NEUROLOGICAL REVIEW New Strategies in the Management of Leptomeningeal Metastases

Morris D. Groves, MD

he management of patients with leptomeningeal metastases (LM) is multifaceted and complex. Even with an aggressive approach, therapeutic outcomes are uniformly dis- appointing. This is because of the relentless growth of the central nervous system (CNS) and/or the systemic cancers, or their lethal complications. Advances in the understand- Ting of the homing of cancer cells to the CNS, and of cancer metastasis in general, and more effec- tive anticancer drugs that are adequately delivered to the CNS and cerebrospinal fluid (CSF) are needed to improve outcomes for patients with LM. These advances may lead to better treatments for this disease and, ultimately, its prevention. Arch Neurol. 2010;67(3):305-312

Despite the passing of nearly 140 years time for the development of CNS metas- since its original description, little progress tases and (2) the use of large-molecule an- has been made in improving survival for tineoplastic agents with limited CNS and patients with LM. Hematologic malignan- CSF penetration may control systemic dis- cies can result in LM in up to 24% of pa- ease but leave LM unaffected behind the tients. The most common solid tumors blood-brain barrier (BBB) and blood- causing LM are breast cancer, lung can- CSF barrier (BCSFB). Paradoxically, the cer, and melanoma,1 with incidences rang- newer large-molecule therapies may im- ing between 5% and 23%. Leptomenin- prove overall cancer survival while in- geal metastases risk rises with longer creasing the incidence of CNS metasta- cancer survival. ses. Longer survival and exposure of tumor In the United States, standard treat- cells to genotoxic may se- ment for LM includes CSF diversion when lect for increasingly chemoresistant cell indicated, radiation, local intrathecal (re- clones, making LM even more resistant to fers to intraventricular administration, un- therapy over time. less otherwise specified) chemotherapy, and systemic chemotherapy. Recent re- THE BIOLOGY OF CNS views discuss management of LM.2,3 With METASTASES AND LM standard interventions, median survival for patients with LM ranges from 8 to 16 Once we understand the biology behind weeks. Roughly 24% to 34% die of LM LM, we can develop therapies targeting alone, 22% to 25% die of LM simulta- these biological changes. Metastasis is a neously with progressive systemic can- cascade of events with multiple cellular and cer, 19% to 44% die of systemic disease molecular changes.7 For LM to develop, progression, and up to 10% die of other 4-6 tumor cells must detach from the pri- causes. mary site, invade a blood or lymphatic ves- The incidence of brain metastases (BM) sel, survive vascular transit, adhere to host and LM may increase in the near future organ endothelium,8 invade the host or- for at least 2 reasons: (1) longer control gan, proliferate, and develop a blood sup- of non-CNS cancers may allow for more ply.7 Molecular factors implicated in CNS metastases and LM include E-cadherin– Author Affiliation: Department of Neuro-Oncology, University of Texas MD catenin complexes, plasmin, urokinase- Anderson Cancer Center, Houston. type plasminogen activator, metallopro-

(REPRINTED) ARCH NEUROL / VOL 67 (NO. 3), MAR 2010 WWW.ARCHNEUROL.COM 305

©2010 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 teinases, tissue inhibitors of metalloproteinases (associated TREATMENTS 9 ␣ ␤ 10 with brain invasion), and activated integrin v 3. Me- talloproteinases can degrade endothelial tight junction Intrathecal typically used in LM in- proteins at the BBB. Along with vascular endothelial clude , , liposomal cytarabine, and growth factor (VEGF)11 and stromal-derived factor 1,12 .3 Systemic therapies are usually chosen based metalloproteinases may allow for transendothelial mi- on tumor histology, drug penetration into the CSF, and gration of tumor cells.13 Other mechanisms that may con- a patient’s prior drug exposure. tribute to the development of LM include an ectodermal origin of the primary tumor, which may allow for ad- Intrathecal Treatments vantageous cell-cell interactions between the metastatic tumor cells and native brain cells.14,15 Further, tumor cell Even though intrathecal chemotherapy is widely used in surface markers, such as the extracellular domain of the the United States for solid-tumor LM, proof of its benefit epidermal growth factor receptor 2 protein, are associ- has not been established in randomized controlled trials.69 ated with a higher risk of BM in breast cancer16 and pos- Randomized controlled trials do suggest modest improve- sibly LM. ments with long-acting over standard intrathecal chemo- therapies,70,71 and some retrospective studies suggest in- DRUG DELIVERY trathecal chemotherapy prolongs survival,72 but there exists contrary evidence.73,74 A recently begun randomized con- The delivery of many anticancer drugs from blood to the trolled trial, European Organization for Research and Treat- brain17,18 and from blood to CSF is restricted, for mul- ment of Cancer 26051, is testing intrathecal liposomal cy- tiple reasons. Drug-related factors include the drug’s level tarabine vs supportive care in solid-tumor LM. of protein binding and its molecular weight, polarity, and Intraventricular (as opposed to intralumbar) chemo- lipid solubility.19 Physical factors include the architec- therapy delivery results in improved CSF drug levels and tural properties of the BBB and BCSFB, such as the tight less interpatient variability of drug distribution. This form junctions between the endothelial cells of brain capillar- of regional chemotherapy has led to effective treatment of ies and the epithelial cells of the choroid plexuses, lim- occult and overt meningeal leukemia in humans, and based iting paracellular diffusion of polar compounds. Fur- on this success, investigators continue its evaluation in pa- ther, adenosine triphosphate–dependent pumps such as tients with solid tumor, hoping for similar outcomes. Phar- the P-glycoprotein system, multidrug resistance pro- macokinetics of commonly used intrathecal anticancer teins, and organic and inorganic ion transporters can me- agents shows that high drug concentrations can be achieved diate efflux of some anticancer drugs away from the in the CSF and leptomeninges but not deep into the brain. brain.19-25 Because of this, intrathecal administration is not effective The BBB and BCSFB are not identical. The BCSFB has for bulky disease in the meninges.75 Further, in solid- a more relaxed tight junction architecture that corre- tumor LM, intraventricular administration, or the use of lates with differential diffusion capacities between it and sustained-release chemotherapeutic agents if the lumbar the BBB.26 Recent work has investigated the effect of P- route is used, appears to improve treatment outcome.76 glycoprotein–modulating drugs on the CSF penetration of some chemotherapies. Tamoxifen, a P-glycoprotein in- Experimental and Newer Agents. The most promising hibitor, decreased the CSF penetration of , sup- recently tested cytotoxic and radiotherapeutic agents are porting the concept that the pumping direction of P- presented in Table 2. The topoisomerase inhibitors ap- glycoprotein at the choroid plexus is in the opposite pear as effective as traditionally used intrathecal agents, direction to the BBB. The P-glycoprotein system ap- and both and hydrochloride have pears to direct natural product toxins away from the brain little toxicity, so may be useful in combination with other into the CSF, and when inhibited, lower CSF drug lev- agents or as prophylaxis.77,78,87 A concentrationϫtime els are found.27 Animal models reveal similar findings with study of intrathecal topotecan is open and accruing the tyrosine kinase inhibitor gefitinib. Its administra- patients within the Pediatric Brain Tumor Consortium. tion results in lower CSF levels and higher brain paren- Because of pain associated with intrathecal administra- chymal levels of the topoisomerase I inhibitor topote- tion, requires slow delivery and premedi- can.28 cation with steroids and narcotics but may be useful in Table 1 shows the CSF:plasma ratios for some of the childhood CNS malignancies to help delay or avoid ra- drugs studied in humans and rhesus monkeys. A CSF: diation exposure.79,80 Because of almost no toxicity and plasma ratio lower than 0.05 signifies nonspecific leak- some efficacy (29% CSF clearance), sodium iodide I 131 age of drug. Table 1 shows that many drugs normally (131I) will be further studied in a phase 2 trial with a higher- achieve CSF:plasma ratios lower than 0.05. However, once dose, multiday schedule.84 For similar reasons, phase 2 LM has arisen, or if radiation is directed to the CNS, leak- studies evaluating serial intrathecal injections of the GD2- age of the BCSFB develops, and larger molecules can leak targeted monoclonal antibody 131I-3F8, are under way.85 from blood into CSF.68 Further, some drugs have an in- Early data suggest efficacy in childhood primitive neu- trinsically high CSF:plasma ratio, suggesting their pos- roectodermal tumors and neuroblastoma. sible utility in treating LM. As the understanding of the BBB and BCSFB advance, we may ultimately be able to Noncytotoxic Intrathecal Therapies. Immunotherapies. facilitate the CNS and CSF penetration of therapeutic mol- The CSF space may be excluded from the benefits of the ecules, which are now excluded. systemic antitumor effects of the immune system, so im-

(REPRINTED) ARCH NEUROL / VOL 67 (NO. 3), MAR 2010 WWW.ARCHNEUROL.COM 306

©2010 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 Table 1. Cerebrospinal Fluid to Plasma (or Serum) Drug Ratios After Intravenous or Oral Administration in Rhesus Monkeys or Humansa

Drug Cerebrospinal Fluid to Plasma Ratio Source Triethylenethiophosphoramide 1.0 Heideman et al29 Thiotepa 1.0 Heideman et al29 0.95 Vassal et al30 0.20-0.33 Ostermann et al31 and Patel et al32 O6-benzylguanine; active metabolite O6-benzyl-8-oxoguanine 0.43; 0.36 Berg et al33 Tiazofurin 0.28 Grygiel et al34 6- 0.27 Zimm et al35 5- 0.155 Kerr et al36 Arabinosyl-5-azacytidine 0.15 Heideman et al37 Cytosine arabinoside 0.06-0.22 Balis and Poplack38 and Slevin et al39 hydrochloride 0.067 Kerr et al40 0.05 Berg et al41 sulfate ND to 0.05 Balis and Poplack38 and Kellie et al42 Spiromustine 0.047 Heideman et al43 0.029-0.03b DeGregorio et al44 and Jacobs et al45 0.028b Jacobs et al45 0.02b Jacobs et al45 Etoposide 0.003-0.05c Hande et al46 and Relling et al47 Methotrexate 0.01-0.04 Thyss et al48 and Balis et al49 Ͻ0.02 Stapleton et al50 Interferon alfa 0.033 Habif et al51 Daunomycin ND Balis and Poplack38 L- ND Balis and Poplack38 Trastuzumab 0.0023-0.02d Pestalozzi and Brignoli52 and Stemmler et al53 hydrochloride; idarubicinol (active metabolite) 0.08-0.15 (2 animals); 0.019 Berg et al54 ; daunorubicinol 0.04-0.12; 0.024±0.019 Berg et al54 Topotecan hydrochloride (lactone) 0.29-0.42 Baker et al55 hydrochloride (SN-38) 0.14%±3% (SN-38Յ0.08) Blaney et al56 Rituximab 0.001 Rubenstein et al57 and Rubenstein et al58 Erlotinib hydrochloride and OSI-420 (erlotinib metabolite) Ͻ0.05 (CSF exposure 30% plasma Meany et al59 free-drug exposure) Imatinib mesylate 0.05 (±2%) (concentrationϫtime AUC) Neville et al60 Depsipeptide 0.02 Berg et al61 Valproate sodium 0.13%±5.1% (total drug) Stapleton et al62 0.57%±8.7% (free drug) Hydroxyurea 0.24e Beckloff et al63 ABT-888 (PARP inhibitor) 0.57 Muscal et al64 Tasidotin hydrochloride ( stabilizer) 1.1±0.4 Kilburn et al65 ; 0.20 (0.00-1.1); 1.2 (0.4-1.6)f Yule et al66

Abbreviations: AUC, area under the curve; CSF, cerebrospinal fluid; ND, not detectable. aAdapted from Levin et al.67 bConcentration of active drug. cNon–protein bound fractional ratio. dOne log increase in CSF levels for patients undergoing cranial irradiation or with neoplastic meningitis. eOral dose 80 mg/kg. fLowest levels in patients receiving dexamethasone.

munotherapeutic approaches to the treatment of LM are total). Mean peak CSF concentration 1 hour postdose rose theoretically attractive. Unfortunately, immune re- to 472 µg/mL and estimated half-life averaged 34.9 hours. sponses are frequently associated with inflammation. In- Cytologic responses were seen in 6 of 10 patients; 4 pa- trathecal administration of interleukin 2 or interferon alfa tients experienced a complete response; 2 patients ex- both resulted in responses in patients with LM but were perienced improvement in intraocular lymphoma; and also fairly toxic, limiting enthusiasm for further 1 patient’s intraparenchymal lymphoma improved. Toxic development.88,89 reactions were limited. Further studies developing this Rituximab. Rituximab is a humanized monoclonal an- promising therapy are under way. Additionally, a study tibody against the CD-20 antigen expressed on most B- of intrathecal rituximab combined with intrathecal metho- cell lymphomas. It has been used intravenously since trexate91 for patients with intraocular or LM lymphoma 1997. Cerebrospinal fluid levels of this large molecule has been initiated. (146 kDa) are only 0.1% of the serum level after intra- Trastuzumab. Trastuzumab is a humanized monoclo- venous administration.57 Several case reports demon- nal antibody that binds to the epidermal growth factor strating safety and possible benefits of intrathecal ad- receptor 2 protein, which is overexpressed in 30% of pri- ministration of rituximab led to a recently reported phase mary breast cancers, as well as some other tumors. Trastu- 1 study.90 In this study, the maximum tolerated dose of zumab inhibits the growth of tumor cells and mediates intrathecal rituximab was 25 mg twice weekly (9 doses antibody-dependent cellular cytotoxicity. A recent study

(REPRINTED) ARCH NEUROL / VOL 67 (NO. 3), MAR 2010 WWW.ARCHNEUROL.COM 307

©2010 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 Table 2. Promising Intrathecal Cytotoxic and Radiotherapeutic Treatmentsa

Induction Intrathecal Dose Agent/Phase/No. of Patients and Frequency Toxicity Efficacy Source Etoposide/2/27 0.5 mg daily for 5 d, every other 18% Mild arachnoiditis 26% CSF clearance; 11% Chamberlain et al77 week for 8 wk 6-mo PFS; 4% 1-y survival Topotecan hydrochloride/2/62 0.4 mg twice a week for 6 wk 32% Mild arachnoiditis 21% CSF clearance; 30% Groves et al78 13-wk PFS; 19% 6-mo PFS; 15-wk median survival Mafosfamide/1/30 and 25b First group: 5 mg twice a week First group: headache and neck First group: 43% response Blaney et al79 for 4 wk; second group: pain; second group: mild or SD and Blaney et al80 14 mg twice a week for 6 wk irritability in all patients (with steroid and morphine) Busulfan/1/28 children 13 mg twice a week for 2 wk First group: myelosuppression First group: 39% SD at 2 wk; Gururangan et al81 and 20 adults and GI symptoms common second group: 30% and Quinn et al82 response or SD 5-Fluoro-2Ј-deoxyuridine/1/25 1.0 mg/d continuous infusion 20% Bacterial meningitis 16% CSF clearance; 8.4-mo Nakagawa et al83 until progression median survival; 100% clinical improvement Sodium iodide I 131/1/31 Single dose, 4.44ϫ107 Bq, NoneϾgrade 1 29% CSF clearance Wong et al84 MTD not reached Iodine 131–labeled MTD 3.7ϫ108 Bq, Self-limited headache, fever, 23% CSF or MRI responses Kramer et al85 monoclonal antibody single dose vomiting 3F8/1/13

Abbreviations: CSF, cerebrospinal fluid; GI, gastrointestinal; MRI, magnetic imaging resonance; MTD, maximum tolerated dose; PFS, progression-free survival; SD, stable disease. aAdapted with permission from Groves.86 bChildren with embryonal tumors.

showed that the CSF:serum trastuzumab ratio in- high doses, methotrexate has favorable CSF penetra- creased from 0.0023 prior to brain radiotherapy to 0.013 tion. A prospective, nonrandomized study comparing in- after completion of radiotherapy and was as high as 0.02 trathecal methotrexate (n=15) vs high-dose systemic with concomitant LM after radiotherapy, revealing that methotrexate (n=16) in patients with LM produced pro- CSF trastuzumab levels are low but can increase if BBB vocative results. High-dose methotrexate (8 g/m2 over 4 function is impaired.68 hours) resulted in a mean peak concentration of 17.1 Promising results from a pilot study using intrathe- µmol/L in the CSF; cytotoxic CSF methotrexate levels re- cal trastuzumab in patients with LM due to breast can- mained measurable much longer than with intrathecal cer, medulloblastoma, or glioblastoma were recently pre- dosing. Furthermore, there was higher CSF tumor cell sented.92 In this report, 16 patients with LM (11 clearance and survival was longer (13.8 months vs 2.3 glioblastoma multiforme, 4 breast cancer, 1 medullo- months, P=.003) in the systemic methotrexate-treated blastoma) were treated with intrathecal trastuzumab cohort.102 Because of the favorable pharmacokinetics of (20-60 mg per dose, either weekly or every other week) high-dose methotrexate, further studies in patients with for 4 treatments. Stable patients continued every-other- LM are warranted, possibly in combination with other week therapy until neurologic progression. Two pa- agents. tients with breast cancer, 7 with glioblastoma multi- forme, and the one with medulloblastoma responded . Capecitabine is a fluoropyrimidine car- without reported adverse events; the epidermal growth bamate designed as an oral alternative to 5-fluorouracil. factor receptor 2 protein status appeared to be predic- Capecitabine is enzymatically converted to 5-fluoroura- tive of response. Based on these results, further study of cil at the tumor site. The increased drug concentration intrathecal trastuzumab is warranted. at the tumor site may enhance its antitumor activity and reduce systemic toxicity. Although there is no formal phar- Systemic Treatments macokinetic data regarding capecitabine’s behavior in the CNS, there are empirical observations of responses to the Numerous reports suggest that systemic therapy im- drug in patients with BM and LM.103,104 Capecitabine has proves survival for patients with LM.72,93-100 Some au- also resulted in responses in a few patients with recur- thors feel systemic therapy is the most important part of rent BM or LM even after previous capecitabine expo- the treatment of LM73,74 and exclude intrathecal therapy sure.104,105 Based on the existing reports, capecitabine is in patients with responsive cancers.94,95,97,101 Agents ca- now frequently being used in patients with LM or BM pable of producing adequate CSF concentrations follow- secondary to breast cancer, and further prospective study ing systemic administration may benefit patients with LM. is under way.

Methotrexate. Methotrexate inhibits dihydrofolate re- Temozolomide. Temozolomide is an orally bioavailable ductase and the synthesis of purine nucleotides and thy- alkylator that reaches CSF levels roughly 20% of those midylate, interfering with DNA synthesis and repair. At in the serum.31 In a pilot study of oral temozolomide in

(REPRINTED) ARCH NEUROL / VOL 67 (NO. 3), MAR 2010 WWW.ARCHNEUROL.COM 308

©2010 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 10 patients with LM, the drug was well tolerated, al- reports of the clinical, CSF, and imaging outcomes were though no responses were seen. Two patients had stable promising; final results are forthcoming (D. Jackman, MD, disease through 2 courses (6 weeks receiving therapy, 4 written communication, June 22, 2009). weeks not receiving therapy) but progressed while not receiving treatment,106 suggesting that continuous treat- Combination and Disease-Specific Treatments ment might be more efficacious. Most reports of intrathecal LM treatments include pa- Hormonal Therapies tients who simultaneously receive systemic agents,5,6,97 and many investigators feel combination intrathecal and There are several case reports of a beneficial contribu- systemic therapy improves outcomes.72,97 Several planned tion of hormonal therapy for patients with LM with hor- studies will evaluate the concept of combination therapy, mone-sensitive tumors (breast and prostate cancer). Re- prospectively. Some clinical trials in development in- sponses are reported lasting more than 12 months. For clude a phase 2 study of intrathecal thiotepa for patients patients with LM from hormone-sensitive cancers, hor- with LM due to primary brain tumors, a phase 2 study monal treatment is reasonable to continue or initiate and of plus cisplatin plus vincristine sulfate and may provide some activity against the LM.98-100 intrathecal liposomal cytarabine for adults with medul- loblastoma and CSF positive for tumor cells, and a phase Experimental Treatment 1/2 study of oral capecitabine plus liposomal cytarabine in patients with breast cancer with LM (R. Soffietti, MD, Pemetrexed. Pemetrexed, a chemotherapeutic mol- written communication, June 27, 2009). ecule similar to methotrexate, is approved for mesothe- Because of a paucity of available patients, LM studies lioma and non–small cell lung cancer and is active in often accrue multiple primary histologies. This hetero- methotrexate-resistant malignancies. The CSF penetra- geneity obscures potential efficacy signals. Investiga- tion of pemetrexed was low in an animal model50; how- tors, with respect to rituximab, gefitinib, and bevaci- ever, the CSF pharmacokinetics of systemically admin- zumab, as noted earlier, are beginning to design LM trials istered pemetrexed are being evaluated in an ongoing with specific histologies in mind. study in patients with LM. The drug is unique from metho- trexate in that it is a “multitargeted” com- EARLY TREATMENT/PREVENTION pound acting through several enzyme systems involved OPPORTUNITIES in folate metabolism. Pemetrexed gains intracellular ac- cess via at least 4 mechanisms, which may increase its Prevention strategies similar to those used for children activity over methotrexate. Early results demonstrate with acute lymphoblastic leukemia113 or in patients with CSF responses in patients with breast cancer with LM aggressive lymphoma 114 may become feasible if genetic (J. Raizer, MD, written communication, June 22, 2009). markers identifying tumors with a propensity to invade the CNS can be identified. High positive predictive value Bevacizumab. Bevacizumab is a systemically adminis- plasma or CSF biomarkers could allow for earlier treat- tered monoclonal antibody directed against VEGF. Be- ment of LM, possibly affording better tumor control. Early vacizumab is approved for use in colorectal, breast, and studies suggest CSF VEGF may be useful as a biomark- non–small cell lung cancers and glioblastoma multi- er,107 but further research is warranted. Until preven- forme. Recent reports have identified elevated VEGF lev- tion is feasible, or biomarker use is validated, unique clini- els in the CSF of the majority of patients with LM due to cal scenarios may still hold opportunities for earlier melanoma or breast or lung cancer.107-109 Preliminary data treatment and better outcomes. suggest that in LM responders CSF VEGF levels fall and correlate with response.109 The degree to which bevaci- BRAIN METASTASES zumab penetrates the CSF is unknown but is likely lim- ited. Testing is under way at MD Anderson Cancer Cen- Patients with BM may be at increased risk of developing ter in patients with LM due to breast and lung cancer and LM, especially if the BM are located in the posterior fossa melanoma to determine if systemically administered be- (BMPF). Among patients undergoing craniotomy for vacizumab can affect CSF VEGF levels or impact tumor BMPF, estimates of the risk of developing LM are re- cells in the CSF. ported as high as 67%.115-117 Recent reports have begun to dissect out the details on the risk of CSF seeding after Gefitinib. Gefitinib is a small-molecule tyrosine kinase craniotomy. In a review of 379 patients with BMPF who inhibitor with activity against lung cancers that contain were treated with either surgical resection or stereotac- mutations of the epidermal growth factor receptor. Case tic radiation, 8.7% developed LM. But, there was a sig- reports have shown responses in patients with LM from nificantly higher risk of LM (14%; rate ratio, 2.45; P=.02) non–small cell lung cancer.110,111 A prospective study in those patients having a piecemeal resection of their evaluating high-dose gefitinib (up to 1250 mg/d) in pa- BMPF when compared with either stereotactic radia- tients with LM with non–small cell lung cancer and sen- tion or en bloc resection.118 A follow-up study of 827 pa- sitizing epidermal growth factor receptor mutations was tients undergoing craniotomy for supratentorial BM found recently closed. High doses of gefitinib were used (stan- a similar result, with a hazard ratio of 5.8 (P=.002) com- dard dose, 250 mg/d) attempting to increase CNS and paring piecemeal resection vs stereotactic radiation and CSF drug levels and improve anticancer effects.112 Early a hazard ratio of 2.7 (P=.009) comparing piecemeal re-

(REPRINTED) ARCH NEUROL / VOL 67 (NO. 3), MAR 2010 WWW.ARCHNEUROL.COM 309

©2010 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 section vs en bloc resection.119 Patients with BM who un- mediated disruption of tight junction proteins in cerebral vessels is reversed dergo piecemeal tumor resection may be a good popu- by synthetic matrix metalloproteinase inhibitor in focal ischemia in rat. J Cereb Blood Flow Metab. 2007;27(4):697-709. lation in which to test biomarker-based or prophylactic 14. Shintani Y, Higashiyama S, Ohta M, et al. Overexpression of ADAM9 in non- interventions against LM. small cell lung cancer correlates with brain metastasis. Cancer Res. 2004; 64(12):4190-4196. CONCLUSIONS 15. Schackert G, Fidler IJ. Site-specific metastasis of mouse melanomas and a fi- brosarcoma in the brain or meninges of syngeneic animals. Cancer Res. 1988; 48(12):3478-3484. Leptomeningeal metastases remain a neurologically dev- 16. Palmieri D, Smith QR, Lockman PR, et al. Brain metastases of breast cancer. astating and fatal late complication of cancer. The mo- Breast Dis. 2006-2007;26:139-147. lecular biology underpinning the development of LM is 17. Levin VA, Patlak CS, Landahl HD. Heuristic modeling of drug delivery to ma- slowly being unraveled. To be effective, new treatments lignant brain tumors. J Pharmacokinet Biopharm. 1980;8(3):257-296. 18. Levin VA. Relationship of octanol/water partition coefficient and molecular weight for LM need to reach the meninges and CSF and inter- to rat brain capillary permeability. J Med Chem. 1980;23(6):682-684. act with relevant molecular targets. Since only about one- 19. Ghersi-Egea JF, Strazielle N. Brain drug delivery, drug metabolism, and multidrug third of patients with LM die solely of LM, therapies that resistance at the choroid plexus. Microsc Res Tech. 2001;52(1):83-88. effectively address the systemic cancer and the LM are 20. Taylor EM. The impact of efflux transporters in the brain on the development of necessary for major improvements in survival. Progress drugs for CNS disorders. Clin Pharmacokinet. 2002;41(2):81-92. 21. Deguchi Y, Yokoyama Y, Sakamoto T, et al. Brain distribution of 6-mercapto- is slowly being made with the testing of newer targeted purine is regulated by the efflux transport system in the blood-brain barrier. agents and combination treatments, but obviously, there Life Sci. 2000;66(7):649-662. is much work to be done to improve outcomes for pa- 22. Potschka H, Fedrowitz M, Loscher W. Multidrug resistance protein MRP2 con- tients with LM. tributes to blood-brain barrier function and restricts antiepileptic drug activity. J Pharmacol Exp Ther. 2003;306(1):124-131. 23. Rao VV, Dahlheimer JL, Bardgett ME, et al. Choroid plexus epithelial expres- Accepted for Publication: July 19, 2009. sion of MDR1 P glycoprotein and multidrug resistance-associated protein con- tribute to the blood-cerebrospinal-fluid drug-permeability barrier. Proc Natl Acad Correspondence: Morris D. Groves, MD, UT MD Ander- Sci U S A. 1999;96(7):3900-3905. son Cancer Center, Department of Neuro-Oncology, 1400 24. Wijnholds J, deLange EC, Scheffer GL, et al. Multidrug resistance protein 1 pro- Holcombe Blvd, Unit 431, Houston, TX 77030 (mgroves tects the choroid plexus epithelium and contributes to the blood-cerebrospinal @mdanderson.org). fluid barrier. J Clin Invest. 2000;105(3):279-285. Financial Disclosure: Dr Groves received research fund- 25. Deeken JF, Loscher W. The blood-brain barrier and cancer: transporters, treat- ment, and Trojan horses. Clin Cancer Res. 2007;13(6):1663-1674. ing from Genentech, Enzon Pharmaceuticals, and 26. Strazielle N, Khuth ST, Ghersi-Egea JF. Detoxification systems, passive and spe- Schering-Plough Research Institute and has been on the cific transport for drugs at the blood-CSF barrier in normal and pathological speakers’ bureau or received honoraria from Enzon Phar- situations. Adv Drug Deliv Rev. 2004;56(12):1717-1740. maceuticals and Schering-Plough Research Institute. 27. Chen J, Balmaceda C, Bruce JN, et al. Tamoxifen paradoxically decreases pa- clitaxel deposition into cerebrospinal fluid of brain tumor patients. J Neurooncol. 2006;76(1):85-92. REFERENCES 28. Zhuang Y, Fraga CH, Hubbard KE, et al. Topotecan central nervous system pen- etration is altered by a tyrosine kinase inhibitor. Cancer Res. 2006;66(23): 1. Posner JB. Neurologic Complications of Cancer. Philadelphia, PA: F. A. Davis 11305-11313. Co; 1995. 29. Heideman RL, Cole DE, Balis F, et al. Phase I and pharmacokinetic evaluation 2. Jaeckle KA. Neoplastic meningitis from systemic malignancies: diagnosis, prog- of thiotepa in the cerebrospinal fluid and plasma of pediatric patients: evidence nosis and treatment. Semin Oncol. 2006;33(3):312-323. for dose-dependent plasma clearance of thiotepa. Cancer Res. 1989;49(3): 3. Gleissner B, Chamberlain MC. Neoplastic meningitis. Lancet Neurol. 2006;5(5): 736-741. 443-452. 30. Vassal G, Gouyette A, Hartmann O, Pico JL, Lemerle J. Pharmacokinetics of 4. Jaeckle KA, Phuphanich S, Bent MJ, et al. Intrathecal treatment of neoplastic high-dose busulfan in children. Cancer Chemother Pharmacol. 1989;24(6): meningitis due to breast cancer with a slow-release formulation of cytarabine. 386-390. Br J Cancer. 2001;84(2):157-163. 31. Ostermann S, Csajka C, Buclin T, et al. Plasma and cerebrospinal fluid popu- 5. Chamberlain MC, Kormanik P. Carcinoma meningitis secondary to non-small cell lation pharmacokinetics of temozolomide in malignant glioma patients. Clin Can- lung cancer: combined modality therapy. Arch Neurol. 1998;55(4):506-512. cer Res. 2004;10(11):3728-3736. 6. Chamberlain MC, Kormanik PR. Carcinomatous meningitis secondary to breast 32. Patel M, McCully C, Godwin K, Balis FM. Plasma and cerebrospinal fluid phar- cancer: predictors of response to combined modality therapy. J Neurooncol. macokinetics of intravenous temozolomide in non-human primates. J Neurooncol. 1997;35(1):55-64. 2003;61(3):203-207. 7. Nguyen DX, Bos PD, Massague J. Metastasis: from dissemination to organ- 33. Berg SL, Gerson SL, Godwin K, Cole DE, Liu L, Balis FM. Plasma and cerebro- specific colonization. Nat Rev Cancer. 2009;9(4):274-284. spinal fluid pharmacokinetics of O6-benzylguanine and time course of periph- 8. Fidler IJ, Yano S, Zhang RD, Fujimaki T, Bucana CD. The seed and soil hypoth- eral blood mononuclear cell O6-methylguanine-DNA methyltransferase inhibi- esis: vascularisation and brain metastases. Lancet Oncol. 2002;3(1):53- tion in the nonhuman primate. Cancer Res. 1995;55(20):4606-4610. 57. 34. Grygiel JJ, Balis FM, Collins JM, Lester CM, Poplack DG. Pharmacokinetics of 9. Groves MD. The pathogenesis of neoplastic meningitis. Curr Oncol Rep. 2003; tiazofurin in the plasma and cerebrospinal fluid of rhesus monkeys. Cancer Res. 5(1):15-23. 1985;45(5):2037-2039. 10. Lorger M, Krueger JS, O’Neal M, Staflin K, Felding-Habermann B. Activation of 35. Zimm S, Ettinger LJ, Holcenberg JS, et al. Phase I and clinical pharmacological tumor cell integrin {alpha}v{beta}3 controls angiogenesis and metastatic growth study of mercaptopurine administered as a prolonged intravenous infusion. Can- in the brain. Proc Natl Acad Sci U S A. 2009;106(26):10666-10671. cer Res. 1985;45(4):1869-1873. 11. Lee TH, Avraham HK, Jiang S, Avraham S. Vascular endothelial growth factor 36. Kerr IG, Zimm S, Collins JM, O’Neill D, Poplack DG. Effect of intravenous dose modulates the transendothelial migration of MDA-MB-231 breast cancer cells and schedule on cerebrospinal fluid pharmacokinetics of 5-fluorouracil in the through regulation of brain microvascular endothelial cell permeability. J Biol monkey. Cancer Res. 1984;44(11):4929-4932. Chem. 2003;278(7):5277-5284. 37. Heideman RL, Balis FM, McCully C, Poplack DG. Preclinical pharmacology of 12. Lee BC, Lee TH, Avraham S, Avraham HK. Involvement of the chemokine re- arabinosyl-5-azacytidine in nonhuman primates. Cancer Res. 1988;48(15): ceptor CXCR4 and its ligand stromal cell-derived factor 1alpha in breast can- 4294-4298. cer cell migration through human brain microvascular endothelial cells. Mol 38. Balis FM, Poplack DG. Central nervous system pharmacology of antileukemic Cancer Res. 2004;2(6):327-338. drugs. Am J Pediatr Hematol Oncol. 1989;11(1):74-86. 13. Yang Y, Estrada EY, Thompson JF, Liu W, Rosenberg GA. Matrix metalloproteinase- 39. Slevin ML, Piall EM, Aherne GW, Harvey VJ, Johnston A, Lister TA. Effect of

(REPRINTED) ARCH NEUROL / VOL 67 (NO. 3), MAR 2010 WWW.ARCHNEUROL.COM 310

©2010 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 dose and schedule on pharmacokinetics of high-dose cytosine arabinoside in 63. Beckloff GL, Lerner HJ, Frost D, Russo-Alesi FM, Gitomer S. Hydroxyurea (NSC- plasma and cerebrospinal fluid. J Clin Oncol. 1983;1(9):546-551. 32065) in biologic fluids: dose-concentration relationship. Cancer Chemother 40. Kerr JZ, Berg SL, Dauser R, et al. Plasma and cerebrospinal fluid pharmacoki- Rep. 1965;48:57-58. netics of gemcitabine after intravenous administration in nonhuman primates. 64. Muscal JA, Thompson PA, Giranda VL, et al. Plasma and cerebrospinal fluid Cancer Chemother Pharmacol. 2001;47(5):411-414. pharmacokinetics of ABT-888 after oral administration in non-human primates. 41. Berg SL, Bonate PL, Nuchtern JG, et al. Plasma and cerebrospinal fluid phar- Cancer Chemother Pharmacol. 2010;65(3):419-425. macokinetics of clofarabine in nonhuman primates. Clin Cancer Res. 2005; 65. Kilburn LB, Bonate PL, Blaney SM, et al. Plasma and cerebrospinal fluid phar- 11(16):5981-5983. macokinetics of tasidotin (ILX-651) and its metabolites in non-human primates. 42. Kellie SJ, Barbaric D, Koopmans P, Earl J, Carr DJ, de Graaf SS. Cerebrospinal Cancer Chemother Pharmacol. 2009;64(2):335-340. fluid concentrations of vincristine after bolus intravenous dosing: a surrogate 66. Yule SM, Price L, Pearson AD, Boddy AV. Cyclophosphamide and ifosfamide marker of brain penetration. Cancer. 2002;94(6):1815-1820. metabolites in the cerebrospinal fluid of children. Clin Cancer Res. 1997; 43. Heideman RL, Kelley JA, Packer RJ, et al. A pediatric phase I and pharmacoki- 3(11):1985-1992. netic study of spirohydantoin mustard. Cancer Res. 1988;48(8):2292-2295. 67. Levin VA, Groves MD, Forman AD. Intraventricular and intrathecal therapy. In: 44. DeGregorio MW, King OY, Holleran WM, et al. Ultrafiltrate and total platinum in Perry MC, ed. The Chemotherapy Sourcebook. 4th ed. Philadelphia, PA: Lip- plasma and cerebrospinal fluid in a patient with neuroblastoma. Cancer Treat pincott Williams and Wilkins; 2008:65-74. Rep. 1985;69(12):1441-1442. 68. Stemmler HJ, Schmitt M, Willems A, Bernhard H, Harbeck N, Heinemann V. 45. Jacobs SS, Fox E, Dennie C, Morgan LB, McCully CL, Balis FM. Plasma and Ratio of trastuzumab levels in serum and cerebrospinal fluid is altered in HER2- cerebrospinal fluid pharmacokinetics of intravenous oxaliplatin, cisplatin, and positive breast cancer patients with brain metastases and impairment of blood- carboplatin in nonhuman primates. Clin Cancer Res. 2005;11(4):1669-1674. brain barrier. Anticancer Drugs. 2007;18(1):23-28. 46. Hande KR, Wedlund PJ, Noone RM, Wilkinson GR, Greco FA, Wolff SN. Phar- 69. Rogers LR, Chamberlain M, Glantz M. Evidence-based review of intrathecal che- macokinetics of high-dose etoposide (VP-16-213) administered to cancer patients. motherapy in outcome of patients with leptomeningeal metastasis [abstract]. J Clin Cancer Res. 1984;44(1):379-382. Oncol 2006 ASCO Annual Meeting Proceedings. 2006;24(18S)(suppl):1529. 47. Relling MV, Mahmoud HH, Pui CH, et al. Etoposide achieves potentially cyto- 70. Glantz MJ, LaFollette S, Jaeckle KA, et al. Randomized trial of a slow-release toxic concentrations in CSF of children with acute lymphoblastic leukemia. J Clin versus a standard formulation of cytarabine for the intrathecal treatment of lym- Oncol. 1996;14(2):399-404. phomatous meningitis. J Clin Oncol. 1999;17(10):3110-3116. 48. Thyss A, Milano G, Deville A, Manassero J, Renee N, Schneider M. Effect of 71. Glantz MJ, Jaeckle KA, Chamberlain MC, et al. A randomized controlled trial dose and repeat intravenous 24 hr infusions of methotrexate on cerebrospinal comparing intrathecal sustained-release cytarabine (DepoCyt) to intrathecal fluid availability in children with hematological malignancies. Eur J Cancer Clin methotrexate in patients with neoplastic meningitis from solid tumors. Clin Can- Oncol. 1987;23(6):843-847. cer Res. 1999;5(11):3394-3402. 49. Balis FM, Blaney SM, McCully CL, Bacher JD, Murphy RF, Poplack DG. Metho- 72. Rudnicka H, Niwinska A, Murawska M. Breast cancer leptomeningeal metastasis— trexate distribution within the subarachnoid space after intraventricular and in- the role of multimodality treatment. J Neurooncol. 2007;84(1):57-62. travenous administration. Cancer Chemother Pharmacol. 2000;45(3):259- 73. Boogerd W, van den Bent MJ, Koehler PJ, et al. The relevance of intraventricu- 264. lar chemotherapy for leptomeningeal metastasis in breast cancer: a ran- 50. Stapleton SL, Reid JM, Thompson PA, et al. Plasma and cerebrospinal fluid phar- domised study. Eur J Cancer. 2004;40(18):2726-2733. macokinetics of pemetrexed after intravenous administration in non-human 74. Siegal T. Leptomeningeal metastases: rationale for systemic chemotherapy or what primates. Cancer Chemother Pharmacol. 2007;59(4):461-466. is the role of intra-CSF-chemotherapy? J Neurooncol. 1998;38(2-3):151-157. 51. Habif DV, Lipton R, Cantell K. Interferon crosses blood-cerebrospinal fluid bar- 75. Fleischhack G, Jaehde U, Bode U. Pharmacokinetics following intraventricular rier in monkeys. Proc Soc Exp Biol Med. 1975;149(1):287-289. administration of chemotherapy in patients with neoplastic meningitis. Clin 52. Pestalozzi BC, Brignoli S. Trastuzumab in CSF. J Clin Oncol. 2000;18(11):2349- Pharmacokinet. 2005;44(1):1-31. 2351. 76. Glantz MJ, Chamberlain MC, Batchelor T, Wong E, Cavalli F, Shapiro WR. 53. Stemmler J, Schmitt M, Willems A, Bernhard H, Harbeck N, Heinemann V. Brain Interaction between route of intra-CSF chemotherapy administration and effi- metastases in HER2-overexpressing metastatic breast cancer: comparative analy- cacy of therapy in patients with neoplastic meningitis [abstract]. J Clin Oncol sis of trastuzumab levels in serum and cerebrospinal fluid [abstract]. J Clin On- 2006 ASCO Annual Meeting Proceedings. 2006;24(18S)(suppl):1530. col 2006 ASCO Annual Meeting Proceedings. 2006;24(18S)(suppl):1525. 77. Chamberlain MC, Tsao-Wei DD, Groshen S. Phase II trial of intracerebrospinal 54. Berg SL, Reid J, Godwin K, et al. Pharmacokinetics and cerebrospinal fluid pen- fluid etoposide in the treatment of neoplastic meningitis. Cancer. 2006;106 etration of daunorubicin, idarubicin, and their metabolites in the nonhuman pri- (9):2021-2027. mate model. J Pediatr Hematol Oncol. 1999;21(1):26-30. 78. Groves MD, Glantz MJ, Chamberlain MC, et al. A multicenter phase II trial of 55. Baker SD, Heideman RL, Crom WR, Kuttesch JF, Gajjar A, Stewart CF. Cere- intrathecal topotecan in patients with meningeal malignancies. Neuro Oncol. brospinal fluid pharmacokinetics and penetration of continuous infusion topo- 2008;10(2):208-215. tecan in children with central nervous system tumors. Cancer Chemother 79. Blaney SM, Balis FM, Berg S, et al. Intrathecal mafosfamide: a preclinical phar- Pharmacol. 1996;37(3):195-202. macology and phase I trial. J Clin Oncol. 2005;23(7):1555-1563. 56. Blaney SM, Takimoto C, Murry DJ, et al. Plasma and cerebrospinal fluid phar- 80. Blaney SM, Boyett J, Friedman H, et al. Phase I clinical trial of mafosfamide in macokinetics of 9-aminocamptothecin (9-AC), irinotecan (CPT-11), and SN-38 infants and children aged 3 years or younger with newly diagnosed embryonal in nonhuman primates. Cancer Chemother Pharmacol. 1998;41(6):464- tumors: a pediatric brain tumor consortium study (PBTC-001). J Clin Oncol. 468. 2005;23(3):525-531. 57. Rubenstein JL, Combs D, Rosenberg J, et al. Rituximab therapy for CNS lym- 81. Gururangan S, Petros WP, Poussaint TY, et al. Phase I trial of intrathecal spar- phomas: targeting the leptomeningeal compartment. Blood. 2003;101(2): taject busulfan in children with neoplastic meningitis: a Pediatric Brain Tumor 466-468. Consortium Study (PBTC-004). Clin Cancer Res. 2006;12(5):1540-1546. 58. Rubenstein JL, Rosenberg J, Damon L. High-dose methotrexate plus ritux- 82. Quinn JA, Glantz M, Petros W, et al. Intrathecal spartaject busulfan phase I trial imab (anti-CD20) monoclonal antibody in the treatment of primary CNS for patients with neoplastic meningitis [abstract]. Neuro-oncol. 2001;3(4):364. lymphoma. Paper presented at: Society for Neuro-Oncology Fourth Annual Meet- 83. Nakagawa H, Miyahara E, Suzuki T, Wada K, Tamura M, Fukushima Y. Con- ing; November 19, 1999; Scottsdale, AZ. tinuous intrathecal administration of 5-fluoro-2’-deoxyuridine for the treat- 59. Meany HJ, Fox E, McCully C, Tucker C, Balis FM. The plasma and cerebrospi- ment of neoplastic meningitis. Neurosurgery. 2005;57(2):266-280. nal fluid pharmacokinetics of erlotinib and its active metabolite (OSI-420) after 84. Wong FC, Groves M, Papadopoulos N, et al. Toxicity and efficacy profiles of intravenous administration of erlotinib in non-human primates. Cancer Che- intrathecal injection of I-131 NaI via intraventricular (IVent) or intralumbar (Ilumb) mother Pharmacol. 2008;62(3):387-392. route for leptomeningeal metastases (LM) therapy [abstract]. J Clin Oncol 2006 60. Neville K, Parise RA, Thompson P, et al. Plasma and cerebrospinal fluid phar- ASCO Annual Meeting Proceedings. 2006;24(18S)(suppl):1549. macokinetics of imatinib after administration to nonhuman primates. Clin Can- 85. Kramer K, Humm JL, Souweidane MM, et al. Phase I study of targeted radio- cer Res. 2004;10(7):2525-2529. immunotherapy for leptomeningeal cancers using intra-Ommaya 131-I-3F8. 61. Berg SL, Stone J, Xiao JJ, et al. Plasma and cerebrospinal fluid pharmacoki- J Clin Oncol. 2007;25(34):5465-5470. netics of depsipeptide (FR901228) in nonhuman primates. Cancer Chemother 86. Groves MD. Leptomeningeal Metastases: Still a Challenge. Alexandria, VA: Ameri- Pharmacol. 2004;54(1):85-88. can Society of Clinical Oncology; 2008:80-87. 62. Stapleton SL, Thompson PA, Ou CN, et al. Plasma and cerebrospinal fluid phar- 87. Blaney SM, Heideman R, Berg S, et al. Phase I clinical trial of intrathecal topo- macokinetics of valproic acid after oral administration in non-human primates. tecan in patients with neoplastic meningitis. J Clin Oncol. 2003;21(1):143- Cancer Chemother Pharmacol. 2008;61(4):647-652. 147.

(REPRINTED) ARCH NEUROL / VOL 67 (NO. 3), MAR 2010 WWW.ARCHNEUROL.COM 311

©2010 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 88. Herrlinger U, Weller M, Schabet M. New aspects of immunotherapy of lepto- meningeal metastases from breast cancer treated with capecitabine mono- meningeal metastasis. J Neurooncol. 1998;38(2-3):233-239. therapy: a case report. Clin Breast Cancer. 2006;7(2):164-166. 89. Chamberlain MC. A phase II trial of intra-cerebrospinal fluid alpha interferon in 106. Davis TH, Fadul CE, Glantz MJ, et al. Pilot phase II trial of temozolomide for the treatment of neoplastic meningitis. Cancer. 2002;94(10):2675-2680. leptomeningeal metastases: preliminary report [abstract]. J Clin Oncol 2003 ASCO 90. Rubenstein JL, Fridlyand J, Abrey L, et al. Phase I study of intraventricular ad- Annual Meeting Proceedings. 2003;22(115a)(suppl):460. ministration of rituximab in patients with recurrent CNS and intraocular lymphoma. 107. Groves MD, Hess KR, Puduvalli VK, et al. Biomarkers of disease: cerebrospinal J Clin Oncol. 2007;25(11):1350-1356. fluid vascular endothelial growth factor (VEGF) and stromal cell derived factor 91. Chamberlain MC, Glantz MJ. Intra-CSF rituximab for lymhomatous meningitis. (SDF)-1 levels in patients with neoplastic meningitis (NM) due to breast can- J Clin Oncol. 2007;25(28):4508-4509. cer, lung cancer and melanoma. J Neurooncol. 2009;94(2):229-234. 92. Allison DL, Glantz M, Werner TL, Kirkegaard SL, Murdock K, Jensen RL. Intra- 108. Stockhammer G, Poewe WF, Burgstaller SF, et al. Vascular endothelial growth CSF trastuzumab in patients with neoplastic meningitis from breast cancer or factor in CSF: a biological marker for carcinomatous meningitis. Neurology. 2000; primary brain tumors [abstract]. J Clin Oncol 2009 ASCO Annual Meeting 54(8):1670-1676. Proceedings. 2009;27(15S)(suppl):2006. 109. Herrlinger U, Wiendl H, Renninger M, Forschler H, Dichgans J, Weller M. 93. Herrlinger U, Forschler H, Kuker W, et al. Leptomeningeal metastasis: survival Vascular endothelial growth factor (VEGF) in leptomeningeal metastasis: diag- and prognostic factors in 155 patients. J Neurol Sci. 2004;223(2):167-178. nostic and prognostic value. Br J Cancer. 2004;91(2):219-224. 94. Siegal T, Lossos A, Pfeffer MR. Leptomeningeal metastases: analysis of 31 pa- 110. Choong NW, Dietrich S, Seiwert TY, et al. Gefitinib response of erlotinib- tients with sustained off-therapy response following combined-modality therapy. refractory lung cancer involving meninges—role of EGFR mutation. Nat Clin Neurology. 1994;44(8):1463-1469. Pract Oncol. 2006;3(1):50-57. 95. Grant R, Naylor B, Greenberg HS, Junck L. Clinical outcome in aggressively treated 111. Kanaji N, Bandoh S, Nagamura N, Kushida Y, Haba R, Ishida T. Significance of meningeal carcinomatosis. Arch Neurol. 1994;51(5):457-461. an epidermal growth factor receptor mutation in cerebrospinal fluid for carci- 96. de Wit M, Lange-Brock V, Kruell A, Bokemeter C. Leptomeningeal metastases: nomatous meningitis. Intern Med. 2007;46(19):1651-1655. results of different therapeutic approaches [abstract]. J Clin Oncol 2007 ASCO 112. High dose gefitinib for the treatment of carcinomatous meningitis in adult pa- Annual Meeting Proceedings. 2007;25(18S)(suppl):2047. tients with non-small cell lung cancer and known or suspected EGFR mutations. 97. Fizazi K, Asselain B, Vincent-Salomon A, et al. Meningeal carcinomatosis in pa- Clinicaltrials.gov Web site. http://clinicaltrials.gov/ct2/show/NCT00372515. Ac- tients with breast carcinoma: clinical features, prognostic factors, and results cessed July 1, 2009. of a high-dose intrathecal methotrexate regimen. Cancer. 1996;77(7):1315- 113. Hill FG, Richards S, Gibson B, et al; UK Medical Research Council Working Party 1323. on Childhood Leukaemia. Successful treatment without cranial radiotherapy of 98. Mencel PJ, DeAngelis LM, Motzer RJ. Hormonal ablation as effective therapy children receiving intensified chemotherapy for acute lymphoblastic leukaemia: for carcinomatous meningitis from prostatic carcinoma. Cancer. 1994;73 results of the risk-stratified randomized central nervous system treatment trial (7):1892-1894. MRC UKALL XI (ISRC TN 16757172). Br J Haematol. 2004;124(1):33-46. 99. Boogerd W, Dorresteijn LD, van Der Sande JJ, de Gast GC, Bruning PF. Re- 114. Hill QA, Owen RG. CNS prophylaxis in lymphoma: who to target and what therapy sponse of leptomeningeal metastases from breast cancer to hormonal therapy. to use. Blood Rev. 2006;20(6):319-332. Neurology. 2000;55(1):117-119. 115. Norris LKF, Grossman SAF, Olivi A. Neoplastic meningitis following surgical 100. Ozdogan M, Samur M, Bozcuk HS, et al. Durable remission of leptomeningeal resection of isolated cerebellar metastasis: a potentially preventable complication. metastasis of breast cancer with letrozole: a case report and implications of J Neurooncol. 1997;32(3):215-223. biomarkers on treatment selection. Jpn J Clin Oncol. 2003;33(5):229-231. 116. Siomin VE, Vogelbaum MA, Kanner AA, Lee SY, Suh JH, Barnett GH. Posterior 101. Boogerd W, Hart AA, van der Sande JJ, Engelsman E. Meningeal carcinoma- fossa metastases: risk of leptomeningeal disease when treated with stereotactic tosis in breast cancer: prognostic factors and influence of treatment. Cancer. radiosurgery compared to surgery. J Neurooncol. 2004;67(1-2):115-121. 1991;67(6):1685-1695. 117. van der Ree TC, Dippel DW, Avezaat CJ, Sillevis Smitt PA, Vecht CJ, van den 102. Glantz MJ, Cole BF, Recht L, et al. High-dose intravenous methotrexate for pa- Bent MJ. Leptomeningeal metastasis after surgical resection of brain metastases. tients with nonleukemic leptomeningeal cancer: is intrathecal chemotherapy J Neurol Neurosurg Psychiatry. 1999;66(2):225-227. necessary? J Clin Oncol. 1998;16(4):1561-1567. 118. Suki D, Abouassi H, Patel AJ, Sawaya R, Weinberg JS, Groves MD. Compara- 103. Giglio P, Tremont-Lukats IW, Groves MD. Response of neoplastic meningitis tive risk of leptomeningeal disease after resection or stereotactic radiosurgery from solid tumors to oral capecitabine. J Neurooncol. 2003;65(2):167-172. for solid tumor metastasis to the posterior fossa. J Neurosurg. 2008;108 104. Ekenel M, Hormigo AM, Peak S, DeAngelis LM, Abrey LE. Capecitabine therapy (2):248-257. of central nervous system metastases from breast cancer. J Neurooncol. 2007; 119. Suki D, Hatiboglu MA, Patel AJ, et al. Comparative risk of leptomeningeal dis- 85(2):223-227. semination of cancer after surgery or stereotactic radiosurgery for a single su- 105. Tham YL, Hinckley L, Teh BS, Elledge R. Long-term clinical response in lepto- pratentorial solid tumor metastasis. Neurosurgery. 2009;64(4):664-674.

Announcement

Sign Up for Alerts—It’s Free! Archives of Neurology of- fers the ability to automatically receive the table of con- tents of Archives when it is published online. This also allows you to link to individual articles and view the ab- stract. It makes keeping up-to-date even easier! Go to http://pubs.ama-assn.org/misc/alerts.dtl to sign up for this free service.

(REPRINTED) ARCH NEUROL / VOL 67 (NO. 3), MAR 2010 WWW.ARCHNEUROL.COM 312

©2010 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021