide array of transporters, may represent an = efficient=20 alternate route for chemotherapeutic drug entry into the = CNS.5 This = barrier is=20 composed of the choroid plexus and the arachnoid membrane.64 = Representing=20 the primary site of CSF production, the choroid plexus is = composed=20 of a rich capillary bed, pia mater, and epithelial cells.7 = Drugs that=20 penetrate the lateral ventricle choroid plexus are conducted = downstream by CSF bulk flow in the ventricular system and = are=20 thereby brought into contact with all regions of the brain = (Figure 2).5, 62 = Although it=20 accounts for only 0.2% of brain weight, the choroid plexus = is=20 necessary for adequate nutrition and function of the = brain.5 = Additional=20 functions of the choroid plexus include renal regulation, = hepatic=20 metabolism, immune cell trafficking, endocrine regulation,=20 maintenance of osmotic balance, and regulation of trophic = factors=20 (Table 2).5, 7

Figure=20 2. Cerebrospinal fluid (CSF) production = and=20 circulation depicted on a coronal brain section of the = posterior central nervous system (CNS). CSF originates = from=20 the choroid plexi of the lateral and third ventricles = and=20 flows downward through the narrow cerebral aqueduct = (arrows).=20 It then empties into the fourth ventricle and is = driven=20 downward around the spinal cord (subarachnoid space) = and=20 upward over the convexities of the cerebral = hemispheres. CSF=20 flows outward into the venous blood of the superior = sagittal=20 sinus and also into the lymphatic system of the eye = and=20 nose.5, 62

Table 2.

Versatile Functions of = the=20 Choroid Plexus5, 7


	Function	Example
	Renal regulation	pH and ion = regulation
	Hepatic = metabolism	P450 metabolism
	Immune-cell = trafficking	Antigen-presenting = cells;=20 leukocyte-trafficking regulation
	Endocrine = regulation	AVP, ANP, volume=20 regulation
	Maintenance of = osmotic=20 balance	NaKCl = cotransport
	Regulation of=20 trophic factors	Vitamins,=20 growth factors

Abbreviations: AVP, = arginine=20 vasopressin; ANP, atrial natriuretic=20 peptide.

The choroid plexus comprises a = heterogeneous=20 population of cells and a diverse complement of cellular = proteins.5 = Strategies for=20 targeted delivery of pharmaceutical agents to the CSF could=20 conceivably harness the unique choroid plexus cellular = mechanisms=20 involved in: (1) the transport of anti-tumor agents between = the=20 blood and CSF (eg, prolactin receptor localized in the = blood-CSF=20 barrier but not the BBB)65; = (2) the=20 Na+/ascorbate cotransporter = that is=20 unique to the blood-CSF barrier66; = (3) viruses=20 that readily infect the choroid plexus epithelium67, = 68, = 69; = or (4)=20 leukocyte traffic across the choroid plexus.70, = 71, = 72 In = principle,=20 researchers could also develop strategies to prevent access = of tumor=20 cells into the CSF by blocking choroid plexus cell-surface = markers=20 to which tumor cells are attracted.69, = 73 = Exploitation=20 of the multivariate functions of the choroid plexus has = potential=20 for the development of novel approaches to CSF-targeted=20 chemotherapy.

Conclusion

Intra-CSF therapy holds significant = promise=20 for the treatment and prevention of NM from both solid and=20 hematologic tumors. There is a paucity of data from = rigorously=20 controlled trials investigating the efficacy and safety of = intra-CSF=20 therapies for solid-tumor NM. Randomized and well-controlled = trials=20 may provide support for the use of available intra-CSF = therapies in=20 patient populations with solid-tumor NM. A combination of = both=20 systemic, intra-CSF, and=E2=80=94in the case of bulky = tumors=E2=80=94RT could be=20 employed both to treat the primary tumor and to prevent = neoplasms=20 from entering the CSF. New therapies and regimens may be = developed=20 that target novel CSF entry points; the choroid plexus may = represent=20 one such therapeutic opportunity.

References

1.=20 1Chamberlain MC. Neoplastic meningitis. = Neurologist.=20 2006;12:179=E2=80=93187. MED= LINE=20 | CrossRef=20

2.=20 2Jaeckle KA. Neoplastic meningitis from systemic=20 malignancies; diagnosis, prognosis and treatment.=20 Semin=20 Oncol. 2006;33:312=E2=80=93323. Abstract=20 | Full=20 Text | Full-Text=20 PDF (348 KB) | MED= LINE=20 | CrossRef=20

3.=20 3Kesari S, = Batchelor TT. Leptomeningeal metastases. = Neurol = Clin.=20 2003;21:25=E2=80=9366. Full=20 Text | Full-Text=20 PDF (651 KB) | MEDLINE=20 | CrossRef=20

4.=20 4Gleissner B, = Chamberlain MC.=20 Neoplastic meningitis. = Lancet = Neurol.=20 2006;5:443=E2=80=93452. Ab= stract=20 | Fu= ll=20 Text | Full-Text=20 PDF (181 KB) | MEDLINE=20 | CrossRef=20

5.=20 5Johanson CE, Duncan JA,=20 Stopa EG, Baird A. Enhanced prospects for drug delivery = and brain=20 targeting by the choroid plexus-CSF route. = Pharm = Res.=20 2005;22:1011=E2=80=931037. ME= DLINE=20 | CrossRef=20

6.=20 6Habgood MD, Begley DJ,=20 Abbott NJ. Determinants of=20 passive drug entry into the central nervous system.=20 Cell Mol=20 Neurobiol. 2000;20:231=E2=80=93253. MED= LINE=20 | CrossRef=20

7.=20 7Ghersi-Egea JF, = Leininger-Muller B,=20 Cecchelli R, Fenstermacher JD. Blood-brain interfaces: relevance to = cerebral=20 drug metabolism. Toxicol Lett. 1995;82=E2=80=9383645-53.

8.=20 8Grant R, Naylor B,=20 Greenberg HS, Junck L. Clinical outcome in aggressively = treated=20 meningeal carcinomatosis. Arch = Neurol.=20 1994;51:457=E2=80=93461. MED= LINE

9.=20 9Glantz MJ, Cole BF, = Recht L,=20 Akerley W, Mills P, Saris S,=20 et al. High-dose=20 intravenous methotrexate for patients with nonleukemic=20 leptomeningeal cancer: is intrathecal chemotherapy=20 necessary?. J Clin Oncol. 1998;16:1561=E2=80=931567.

10.=20 10Shapiro WR, Young DF,=20 Mehta BM. Methotrexate=20 distribution in cerebrospinal fluid after intravenous, = ventricular=20 and lumbar injections. N Engl J Med. 1975;293:161=E2=80=93166. ME= DLINE

11.=20 11Balis RM, Blaney SM,=20 McCully CL, Bacher JD, Jurphy RF,=20 Poplack DG. Methotrexate=20 distribution within the subarachnoid space after = intraventricular=20 and intravenous administration. Cancer = Chemother=20 Pharmacol. 2000;45:259=E2=80=93264. MED= LINE=20 | CrossRef=20

12.=20 12Hryniuk WM, = Bertino JR. Treatment of leukemia with large doses = of=20 methotrexate and folinic acid: clinical-biomedical=20 correlates. J Clin Invest. 1969;48:2140=E2=80=932155. ME= DLINE=20 | CrossRef=20

13.=20 13Chabner BA, = Young R. Threshold methotrexate concentration = for in vivo=20 inhibition of DNA synthesis in normal and tumorous target=20 tissues. J Clin Invest. 1973;52:1804=E2=80=931811. ME= DLINE=20 | CrossRef=20

14.=20 14Green MR, Chowdhary S,=20 Lombardi KM, Chalmers LM, = Chamberlain M. Clinical utility and pharmacology of = high-dose=20 methotrexate in the treatment of primary CNS = lymphoma.=20 Expert=20 Rev Neurother. 2006;6:635=E2=80=93652. CrossRef=20

15.=20 15Strother DR, = Glynn-Barnhart A,=20 Kovnar E. Variability in the=20 disposition of intraventricular methotrexate: A proposal for = rational dosing. J Clin Oncol. 1989;7:1741=E2=80=931747.

16.=20 16Bleyer WA, Drake JC,=20 Chabner BA. Neurotoxicity and=20 elevated cerebrospinal-fluid methotrexate concentration in = meningeal=20 leukemia. N Engl J Med. 1973;289:770=E2=80=93773. ME= DLINE

17.=20 17Lopez JA, Nassif E,=20 Vannicola P, Krikorian JG, Agarwal RP. = Central nervous system = pharmacokinetics of=20 high-dose cytosine arabinoside. J = Neurooncol.=20 1985;3:119=E2=80=93124. CrossRef=20

18.=20 18Slevin ML, Piall EM, = Aherne GW,=20 Harvey VJ, Johnston A, Lister TA. = Effect of dose and schedule on = pharmacokinetics=20 of high-dose cytosine arabinoside in plasma and = cerebrospinal=20 fluid. J Clin Oncol. 1983;1:546=E2=80=93551.

19.=20 19DeAngelis LM, Kreis W, = Chan K,=20 Dantis E, Akerman S. Pharmacokinetics of ara-C and ara-U in = plasma=20 and CSF after high-dose administration of cytosine=20 arabinoside. Cancer Chemother Pharmacol. = 1992;29:173=E2=80=93177. MED= LINE=20 | CrossRef=20

20.=20 20Sutoh H, Yamauchi T, = Gotoh N,=20 Sugiyama M, Ueda T. Pharmacological study of modified=20 intermediate-dose cytarabine therapy in patients with acute = myeloid=20 leukemia. Anticancer Res. 2003;23:5037=E2=80=935042. ME= DLINE

21.=20 21Muldoon LL, Soussain C,=20 Jahnke K, Johanson C, Siegal T, = Smith QR,=20 et al. Chemotherapy=20 delivery issues in central nervous system malignancy: a = reality=20 check. J Clin Oncol. 2007;25:2295=E2=80=932305. CrossRef=20

22.=20 22Kim L, Glantz MJ. = Neoplastic meningitis. = Curr Treat = Options=20 Oncol. 2001;2:517=E2=80=93527. MEDL= INE=20 | CrossRef=20

23.=20 23Grossman SA, Reinhard CS,=20 Loats HL. The = intracerebral=20 penetration of intraventricularly administered methotrexate: = a=20 quantitative autoradiographic study. J = Neurooncol.=20 1989;7:319=E2=80=93328. CrossRef=20

24.=20 24Burch PA, Grossman SA,=20 Reinhard CS. Spinal = cord=20 penetration of intrathecally administered cytarabine and=20 methotrexate: a quantitative autoradiographic study.=20 J Natl=20 Cancer Inst. 1988;80:1211=E2=80=931216. ME= DLINE

25.=20 25Blasberg RG, Patlak C,=20 Fenstermacher JD. Intrathecal=20 chemotherapy: brain tissue profiles after = ventriculocisternal=20 perfusion. J Pharmacol Exp Ther. 1975;195:73=E2=80=9383. MED= LINE

26.=20 26Blasberg RG, Patlak CS,=20 Shapiro WR. Distribution of=20 methotrexate in the cerebrospinal fluid and brain after=20 intraventricular administration. Cancer = Treat=20 Rep. 1977;61:633=E2=80=93641. MED= LINE

27.=20 27Blasberg RG. Methotrexate, cytosine arabinoside, = and BCNU=20 concentration in brain after ventriculocisternal = perfusion.=20 Cancer=20 Treat Rep. 1977;61:625=E2=80=93631. MED= LINE

28.=20 28Bleyer WA, = Poplack DG. Intraventricular versus intralumbar = methotrexate=20 for central-nervous-system leukemia: Prolonged remission = with the=20 Ommaya reservoir. Med Pediatr Oncol. 1979;6:207=E2=80=93213. MEDL= INE=20 | CrossRef=20

29.=20 29Glantz MJ, Jaeckle KA,=20 Chamberlain MC, Phuphanich S, Recht L,=20 Swinnen LJ, et al. A=20 randomized controlled trial comparing intrathecal = sustained-release=20 cytarabine (DepoCyt) to intrathecal methotrexate in patients = with=20 neoplastic meningitis from solid tumors. Clin = Cancer=20 Res. 1999;5:3394=E2=80=933402. MED= LINE

30.=20 30Kim S, Khatibi S, = Howell SB,=20 McCully C, Balis FM, Poplack DG. Prolongation of drug exposure in = cerebrospinal=20 fluid by encapsulation into DepoFoam. Cancer = Res.=20 1993;53:1596=E2=80=931598. ME= DLINE

31.=20 31Rueda Dominguez A, Olmos = Hidalgo D,=20 Viciana Garrido R, Torres Sanchez E. Liposomal cytarabine (DepoCyte) for = the=20 treatment of neoplastic meningitis. Clin = Transl=20 Oncol. 2005;7:232=E2=80=93238. CrossRef=20

32.=20 32Chamberlain MC, = Kormanik P,=20 Howell SB, Kim S. Pharmacokinetics of intralumbar = DTC-101 for the=20 treatment of leptomeningeal metastases. Arch = Neurol.=20 1995;52:912=E2=80=93917. MED= LINE

33.=20 33Cytarabine prescribing = information.=20 Bedford, OH: Bedford = Laboratories;=20 2000;.

34.=20 34Methotrexate prescribing = information.=20 Floral, KY: Xanodyne = Pharmacal Inc;=20 2003;.

35.=20 35Glantz MJ, Hall WA, = Cole BF,=20 Chozick BS, Shannon CM, Wahlberg L,=20 et al. Diagnosis,=20 management, and survival of patients with leptomeningeal = cancer=20 based on cerebrospinal fluid-flow status. = Cancer. 1995;75:2919=E2=80=932931.

36.=20 36Chamberlain MC, = Kormanik PA,=20 Barba D. Complications=20 associated with intraventricular chemotherapy in patients = with=20 leptomeningeal metastases. J = Neurosurg.=20 1997;87:694=E2=80=93699. MED= LINE=20 | CrossRef=20

37.=20 37Siegal T, Lossos A,=20 Pfeffer MR. Leptomeningeal=20 metastases: analysis of 31 patients with sustained = off-therapy=20 response following combined-modality therapy. = Neurology.=20 1994;44:1463=E2=80=931469. ME= DLINE

38.=20 38Boogerd W, van der = Sande JJ,=20 Moffie D. Acute = fever and=20 delayed leukoencephalopathy following low dose = intraventricular=20 methotrexate. J Neurol Neurosurg Psychiatry. = 1988;51:1277=E2=80=931283. ME= DLINE=20 | CrossRef=20

39.=20 39Grossman SA, = Krabak MJ. Leptomeningeal carcinomatosis.=20 Cancer=20 Treat Rev. 1999;25:103=E2=80=93119. Abstr= act=20 | Full-Text=20 PDF (600 KB) | MEDLINE=20 | CrossRef=20

40.=20 40Grossman SA, Trump DL, = Chen DC,=20 Thompson G, Camargo EE. Cerebrospinal fluid flow abnormalities = in=20 patients with neoplastic meningitis (An evaluation using 111 = indium-DTPA ventriculography). Am J = Med. 1982;73:641=E2=80=93647. Abstract=20 | Full-Text=20 PDF (870 KB) | MEDLINE= =20 | CrossRef=20

41.=20 41Chamberlain MC,=20 Corey-Bloom J. Leptomeningeal=20 metastases: 111 indium-DTPA CSF flow studies. = Neurology.=20 1991;41:1765=E2=80=931769. ME= DLINE

42.=20 42Chamberlain MC, = Kormanik PA.=20 Prognostic significance of 111 = indium-DTPA=20 CSF flow studies in leptomeningeal metastases. = Neurology.=20 1996;46:1674=E2=80=931677. ME= DLINE

43.=20 43Mason WP, Yeh SD,=20 DeAngelis LM. 111=20 Indium-diethylenetriamine pentaacetic acid cerebrospinal = fluid flow=20 studies predict distribution of intrathecally administered=20 chemotherapy and outcome in patients with leptomeningeal=20 metastases. Neurology. 1998;50:438=E2=80=93444. MED= LINE

44.=20 44Chamberlain MC, Nolan C,=20 Abrey LE. Leukemic = and=20 lymphomatous meningitis: incidence, prognosis and = treatment.=20 J=20 Neurooncol. 2005;75:71=E2=80=9383. CrossRef=20

45.=20 45Chamberlain MC. Chemotherapy for brain metastases due = to lung=20 cancer and melanoma. Cancer Treat Res. 2007;136:199=E2=80=93213.

46.=20 46Price SA, Polk HC. = Prophylactic and therapeutic use of = antibiotics=20 in pelvic surgery. J Surg Oncol. 1999;71:261=E2=80=93268. MED= LINE=20 | 3.0.CO;2-X','crossRef'); return false;"=20 = href=3D"http://www.seminoncol.org/article/PIIS0093775409000967/fulltext#"= >CrossRef=20

47.=20 47Page CP, Bohnen JM,=20 Fletcher JR, McManus AT, Solomkin JS,=20 Wittmann DH. Antimicrobial=20 prophylaxis for surgical wounds (Guidelines for clinical=20 care). Arch Surg. 1993;128:79=E2=80=9388. MED= LINE

48.=20 48Shapiro WR, Posner JB, = Ushio Y,=20 Chemik NL, Young DF. Treatment of meningeal = neoplasms.=20 Cancer=20 Treat Rep. 1977;61:733=E2=80=93743. MED= LINE

49.=20 49Wasserstrom WR, Glass JP,=20 Posner JB. Diagnosis = and=20 treatment of leptomeningeal metastases from solid tumors: = experience=20 with 90 patients. Cancer. 1982;49:759=E2=80=93772.

50.=20 50Yap HY, Yap BS, = Rasmussen S,=20 Levens ME, Hortobagyi GN, = Blumenschein GR.=20 Treatment for meningeal = carcinomatosis in=20 breast cancer. Cancer. 1982;50:219=E2=80=93222.

51.=20 51Ongerboer de Visser BW, = Somers R,=20 Nooyen WH, van Heerde P, Hart AA,=20 McVie JG. Intraventricular=20 methotrexate therapy of leptomeningeal metastasis from = breast=20 carcinoma. Neurology. 1983;33:1565=E2=80=931572. ME= DLINE

52.=20 52Clamon G, = Doebbeling B. Meningeal carcinomatosis from breast = cancer:=20 spinal cord vs. brain involvement. Breast = Cancer Res=20 Treat. 1987;9:213=E2=80=93217. MEDL= INE=20 | CrossRef=20

53.=20 53Jayson GC, Howell A, = Harris M,=20 Morgenstern G, Chang J, Ryder WD. = Carcinomatous meningitis in patients = with breast=20 cancer (An aggressive disease variant). Cancer. 1994;74:3135=E2=80=933141.

54.=20 54Boogerd W, Hart AA, van = der=20 Sande JJ, Engelsman E. Meningeal carcinomatosis in breast = cancer=20 (Prognostic factors and influence of treatment). = Cancer. 1991;67:1685=E2=80=931695.

55.=20 55Bokstein F, Lossos A,=20 Siegal T. Leptomeningeal=20 metastases from solid tumors: a comparison of two = prospective series=20 treated with and without intra-cerebrospinal fluid=20 chemotherapy. Cancer. 1998;82:1756=E2=80=931763.

56.=20 56Hitchins RN, Bell DR, = Woods RL,=20 Levi JA. A = prospective=20 randomized trial of single-agent versus combination = chemotherapy in=20 meningeal carcinomatosis. J Clin = Oncol.=20 1987;5:1655=E2=80=931662.

57.=20 57Grossman SA, = Finkelstein DM,=20 Ruckdeschel JC, Trump DL, Moynihan T,=20 Ettinger DS. Randomized=20 prospective comparison of intraventricular methotrexate and = thiotepa=20 in patients with previously untreated neoplastic meningitis = (Eastern=20 Cooperative Oncology Group). J Clin = Oncol.=20 1993;11:561=E2=80=93569.

58.=20 58Boogerd W, van den = Bent MJ,=20 Koehler PJ, Heimans JJ, van der Sande JJ,=20 Aaronson NK, et al. The relevance of intraventricular = chemotherapy=20 for leptomeningeal metastasis in breast cancer: a randomized = study. Eur J Cancer. 2004;40:2726=E2=80=932733. Abstract=20 | Full=20 Text | Full-Text=20 PDF (278 KB) | MED= LINE=20 | CrossRef=20

59.=20 59Clatot F, Ouvrier M, Guillemet C, = Veyret C,=20 Blot E. Correlation of normalization of cerebrospinal fluid = cytology=20 (CSFC) with survival in breast cancer-related malignant = meningitis=20 (BMM) [abstract 1108]. Poster presented at the 44th Annual = Meeting=20 of the American Society of Clinical Oncology, Chicago, IL, = May=20 30-June 3, 2008.

60.=20 60Kim S, Chatelut E, = Kim JC,=20 Howell SB, Cates C, Kormanik PA,=20 et al. Extended = CSF=20 cytarabine exposure following intrathecal administration of = DTC=20 101. J Clin Oncol. 1993;11:2186=E2=80=932193.

61.=20 61Phuphanich S, Maria B,=20 Braeckman R, Chamberlain M. A pharmacokinetic study of intra-CSF=20 administered encapsulated cytarabine (DepoCyt) for the = treatment of=20 neoplastic meningitis in patients with leukemia, lymphoma, = or solid=20 tumors as part of a phase III study. J = Neurooncol.=20 2007;81:201=E2=80=93208. CrossRef=20

62.=20 62Johanson CE. Choroid plexus-cerebrospinal fluid = circulatory=20 dynamics: impact on brain growth, metabolism, and = repair.=20 In: Conn PM editors. = Neuroscience in medicine. = Totowa, NJ:=20 Humana Press; 2008;p. 173=E2=80=93200. =

63.=20 63Johanson CE, Duncan JA,=20 Klinge PM, Brinker T, Stopa EG,=20 Silverberg GD. Multiplicity of=20 cerebrospinal fluid functions: new challenges in health and=20 disease. Cerebrospinal Fluid Res. 2008;5:10.

64.=20 64Johanson CE. Arachnoid membrane, subarachnoid CSF = and=20 pia-glia. In: Pardridge W editors. = An introduction to the blood-brain = barrier:=20 methodology and biology. Cambridge: Cambridge = University=20 Press; 1998;p. 259=E2=80=93269. =

65.=20 65Mangurian LP, Walsh RJ,=20 Posner BI. Prolactin = enhancement of its own uptake at the choroid plexus.=20 Endocrinology. 1992;131:698=E2=80=93702. ME= DLINE=20 | CrossRef=20

66.=20 66Angelow S, Haselbach M,=20 Galla HJ. Functional = characterization of the active ascorbic acid transport into=20 cerebrospinal fluid using primary cultured choroid plexus=20 cells. Brain Res. 2003;988:105=E2=80=93113. ME= DLINE=20 | CrossRef=20

67.=20 67Petito CK. Human immunodeficiency virus type 1=20 compartmentalization in the central nervous system.=20 J=20 Neurovirol. 2004;10(Suppl=20 1):21=E2=80=9324.=20 MEDL= INE=20 | CrossRef=20

68.=20 68Chen H, Wood C,=20 Petito CK. Comparisons of=20 HIV-1 viral sequences in brain, choroid plexus and spleen: = potential=20 role of choroid plexus in the pathogenesis of HIV=20 encephalitis. J Neurovirol. 2000;6:498=E2=80=93506. MEDL= INE=20 | CrossRef=20

69.=20 69Levine S. Choroid plexus: target for systemic = disease and=20 pathway to the brain. Lab Invest. 1987;56:231=E2=80=93233. MED= LINE

70.=20 70Kivis=C3=A4kk P, Mahad DJ, = Callahan MK, Trebst C, Tucky B, Wei T,=20 et al. Human=20 cerebrospinal fluid central memory CD4+ T cells: evidence for = trafficking through=20 choroid plexus and meninges via P-selectin. = Proc Natl = Acad Sci U S=20 A. 2003;100:8389=E2=80=938394. M= EDLINE=20 | CrossRef=20

71.=20 71Chodobski A, Chung I,=20 Ko=C3=BCniewska E, Ivanenko T, Chang W,=20 Harrington JF, et al. Early neutrophilic expression of = vascular=20 endothelial growth factor after traumatic brain = injury.=20 Neuroscience. 2003;122:853=E2=80=93867. ME= DLINE=20 | CrossRef=20

72.=20 72Oldstone MB, = Southern PJ.=20 Trafficking of activated = cytotoxic T=20 lymphocytes into the central nervous system: use of a = transgenic=20 model. Neuroimmunology. 1993;46:25=E2=80=9331.

73.=20 73Lampson LA. New animal models to probe brain tumor = biology,=20 therapy, and immunotherapy: advantages and remaining=20 concerns. J Neurooncol. 2001;53:275=E2=80=93287. CrossRef=20

a Division of Neurology, Director = Neuro-Oncology=20 Program, Barrow Neurological Institute, Phoenix, = AZ

b Department of Clinical Neurosciences, = Warren=20 Alpert Medical School at Brown University, Providence, = RI

c Department of Neuro-oncology, = Netherlands=20 Cancer Institute, Amsterdam, Netherlands

Address = correspondence=20 to William R. Shapiro, MD, Division of Neurology, Barrow=20 Neurological Institute, 350 West Thomas Rd, Phoenix, AZ=20 85013

STATEMENT OF CONFLICT OF = INTEREST:=20 The authors have nothing to disclose.

PII: S0093-7754(09)00096-7

doi:10.1053/j.seminoncol.2009.05.006

=C2=A9 2009 = Published by=20 Elsevier Inc.

3D""=20
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