Volume=20 36, Supplement=20 2, Pages S35-S45 (August = 2009)

7 of 10

ABSTRACT

FULL=20 TEXT

FULL-TEXT PDF (466=20 KB)

Diagnostic Tools for Neoplastic = Meningitis:=20 Detecting Disease, Identifying Patient Risk, and Determining = Benefit=20 of Treatment

Marc=20 C. Chamberlaina 3D"Corresponding

, Michael Glantzb, = Morris=20 D. Grovesc, = Wyndham=20 H. Wilsond

Three methods are routinely = used to=20 diagnose neoplastic meningitis (NM): clinical signs and = symptoms,=20 cerebrospinal fluid (CSF) cytology, and magnetic resonance = imaging=20 (MRI) of the brain and spine. Clinical manifestations are = often=20 subtle or may be ascribed to other cancer complications, eg, = treatment-related disorders or brain parenchymal metastases. = CSF=20 cytology has a high specificity (>95%), but its = sensitivity is=20 generally less than 50%. MRI sensitivity and specificity = vary with=20 the type of primary cancer; overall, MRI findings consistent = with=20 leptomeningeal disease are detected in fewer than 50% of NM=20 patients. While most clinicians evaluate CSF cytology along = with MRI=20 and the clinical examination, underdiagnosis is a major = problem,=20 since many patients are both cytologically and = radiographically=20 negative. Failure to consider NM in the differential = diagnosis=20 magnifies the problem of underdiagnosis. CSF flow cytometry = is=20 particularly promising for evaluating NM from hematologic = cancers,=20 with a diagnostic sensitivity many fold greater than = conventional=20 cytology. Research has focused on identifying biochemical = markers of=20 tumor cells in the CSF. For example, molecules involved in = CNS=20 penetration (eg, matrix metalloproteinases and cathepsins), = tumor=20 cell tropism (eg, chemokines CXCL8 and CCL18), and = angiogenesis (eg,=20 vascular endothelial growth factor) are elevated in the CSF = of=20 patients with NM. Evidence that some tumor types are more = likely to=20 infiltrate the CNS also has stimulated research into primary = tumor=20 markers predictive of CNS metastases. At present, there is = no tumor=20 marker or patient characteristic that reliably predicts the=20 development of NM, and diagnosis still relies on suggestive = signs=20 and symptoms, positive CSF cytology, or a consistent = MRI=E2=80=94all late=20 manifestations of NM. Until techniques capable of detecting = NM early=20 are developed, increased awareness of the disease and = standardized=20 evaluation are likely to have the greatest impact on = improving=20 diagnosis and implementing earlier = treatment.

Article Outline

=E2=80=A2 Abstract

=E2=80=A2 CSF=20 Cytology and MRI

=E2=80=A2 Flow=20 Cytometry and Polymerase Chain Reaction

=E2=80=A2 Biological=20 Markers for Diagnosing and Monitoring Response of NM

=E2=80=A2 Designing=20 Clinical Trials to Assess Biomarkers and Treatment = Outcome

=E2=80=A2 Diagnostically=20 Distinct Subcategories of NM

=E2=80=A2 Systemic=20 Tumor Markers Predictive of CNS Disease

=E2=80=A2 Treatment-Related=20 Factors Predictive of NM

=E2=80=A2 Conclusions

=E2=80=A2 References

=E2=80=A2 Copyright

Neoplastic meningitis (NM) is a = devastating=20 neurologic complication of cancer that is clinically = diagnosed in 4%=20 to 15% of patients with solid tumors, 5% to 15% of patients = with=20 leukemia and lymphoma, and 1% to 2% of patients with primary = brain=20 tumors.1, 2 = However, NM=20 remains underdiagnosed, as postmortem estimates of the true=20 incidence of the disease across all cancers approach 5%.2, 3 = Currently, three=20 independent methods are used to diagnose NM: clinical = presentation=20 (ie, neurological signs and symptoms), cerebral spinal fluid = (CSF)=20 cytology and flow cytometry, and central nervous system = (CNS)=20 neuroradiographic examination with magnetic resonance = imaging=20 (MRI).2, 4 = Nonetheless,=20 each of these methods is limited by either suboptimal = sensitivity or=20 specificity. For example, CNS signs and symptoms, which are = the=20 first indication of NM in the majority (>90%) of = patients, are=20 often subtle, unrecognized, and may be difficult to = distinguish from=20 manifestations of the primary disease or the neurological = side=20 effects of cancer treatment.2 In = contrast, the=20 often touted standard for NM diagnosis, cytological = detection of=20 malignant cells in the CSF, is highly specific for NM but = has a low=20 sensitivity (<50%), based on the only autopsy study = comparing=20 pre- and postmortem diagnosis.3 The=20 neuroradiographic method of choice, contrast-enhanced brain = and=20 spine MRI, is limited to detecting NM in approximately 40% = to 60% of=20 cases.5

The lack of sensitive and specific = diagnostic=20 tools has presented difficulties for the diagnosis and = treatment of=20 patients with NM, as well as for the design of clinical = trials=20 evaluating new treatments (Table 1).6 To = date, all=20 clinical trials evaluating the treatment of NM have relied = upon=20 either the demonstration of positive CSF cytology or=20 neuroradiography consistent with a diagnosis of NM. = Furthermore,=20 there are limited data comparing outcomes in patients = diagnosed with=20 NM by positive CSF cytology and negative neuroradiography = versus=20 patients with negative (or positive) CSF cytology and = positive=20 neuroradiography.7 Some = authors=20 have proposed that patients with NM and radiographic bulky = disease,=20 as defined by MRI of the brain and spine, represent a = population of=20 NM patients in whom outcome is poor,6, 8, 9 = although the one=20 study evaluating this hypothesis found that tumor burden did = not=20 inversely correlate with survival outcome.9 = Suboptimal=20 diagnostic sensitivity presents a challenge when defining=20 appropriate treatment group assignment in clinical trials, = and=20 reduces the reliability of treatment end points. Also, not = all=20 patients with NM are appropriate candidates for treatment, = and risk=20 stratification of patients with NM would likely improve = outcome in=20 good-prognosis patients by allowing NM-directed therapy to = be more=20 appropriately utilized.5, 8, 10, = 11, = 12 = Regardless,=20 there is an urgent need for new, clinically applicable = diagnostic=20 and monitoring laboratory tests of NM with increased = sensitivity and=20 specificity. This review discusses the limitations of = current NM=20 diagnostic methodologies and looks at some of the more = promising=20 recent innovations for NM diagnosis.

Table 1.

Problems Associated = With the End=20 Points Currently Used to Assess Treatment Response in = Patients=20 With Neoplastic=20 Meningitis


End Point	NM-Specific Examples	Confounders and Concerns
Tumor response	CSF cytologic=20 clearing Resolution of MRI=20 abnormalities	Lack of correlation with other=20 measures Test = imprecision Ignores quality of=20 survival
Survival	Time from diagnosis to=20 death Time from first treatment to=20 death	Variation in subsequent=20 care Death from non-CNS=20 cancer Ignores quality of=20 survival
Cause of death	NM-specific death	Variation in subsequent=20 care Lack of reliable=20 criteria Poor correlation with other end=20 points Usually=20 unblended
Surrogate = markers	Change in CSF=20 markers Quantitative CSF=20 cytology	Restricted=20 availability Lack of correlation with other=20 measures Ignores quality of=20 survival
Time to tumor = progression=20 (laboratory)	MRI = improvement Quantitative change in=20 cytology	Lack of correlation with other=20 measures Test=20 imprecision
Time to = tumor=20 progression (clinical)	Measures of performance (KPS,=20 etc) Quality-of-life=20 assessment Change in cognitive=20 performance	Usually = unblinded Often = cumbersome Test=20 imprecision

Abbreviations: NM, = neoplastic=20 meningitis; CNS, central nervous system; CSF, = cerebrospinal=20 fluid; MRI, magnetic resonance imaging; KPS, Karnofsky = performance = score.

CSF Cytology and=20 MRI

Any one of the three standard = methods=20 (neurological examination, CSF cytology, and MRI) can = accurately=20 diagnose NM. However, the clinical presentation is = challenging, as=20 neurological symptoms and signs may be subtle, may not be = elicited=20 from the patient's medical history unless a specific = neurologic=20 record is obtained, and often are attributable to other = aspects of=20 the patient's cancer (eg, coexisting brain or spine = metastases,=20 metabolic encephalopathy, or treatment-related = neuropathy).2, 6 = Consequently, if=20 lumbar puncture is feasible, CSF examination including = cytological=20 evaluation for malignant cells should be performed in all = cases of=20 suspected NM. CSF cytology is estimated to have a >95%=20 specificity for NM.4 = However, it has=20 a relatively low sensitivity (<50%) and consequently is = often=20 falsely negative. A retrospective analysis of cytology = results=20 across 18 studies (N =3D 874) reported sensitivities of CSF = cytology=20 ranging from 45% to 100% depending on how many times the = lumbar=20 puncture was repeated.4 = Perhaps most=20 importantly, these studies defined NM by either positive CSF = cytology or neuroradiographic finding consistent with NM, = and=20 therefore do not clarify the frequency with which patients = with NM=20 have negative CSF cytology.12

The lack of standardized techniques = for=20 obtaining and evaluating CSF cytology may in part contribute = to the=20 high false-negative rates. The sensitivity of cytology may = be=20 improved by ensuring optimal conditions for CSF sampling and = evaluation. In one prospective analysis of 39 untreated = patients=20 with NM, four sources of error were identified, including=20 insufficient sample volume, delayed processing, obtaining = CSF=20 distant from the site of symptoms, and acquiring fewer than = two=20 samples.13 = The initial=20 diagnosis of NM is most reliably established when: (1) the = CSF=20 sample volume is at least 10.5 mL; (2) CSF is obtained near = the site=20 of clinical or radiological disease; (3) the specimen is = processed=20 immediately; and (4) at least two CSF samples are = obtained.4, 13, = 14 = Because the=20 shedding of malignant cells into the CSF may occur = intermittently=20 and in low numbers, CSF specimens may fail to capture = malignant=20 cells. Other CSF indices, such as opening pressure during = lumbar=20 puncture, white blood cell (WBC) count, and protein and = glucose=20 levels may be abnormal in patients with NM but are = nonspecific and=20 likely do not occur in patients with very low volume = disease.2, 4 = Still=20 controversial is whether patients with suspected NM can be = diagnosed=20 with negative CSF cytology and neuroradiography based on = nonspecific=20 CSF abnormalities, a history of cancer, and a clinical = syndrome=20 consistent with NM.7

Gadolinium-enhanced brain and spine = MRI is a=20 preferred radiographic method for establishing a diagnosis = of NM.2, 15 = Findings that=20 are indicative of NM include enhancement and/or enlargement = of=20 cranial nerves, nodular or linear leptomeningeal enhancement = extending into sulci or basal cisterns, and = intradural-enhancing=20 nodules, especially in the cauda equina.2 The = sensitivity=20 of MRI for NM depends on the type of primary cancer. One = study found=20 that MRI was capable of detecting 100% of cases of NM from = solid=20 tumors (n =3D 14) but only 44% of those from B-cell acute=20 lymphoblastic leukemia (n =3D 5) and 48% from non-Hodgkin = lymphoma=20 (NHL; n =3D 20).16 = The average=20 specificity of MRI across all malignancies was 93%, ranging = from 89%=20 for acute myelogenous leukemia to 100% for solid tumors.16 = Therefore, the=20 potential for false-negative rates as high as 65% and = false-positive=20 rates approaching 10% limit the use of MRI as a stand-alone=20 diagnostic tool.4, 6, 12, = 16

Flow Cytometry and = Polymerase=20 Chain Reaction

To ensure optimal treatment and = reduce=20 unnecessary prophylactic treatment, there has been a strong = drive to=20 develop and validate sensitive analytical methods for occult = NM in=20 patients with aggressive B-cell lymphomas.17, = 18, = 19 = (See also the=20 article in this supplement by Drs Pui and Thiel.) Flow = cytometry is=20 an extremely sensitive method capable of detecting abnormal=20 monoclonal B-cells, which comprise as little as 0.01% of = total=20 lymphocytes.19, = 20 = The diagnostic=20 utility of flow cytometry for detecting aberrant B cells in = the CSF=20 was evaluated in a study of 51 newly diagnosed and nine = previously=20 treated patients with diffuse large B-cell lymphoma (DLBCL) = at risk=20 for CNS involvement.19 = Multicolor=20 flow cytometry conducted within 1 to 2 hours of CSF sampling = (1.2=E2=80=935.0 mL sample volumes) used multiple antibody = panels for light=20 chains and B- and T-cell antigens. The sensitivity of CSF = flow=20 cytometry was found to greatly exceed that of conventional = CSF=20 cytology. While cytology was positive in only one (2%) of = the 51=20 newly diagnosed high-risk patients, flow cytometry markers = were=20 positive in 11 (22%) of these same patients (P =3D = .002).19 = The low=20 detection rate of standard cytology likely reflects the low = median=20 tumor cell percentage in these patients (median, 7%; range,=20 0.2%=E2=80=9399%), as quantified by flow cytometry. Not = surprisingly, the=20 single patient for whom CNS involvement was detected by both = methods=20 had the highest percentage of tumor cells in the CSF = (99%).19 As = for the=20 nine previously treated patients with relapsed DLBCL, only = one (11%)=20 had positive cytology results, while three (33%) were = positive for=20 CNS lymphoma by flow cytometry. The median percent of tumor = cells in=20 this patient group was similar to the larger, untreated = population=20 (6%; range, 3%=E2=80=9345%).19

CSF chemistry and cell counts also = were=20 evaluated in the study by Hegde et al and were similar for = patients=20 with and without lymphomatous meningitis.19 = There were no=20 differences in total protein (P =3D .35), WBC count = (P =3D=20 .06), red blood cell count (P =3D .29), or flow = cytometry=20 lymphocytes (P =3D .96) for the newly diagnosed NHL = patients=20 with positive (n =3D 11) versus negative (n =3D 40) CSF = cytology.=20 However, as expected, there was a significant difference in = flow=20 cytometry percent tumor cells (P <.001). = Additional=20 analyses evaluated whether previously identified risk = factors for=20 CNS relapse correlated with positive flow cytometry. Only = the=20 presence of more than two extranodal sites of disease was=20 significantly correlated with positive flow cytometry = results=20 (P =3D .0057).19 = This=20 correlation is suggestive of a biologic phenotype that = bestows upon=20 certain tumor cells the ability to thrive outside of the = lymph node=20 microenvironment and allows for colonization of extranodal = sites and=20 CNS spread.

After CSF evaluation by cytology and = flow=20 cytometry, all patients were staged and treated with = dose-adjusted=20 EPOCH (infusional etoposide, vincristine, and doxorubicin, = with=20 bolus prednisone and cyclophosphamide) with or without = rituximab.19 = Newly=20 diagnosed patients considered at risk for CNS lymphoma, but = with no=20 CSF evidence of disease, received prophylactic intrathecal=20 methotrexate (MTX; 12 mg on days 1 and 5 of cycles 3 to 6 = for a=20 total of 8 doses), whereas patients with leptomeningeal = lymphoma=20 were actively treated for CNS disease (12 mg of MTX given=20 intrathecally twice weekly until 2 weeks after CSF = clearance,=20 followed by a consolidation of six weekly treatments and = maintenance=20 of four monthly treatments). All 40 patients who were = negative for=20 CNS lymphomas by flow cytometry were treated = prophylactically, and=20 only three (8%) experienced CNS relapse and death. Of the 11 = patients diagnosed by flow cytometry, nine were treated with = the=20 active disease regimen, one was treated with the = prophylactic=20 regimen, and one withdrew from the study. Despite receiving = early=20 active treatment for CNS disease, five (45%) of these 11 = patients=20 had CNS relapse and died. Therefore, even though flow = cytometry=20 facilitated earlier detection of CNS disease than had = previously=20 been possible, survival rates did not improve. This might be = due to=20 the suboptimal CNS-directed therapy used in this study = (intrathecal=20 MTX alone).

More recently, the diagnostic = sensitivity of=20 flow cytometry was found to be more than twice that of = conventional=20 cytology in a study that included 60 patients with NM caused = by=20 hematological malignancies.21 = With the first=20 CSF sample, flow cytometry was positive in 44 (73%) of these = patients, whereas cytology identified only 19 (32%). Because = of its=20 increased sensitivity, the National Comprehensive Cancer = Network now=20 recommends the routine use of flow cytometry for the = diagnosis of=20 CNS lymphoma.22 = However,=20 because the Bromberg study also found that some = false-negatives by=20 flow cytometry are detectable by conventional cytology,21 it = is=20 recommended that cytomorphologic examination of the CSF = still be=20 performed in conjunction with flow cytometry.

Polymerase chain reaction (PCR) also = has the=20 potential to improve sensitivity in detecting CSF = malignancy.=20 However, PCR requires the selection of primers specific for = tumor=20 cell=E2=80=93derived DNA. Two approaches to selecting = primers for detecting=20 NM have been evaluated thus far. One study in lymphoma = patients (N =3D=20 21) used clonal rearrangements of the immunoglobulin gene as = DNA=20 markers for CSF malignancy.23 = The use of=20 consensus primers from the immunoglobulin V and J regions = allowed=20 for the detection of CNS lymphoma in five of seven specimens = from=20 patients with negative cytology and suspected CNS = malignancy.23 = However,=20 false-negatives did occur with PCR, as two of the four = specimens=20 that were positive by conventional cytology were negative by = PCR.23 A = second study=20 used nested PCR of the complimentarity determining region = III.24 = Using this=20 approach, PCR results and CSF cytology were discordant in 10 = of 17=20 patients with primary CNS lymphoma.24 = However,=20 patients in this study had been treated already, and further = analysis of CSF samples obtained immediately after diagnosis = would=20 be required for a true evaluation of diagnostic utility. It = is=20 important to note that the PCR primers used in both of these = studies=20 were specific for lymphoma B-cell mutations.23, = 24 = For a PCR test=20 to be applicable to the diagnosis of NM derived from a range = of=20 primary cancers, the use of primers for DNA sequences common = to all=20 metastatic cells would be ideal, but the use of sequences = for=20 specific primary cancer histopathologies might provide a = more=20 practical option, as many are known already. There also is a = need=20 for more broad-spectrum tumor cell-specific antigens that = could be=20 labeled for flow cytometric detection of CNS malignancy. = This will=20 first require improved understanding of the biology of = metastases in=20 general and, perhaps more specifically, the process of CSF=20 penetration by tumor cells.

Biological Markers = for=20 Diagnosing and Monitoring Response of NM

Numerous biochemical markers of = tumor cells in=20 the CSF have been evaluated for their accuracy in detecting = NM,=20 including =CE=B22-microglobulin, lactic=20 dehydrogenase, =CE=B1-fetoprotein, and human chorionic = gonadotropin,=20 among others.25, = 26, = 27, = 28 = However, their=20 use generally has been limited by their low sensitivity.2 = Furthermore,=20 these biomarkers are of little clinical significance without = a=20 thorough understanding of the biology of metastatic disease = in=20 general and brain metastasis in particular.29 = Studying the=20 biology of disease progression and the molecular processes = of tumor=20 metastasis may identify new biomarkers with increased = sensitivity=20 and specificity for NM that also could serve as surrogates = of CSF=20 tumor burden and response to therapy (Table 2) (M.D. Groves, personal = communication).29, = 30, = 31, = 32, = 33, = 34, = 35, = 36, = 37 = Ideally, such=20 markers would allow for an earlier diagnosis and carry some=20 prognostic value, thus helping to select therapy.

Table 2.

Currently Identified=20 Cerebrospinal Fluid Biomarkers That May Be Indicative = of CSF=20 Malignancy


First Author, Year	n	Cancer(s)	Marker(s)	AUC-ROC (95% CI)	Sensitivity, % (95% CI)	Specificity, % (95% CI)	PPV, % (95% CI)	NPV, % (95% CI)
Brandsma, 200630	57	BC, NHL, LC, M, GI, = OC	Protein, glucose, IL-8 = (CXCL-8), PARC (CCL18), IP-10 (CXCL10)	0.95(0.9=E2=80=930.99)
van de Langerijt, = 200631	19	LC, M, urothelial, = unknown	Log VEGF index/log tPA = index		100 = (79=E2=80=93100)	73 = (57=E2=80=9386)	54 = (33=E2=80=9374)	100 = (91=E2=80=93100)
Reijneveld, 200532	53	BC, LC, NHL, M, = unknown, GI,=20 OC	CSF VEGF, CSF uPA
Friedberg, 199833	5	SCLC, BC, M	MMP2, MMP9
Herrlinger, 200434	39	BC, LC, M, CUP, OC, = other	CSF VEGF		51	98
Stockhammer, 200035	11	BC, LC, OC	CSF VEGF
Nagai, 200336	10	Prostate, LC, pharynx, = GI	CSF cathepsin B, H = cystatin=20 C
Groves, personal=20 communication	7+/24=E2=88=92	BC	CXCL12, ER = status/protein/WBC=20 count	0.97(0.88=E2=80=931.00)
Groves, personal=20 communication	7+/24=E2=88=92	BC	VEGF >20 = pg/mL CXCL12 (>950=20 pg/mL)		57 86	100 97	100 86	89 97
Groves, personal=20 communication	15+/22=E2=88=92	LC	VEGF CXCL12		69 38	100 95	100 83	83 72
Groves, personal=20 communication	4+/8=E2=88=92	M	VEGF CXCL12		50 75	100 100	100 100	75 88
Roy, = 200837	24+/77=E2=88=92	NHL	Antithrombin=20 III	0.912	75	98.7

Abbreviations: CSF, = cerebrospinal=20 fluid; AUC-ROC, area under curve-receiver operating = curve; BC,=20 breast cancer; CI, confidence interval; CUP, cancer of = unknown=20 primary; ER, estrogen receptor; GI, gastrointestinal; = IL,=20 interleukin; LC, lung cancer; M, melanoma; MMP, matrix = metalloproteinases; NHL, non-Hodgkin lymphoma; NPV, = negative=20 predictive value; OC, ovarian cancer; PPV, positive = predictive=20 value; SCLC, small-cell lung cancer; tPA, tissue-type=20 plasminogen activator; VEGF, vascular endothelial = growth=20 factor; WBC, white blood=20 cell.

During the metastatic process, cells = from=20 primary tumors develop motility and invasive potential, = allowing for=20 penetration into capillaries, venules, and lymphatic = channels. Tumor=20 cell extravasation and penetration of the CNS also involve = migration=20 through endothelial or other basement membranes to reach the = CSF and=20 meninges.29 = Some molecules=20 involved in this process, such as matrix metalloproteinases = (MMP)=20 and cathepsins, have been evaluated in the CSF of patients = with NM.=20 For example, MMP-2 and MMP-9, which digest portions of the=20 extracellular matrix, have been detected in the CSF of = patients with=20 metastatic brain tumors and positive CSF cytology.33 = Other=20 proteases (cathepsin B and H) and protease inhibitors = (cystatin C)=20 also may be useful indicators of NM.36 = High=20 activities of cathepsins B and H, along with decreased = cystatin C=20 concentrations, have been observed in the CSF of patients = with NM as=20 compared with cancer patients who did not have CNS = disease.36

Molecules linked to tumor cell = tropism for=20 specific organs also may be useful for diagnosing and = monitoring NM.=20 Some success in this regard has been achieved with the = chemokine=20 markers CXCL-8, CXCL-10, and CCL18 (Table 2). Brandsma and colleagues found = that when=20 assayed together with protein and glucose levels, CXCL-8, = CXCL-10,=20 and CCL18 levels could accurately predict the presence of = CNS=20 disease (0.95 area under curve [AUC]-receiver operating = curve [ROC];=20 95% confidence interval [CI], 0.9=E2=80=930.99).30 = Another=20 chemokine, CXCL12, a homing ligand for leukocytes and tumor = cells,=20 had a high diagnostic accuracy when combined with others = markers,=20 including WBC count, protein level, and estrogen receptor = status=20 (0.97 AUC-ROC; 95% CI, 0.88=E2=80=931.00) in breast cancer = patients (M.D.=20 Groves, personal communication; Table 2).

Molecules involved in angiogenesis = are also=20 important in the metastatic process. Although angiogenesis = has not=20 been established as essential for the progression of NM,29 = several=20 molecules involved in angiogenesis (eg, vascular endothelial = growth=20 factor [VEGF], urokinase-type plasminogen activator, = tissue-type=20 plasminogen activator [tPA], and antithrombin III) appear to = have=20 diagnostic value (Table 2). Elevated VEGF levels, in = particular,=20 have been repeatedly demonstrated in the CSF of patients = with NM=20 compared with cancer patients without NM (M.D. Groves, = personal=20 communication).31, = 32, = 34, = 35 = However, the=20 diagnostic specificity and sensitivity and the threshold = VEGF=20 concentrations used vary from study to study. For example,=20 Herrlinger et al observed a 98.3% diagnostic specificity but = a=20 relatively low sensitivity of 51.4% for NM using threshold = VEGF=20 levels of 250 pg/mL (73% sensitivity for a threshold of 100=20 pg/mL).34 A = similarly=20 low sensitivity (50%=E2=80=9369%) but high specificity = (100%) using a=20 threshold VEGF level of 20 pg/mL was observed in three other = recent=20 studies (Table 2). Another study identifying = decreases in=20 tPA in the CSF of patients with NM, which used a combination = index=20 of the log of VEGF and tPA, obtained a sensitivity of 100% = but a=20 substantially lower specificity (73%) than observed in = previous VEGF=20 studies.31

Even as the diagnostic utility of = VEGF remains=20 to be established, some studies suggest that it has = prognostic=20 value. Herrlinger et al observed that VEGF levels mirror the = clinical course in some patients, appearing markedly reduced = following therapy and increased upon relapse.34 = Likewise,=20 Stockhammer and colleagues reported a drop in CSF VEGF = levels in=20 response to treatment in four of five patients with various = primary=20 cancers.35 We = have=20 observed similar trends in our experience (Figure 1). Although further extensive = study is=20 required, tracking of VEGF levels over time may prove a = useful tool=20 for monitoring the response of NM to therapy.

Figure=20 1. Levels of vascular endothelial growth = factor in=20 the cerebrospinal fluid over time.

The use of CSF biomarkers is subject = to=20 several inherent problems that must be carefully considered = when=20 developing new diagnostic tests. First, assay = standardization=20 between institutions is essential. Additionally, CSF flow=20 abnormalities are common in patients with NM, and uneven CSF = flow=20 can alter biomarker concentrations in areas of low flow, = leading to=20 highly variable measurements at different sampling sites.38, = 39 = Sampling of=20 CSF from a lumbar versus a ventricular source also can alter = biomarker levels, depending on the location of metastases = along the=20 neuraxis.14 = Different=20 tumor histologies are likely to be associated with different = levels=20 of certain biomarkers as well, although the more generic = markers of=20 malignancy (eg, VEGF) may allow for more consistency. The = time point=20 of CSF sampling is also important, since molecular = expression may=20 change with disease progression.

Designing Clinical = Trials to=20 Assess Biomarkers and Treatment Outcome

The clinical relevance of novel CSF = biomarkers=20 remains to be firmly established. Patients with microscopic=20 involvement may be least likely to have positive biomarkers. = Even if=20 biomarkers allow for higher detection rates or earlier = detection,=20 they need to be highly specific, and the natural history of = those=20 newly diagnosable cases must be documented. Will such = patients=20 ultimately develop symptomatic NM? Is the natural history of = such=20 cases the same as for cytologically diagnosed NM? Are = effective=20 treatments available? These questions require careful = evaluation in=20 future clinical trials. A plausible design for such a = clinical trial=20 is outlined in Figure 2. Important considerations for = trial=20 design include: (1) selection of a validated biomarker; (2)=20 determination of a gold standard for disease detection (flow = cytometry/cytology=E2=80=94no standard established yet); (3) = whether to=20 exclude from treatment patients who are negative by the gold = standard but positive by the biomarker; (4) the choice of = treatment=20 intervention for biomarker-positive patients; (5) biomarker = sampling=20 location (ie, ventricular v lumbar); (6) end point = selection;=20 and (7) consideration that the therapeutic intervention = and/or=20 biomarker may fail. At the same time, any trial assessing = biomarker=20 utility and NM therapy also must include conventional = diagnostic=20 response measures, ie, clinical status, cytology, and = MRI.

Figure=20 2. Proposed clinical trial design for = assessing=20 the diagnostic utility of biomarkers in patients at = high risk=20 for developing neoplastic meningitis (NM). CSF, = cerebrospinal=20 fluid; IT, intrathecal; PF Mets, posterior fossa=20 metastasis.

A number of outcome measures have = been used to=20 assess treatment response in patients with NM, many of which = are=20 inherently problematic (Table 1). Given the high specificity of = flow=20 cytometry for the detection of NM in hematologic cancers,19, = 21 it = is likely=20 that flow cytometric monitoring of CSF clearance will become = a=20 standard measure of treatment outcome in patients with other = underlying tumors. Nevertheless, most treatment response=20 determinations in clinical trials have conventionally been = based on,=20 in rank of importance, standard CSF cytology, imaging = results, and=20 clinical outcome/survival. A strong case can be made that = the=20 importance of these end points should be reversed, with = patient=20 status viewed as a primary end point, in part because this = is the=20 most clinically meaningful outcome and in part because of = the=20 inherent problems with CSF cytology and neuro-imaging in = patients=20 with NM (Table 1).6 Some = success has=20 been achieved using patient status as a primary end point in = studies=20 using a blinded external review committee to evaluate = neurological=20 and neurocognitive progression.40, = 41, = 42

Another approach to assess = neurologic=20 progression as a treatment end point, one that could be = easily=20 applied by any clinician, is a short checklist grading = cognitive,=20 motor, and cranial nerve functions pertinent to the NM = process on a=20 scale of 1 to 5 (Table 3). This type of survey has been = evaluated=20 by Glantz and Jaeckle in pilot studies, and results obtained = have=20 correlated well with traditional methods for determining=20 progression, such as survival and CSF cytology (M. Glantz, = personal=20 communication). While these tools offer an alternative = approach to=20 assessing neurological function, they do not provide an = assessment=20 of the actual tumor burden. Also, clinical manifestations = often do=20 not appear until late in the disease process. To optimally = guide=20 treatment decisions and assess treatment outcome, patients = with NM=20 must be identified much earlier, even before the appearance = of=20 clinical signs, cytology, or imaging.

Table 3.

Grading Scale of = Clinical=20 Indicators of Neurologic=20 Progression


Indicator	Grade 0	Grade 1	Grade 2	Grade 3
Pain
A	Headache	None	Requiring non-opiate=20 analgesics	Requiring use of = opiate=20 analgesics (oral, transcutaneous bolus IV, SC)	Requires continuous=20 parenteral opiates
	Back/radicular neck = pain	None	Requiring non-opiate=20 analgesics	Requiring use of = opiate=20 analgesics (oral, transcutaneous bolus IV, SC)	Requires continuous=20 parenteral opiates
B	Motor	None	Mild motor loss not = affecting=20 function; minor assistance required	Loss affects function, = moderate assistance required	Loss severely = impairs=20 function, requires near full-time/major = assistance
C	Ambulation	Normal	Mild impairment, walks = without=20 assistance	Moderate instability, = requires=20 assistance, cane or walker	Non-ambulatory, = requires=20 wheelchair
D	Alertness	Normal	Mild alterations not = impairing=20 function or requiring minimal assistance or = supervision	Moderate, affects = function,=20 requiring moderate assistance or supervision	Severe impairment = preventing=20 function and requiring nearly full-time assistance and = supervision
E	Ataxia (truncal or=20 appendicular)	None	Mild, not impairing=20 function	Moderate, impairs = function	Severe impairment = preventing=20 function
Cranial nerves (changes may be uni- or=20 bilateral)
F	Corrected visual = acuity, CN=20 (II)	Normal	Deficit present, does = not=20 interfere with function	NA	Significant deficit=20 (finger-counting, light perception, blindness)
	Eye movement = abnormality, CN=20 (III, IV, VI)	None	Present but = stable	NA	New or additional=20 abnormality
	Facial CN (VII)	None	Some paresis present = but=20 stable	NA	New or additional = deficit
	Dysphagia/dysarthria, = CN (X,=20 XI, XII)	None	Some loss present, = does not=20 interfere with function	NA	Significant deficit, = interferes with function
	Hearing, CN = (VIII)	Normal	Some loss present, = does not=20 interfere with function	Significant deficit,=20 interferes with function	NA
G	Nausea/vomiting	None	Requires oral or = parenteral=20 antiemetics	Requires IV hydration = or=20 hospitalization	NA
H	Sensory	None	Sensory loss not = affecting=20 function	Loss impairs = function	NA
I	Urinary/fecal = incontinence or=20 retention	None	Minor, not requiring=20 medication or intervention	Requirement for=20 catheterization	NA
J	Mental = status	Normal, = score of=20 30 on MMSE	Score of = 29-20=20 on MMSE	Score of = <20=20 on MMSE	NA

Abbreviations: CN, = cranial nerve;=20 IV, intravenous; NA, not applicable; MMSE, Mini-Mental = State=20 Examination; SC,=20 = subcutaneous.

Diagnostically = Distinct=20 Subcategories of NM

Some clinicians have observed that = the=20 relative incidences of positive results from cytology versus = MRI=20 versus neurological examination are suggestive of three = distinct=20 diagnostic categories of NM. For example, it has been = estimated that=20 roughly 25% of all patients with NM present with a clinical = syndrome=20 consistent with NM irrespective of CSF cytology or = neuroradiology=20 results, whereas about 50% have positive CSF cytology = regardless of=20 the clinical syndrome or MRI findings, and about 40% present = with=20 positive radiology irrespective of clinical syndrome or CSF=20 cytology.43, = 44

There has been some speculation that = differences in the features by which NM is diagnosed may be=20 indicative of inherently distinct forms of NM associated = with=20 different prognostic outcomes. However, few studies have = evaluated=20 clinical response based on the method of diagnosis. Data = from a=20 recent phase II study evaluating NM treatment with intra-CSF = topotecan (400 =CE=BCg, twice weekly) suggest that clinical = response may=20 indeed vary with the diagnostic method.45 In = this study,=20 80% of the topotecan-treated patients who had positive CSF = cytology=20 but negative MRI findings at diagnosis were stable or = improved after=20 a 6-week induction period (Table 4; M.D. Groves, personal = communication).=20 Patients with negative cytology and positive imaging had a = lower=20 response rate, with only 55% stable or improved. The poorest = prognosis was observed in patients who had both positive = cytology=20 and MRI results at diagnosis: only 29% were stable or = improved after=20 6 weeks of topotecan treatment (Table 4).45 = However, it=20 should be noted that despite these apparent differences in = response=20 rate depending on CSF and MRI status, overall survival rates = were=20 nearly identical in all groups.

Table 4.

Patient Outcome Varies = With the=20 Diagnostic Modality by Which Neoplastic Meningitis Was = Diagnosed (M.D. Groves, personal=20 = communication)


	Stable Disease or Improved, n (%)	Median Survival (wk)	Range (wk)
CSF-positive = MRI-negative	12/15(80)	12.5	4=E2=80=9370
CSF-negative = MRI-positive	6/11(55)	15.1	3=E2=80=93128
CSF-positive=20 MRI-positive	10/35(29)	12	2=E2=80=9382

Abbreviations: CSF, = cerebrospinal=20 fluid; MRI, magnetic resonance=20 imaging.

Additional data from a = single-investigator=20 institutional data set suggest that patients diagnosed by = cytology=20 versus MRI also differ in terms of primary systemic cancer = and other=20 specific NM disease characteristics (Table 5) (M.C. Chamberlain, unpublished = data).12 = For example,=20 90% of patients with NM from NHL had positive CSF cytology, = but only=20 10% were diagnosed by MRI alone. In contrast, only 60% of NM = cases=20 from melanoma had positive cytology results, and as many as = 40% were=20 diagnosed only by MRI (Table 5). Treatment response also = varied across=20 patient groups. The highest rates of CSF cytology conversion = from=20 positive to negative were observed in NHL patients (38%), = the lowest=20 rates in melanoma patients (18%). These observations are = suggestive=20 of distinct biological forms of leptomeningeal disease that = differ=20 in the relative degree of cell shedding into the CSF as well = as in=20 treatment response.7, 46, = 47, = 48 = However, a=20 recent report of 110 melanoma patients with NM reported that = disease=20 burden of NM, based on CSF and MRI as measures of extent of = disease,=20 did not have an impact on survival outcomes,9 = suggesting that,=20 at least in melanoma patients, segregating good-prognosis = and=20 poor-prognosis patients based on evidence of disease burden = of NM=20 may not be very useful.

Table 5.

Diagnostic and Response = Characteristics of Neoplastic Meningitis in Patients = With=20 Different Primary Cancers (M.C. Chamberlain, = unpublished=20 data)


	Breast Cancer	Melanoma	Non-Small Cell Lung Cancer	NHL
No. of patients	66	30	50	40
Positive = cytology	75%	60%	80%	90%
Positive radiology = alone	25%	40%	20%	10%
Active systemic = disease	70%	80%	80%	90%
CSF cytology = conversion from=20 positive to negative	30%	18%	28%	38%
Median survival = (range)	7 mo = (0.25=E2=80=9319)	2.8 mo=20 (0.25=E2=80=936)	3 mo = (0.25=E2=80=937)	7 mo=20 (0.25=E2=80=9327)
Cause of death
LMD	30%	40%	20%	15%
LMD + systemic disease	30%	40%	40%	25%
Systemic disease	40%	20%	40%	60%

Abbreviations: CSF, = cerebrospinal=20 fluid; LMD, leptomeningeal=20 disease.

Systemic Tumor = Markers=20 Predictive of CNS Disease

Evidence that some tumor types are = more likely=20 than others to infiltrate the CNS and develop into active = CNS=20 disease has stimulated research into biomarkers of these = tumors that=20 might be used to identify patient groups that would benefit = from CNS=20 prophylaxis. One potentially useful marker identified in = breast=20 cancer patients, overexpression of the human epidermal = growth factor=20 receptor 2 (HER2), occurs in about 20% to 25% of invasive = breast=20 cancers and has been linked to an increased risk for brain=20 metastases.49, = 50 A=20 retrospective study of 664 breast cancer patients found that = brain=20 metastases occurred in significantly more patients with HER2 = overexpression (HER2+: 9%, = 27/301)=20 than in patients with normal HER2 expression (HER2=E2=88=92: 1.9%, 7/363; hazard = ratio, 4.23; CI,=20 1.84=E2=80=939.74; P =3D .0007) after a median = follow-up of 3.9 years.=20 Five-year event-free survival (EFS) and overall survival = rates were=20 also significantly lower for HER2+=20 than for HER2=E2=88=92 = patients (5-year EFS:=20 64% v 85%, P <.001; 5-year overall = survival: 73%=20 v 87%, P <.001). The use of HER2-directed = therapy,=20 ie, trastuzumab, has improved systemic control in HER2+ breast cancer patients, but the = CNS=20 appears to remain a sanctuary site for disease, perhaps = because of=20 the limited blood-brain barrier (BBB) penetration of = intravenous=20 trastuzumab.50, = 51 = Newer drugs=20 that disrupt the HER2 pathway and can penetrate the BBB may = improve=20 CNS control in HER2+ breast = cancer=20 patients.52, = 53 = Therefore,=20 while HER2 positivity has not provided an ideal marker for = selecting=20 patients to target with standard CNS-directed prophylaxis = (only 9%=20 of HER2+ patients at the = time of=20 diagnosis ultimately developed CNS disease),49 it = has=20 provided a rationale for developing and using targeted = therapies=20 that penetrate the CNS. Further study into the biology of = CNS=20 penetration by tumor cells may provide additional insight = into risk=20 factors for CNS disease and perhaps allow for molecular = profiling of=20 newly diagnosed cancer patients to predict which patients = will=20 develop brain metastases.54

Treatment-Related = Factors=20 Predictive of NM

Cancer patients who develop = posterior fossa=20 brain metastases may be susceptible to the later development = of=20 NM.55 A = recent=20 retrospective study of 379 patients with posterior fossa = brain=20 metastases found that those who underwent a piecemeal = resection of=20 lesions had a 2.45 relative risk of the later development of = NM (14%=20 of patients developed NM) compared with patients who = underwent en=20 bloc resection or were treated with stereotactic = radiosurgery (6% in=20 each group later developed NM).56 = Therefore, it=20 is uncertain whether patients with posterior fossa brain = metastases=20 are a group at increased risk for NM and therefore require = closer=20 surveillance for NM, or possibly, if combined with other = predictive=20 CSF biomarkers or tumor markers, even considered for = prophylactic=20 NM-directed treatments.

Conclusions

Although current diagnostic and = monitoring=20 tools lack sensitivity and/or specificity for NM, these = studies=20 nonetheless should continue to be used when evaluating = patients for=20 NM-directed treatment. Newer tools, such as flow cytometry = and=20 biomarkers of tumor cells in the CSF, may offer increased=20 sensitivity and specificity and allow for earlier = identification of=20 CNS involvement. CSF flow cytometry and novel CSF biomarkers = could=20 enable earlier treatment of NM and may provide a rationale = for=20 CNS-directed prophylaxis before symptomatic disease and = fixed=20 neurological deficits become established. However, further=20 validation of these tools, in particular novel CSF = biomarkers, in=20 clinical trials is warranted.

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55.=20 55Chamberlain MC. Risk of neoplastic meningitis = following surgical=20 resection of cerebellar metastases. J = Neurooncol.=20 2008;89:105=E2=80=93107. CrossRef=20

56.=20 56Suki D, Abouassi H, = Patel AJ,=20 Sawaya R, Weinberg JS, Groves MD. = Comparative risk of leptomeningeal = disease after=20 resection or stereotactic radiosurgery for solid tumor = metastasis to=20 the posterior fossa. J Neurosurg. 2008;108:248=E2=80=93257. CrossRef=20

a Department of Neurology and = Neurological=20 Surgery, Division of Neuro-Oncology, University of = Washington,=20 Seattle, WA

b Department of Neurosurgery, Penn = State Hershey=20 Medical Center, Hershey, PA

c The University of Texas, M. D. = Anderson Cancer=20 Center, Houston, TX

d Lymphoma Therapeutics Section, = Metabolism=20 Branch, Center for Cancer Research, National Cancer = Institute,=20 Bethesda, MD

Address = correspondence=20 to Marc Chamberlain, MD, University of Washington, = Department of=20 Neurology and Neurological Surgery, Chief, Division of=20 Neuro-Oncology, Seattle Cancer Care Alliance, 825 Eastlake = Ave E,=20 Mail Stop G4-940, Seattle, WA 98109-1023

STATEMENT OF CONFLICT OF = INTEREST:=20 All four authors have received honorarium from Enzon=20 Pharmaceuticals, as well as serving on the Enzon speaker's = bureau.=20 M.G. and M.D.G. have received research support from Enzon=20 Pharmaceuticals.

PII: S0093-7754(09)00095-5

doi:10.1053/j.seminoncol.2009.05.005

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