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Anticancer Therapies And CNS Relapse: Overcoming Blood–brain And Blood–cerebrospinal Fluid Barrier Impermeability

M. Chamberlain
Published 2010 · Medicine

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Prolonged survival with targeted therapies has sometimes come at the expense of an increased risk of CNS relapse; because many of these agents poorly penetrate the BBB, malignant cells may remain viable within the CNS. The ability of anticancer drugs to penetrate the BBB is a major consideration in the treatment of CNS parenchymal metastases. Optimal chemotherapy approaches for treating CNS metastases remain unclear due to a lack of evidence-based recommendations. Recent hypothesis-generating studies evaluating intra-cerebrospinal fluid administration of targeted agents indicate that these drugs may be effective in treating leptomeningeal disease and are associated with a low incidence of drug-related adverse events. Newer strategies for treating cerebrospinal fluid metastases may co-opt endogenous systems of the BBB, such as those involved in receptor-mediated transcytosis or classic carrier-mediated transporter systems to facilitate drug delivery across the BBB.
This paper references
CNS events in elderly patients with aggressive lymphoma treated with modern chemotherapy (CHOP-14) with or without rituximab: an analysis of patients treated in the RICOVER-60 trial of the German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL).
V. Boehme (2009)
Brain metastases in HER2-overexpressing metastatic breast cancer: Comparative analysis of trastuzumab levels in serum and cerebrospinal fluid.
J. Stemmler (2006)
The Blood-Brain Barrier and Cancer: Transporters, Treatment, and Trojan Horses
J. Deeken (2007)
Trastuzumab treatment improves brain metastasis outcomes through control and durable prolongation of systemic extracranial disease in HER2-overexpressing breast cancer patients
Y. Park (2009)
Rituximab maintenance improves clinical outcome of relapsed/resistant follicular non-Hodgkin lymphoma in patients both with and without rituximab during induction: results of a prospective randomized phase 3 intergroup trial.
M. V. van Oers (2006)
Management strategies for recurrent non-small cell lung cancer.
F. Fossella (1997)
Stage-specific outcomes of patients with uterine leiomyosarcoma: a comparison of the international Federation of gynecology and obstetrics and american joint committee on cancer staging systems.
O. Zivanovic (2009)
Treatment of Single Brain Metastasis with Resection, Intracavity Carmustine Polymer Wafers, and Radiation Therapy Is Safe and Provides Excellent Local Control
M. Ewend (2007)
Incidence proportions of brain metastases in patients diagnosed (1973 to 2001) in the Metropolitan Detroit Cancer Surveillance System.
J. Barnholtz-Sloan (2004)
Intra-CSF trastuzumab in patients with neoplastic meningitis from breast cancer or primary brain tumors.
D. Allison (2009)
Convection-enhanced delivery for treatment of brain tumors
S. Ferguson (2007)
Cytarabine injection, package insert
High-dose methotrexate with folinic acid in the treatment of advanced non-Hodgkin lymphoma including CNS involvement.
A. Skarin (1977)
Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: results from a randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer)
N. Thatcher (2005)
Recurrent lymphomatous meningitis treated with intra-CSF rituximab and liposomal ara-C
M. Chamberlain (2008)
Intrathecal trastuzumab and thiotepa for leptomeningeal spread of breast cancer.
C. Ferrario (2009)
A pilot study: 131I-antitenascin monoclonal antibody 81c6 to deliver a 44-Gy resection cavity boost.
D. Reardon (2008)
Evidence-based review of intrathecal chemotherapy in outcome of patients with leptomeningeal metastasis.
L. Rogers (2006)
A Phase II trial of intra‐cerebrospinal fluid alpha interferon in the treatment of neoplastic meningitis
M. Chamberlain (2002)
Incidence of brain metastases in a cohort of patients with carcinoma of the breast, colon, kidney, and lung and melanoma
L. Schouten (2002)
Metastatic pattern of malignant melanoma
JK Patel (1978)
High incidence of occult leptomeningeal disease detected by flow cytometry in newly diagnosed aggressive B-cell lymphomas at risk for central nervous system involvement: the role of flow cytometry versus cytology.
U. Hegde (2005)
Effectiveness of intrathecal rituximab in patients with acute lymphoblastic leukaemia relapsed to the CNS and resistant to conventional therapy
J. Jaime-Pérez (2009)
Thiotepa injection, package insert
A multicenter phase II trial of intrathecal topotecan in patients with meningeal malignancies.
M. Groves (2008)
A phase III trial of topotecan and whole brain radiation therapy for patients with CNS-metastases due to lung cancer
T. Neuhaus (2009)
Identification of leptomeningeal disease in aggressive B-cell non-Hodgkin's lymphoma: improved sensitivity of flow cytometry.
S. Quijano (2009)
The Role of Efflux and Uptake Transporters in N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methylsulfonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine (GW572016, Lapatinib) Disposition and Drug Interactions
J. Polli (2008)
High incidence of disease recurrence in the brain and leptomeninges in patients with nonsmall cell lung carcinoma after response to gefitinib
A. Omuro (2005)
Temozolomide and concomitant whole brain radiotherapy in patients with brain metastases: a phase II randomized trial.
E. Verger (2005)
A randomized controlled trial comparing intrathecal sustained-release cytarabine (DepoCyt) to intrathecal methotrexate in patients with neoplastic meningitis from solid tumors.
M. Glantz (1999)
Poster P01.086)
SH Bernstein (2009)
Phase II trial of intracerebrospinal fluid etoposide in the treatment of neoplastic meningitis
M. Chamberlain (2006)
An Open Label Trial of Sustained-release Cytarabine (DepoCyt™) for the Intrathecal Treatment of Solid Tumor Neoplastic Meningitis
K. Jaeckle (2004)
Efficacy and safety of liposomal cytarabine in lymphoma patients with central nervous system involvement from lymphoma
J. García‐Marco (2009)
Compartment-specific roles of ATP-binding cassette transporters define differential topotecan distribution in brain parenchyma and cerebrospinal fluid.
J. Shen (2009)
Ratio of trastuzumab levels in serum and cerebrospinal fluid is altered in HER2-positive breast cancer patients with brain metastases and impairment of blood–brain barrier
H. Stemmler (2007)
Ventricular organisation of cerebrospinal fluid: blood-brain barrier, brain edema, and hydrocephalus
J Laterra (2000)
First-line single agent treatment with gefitinib in patients with advanced non-small-cell lung cancer: a phase II study.
S. Niho (2006)
Avid (2001)
Brain metastases in HER 2 - overexpressing metastatic breast cancer : comparative analysis of trastuzumab levels in serum and cerebrospinal fluid [ abstract 1525 ]
J Stemmler (2006)
Survival and neurologic outcomes in a randomized trial of motexafin gadolinium and whole-brain radiation therapy in brain metastases.
M. Mehta (2003)
High-dose intravenous methotrexate for patients with nonleukemic leptomeningeal cancer: is intrathecal chemotherapy necessary?
M. Glantz (1998)
Prognostic Significance of Human Epidermal Growth Factor Receptor Positivity for the Development of Brain Metastasis After Newly Diagnosed Breast Cancer
M. Melisko (2007)
Ultrafiltrate and total platinum in plasma and cerebrospinal fluid in a patient with neuroblastoma.
M. Degregorio (1985)
Neoplastic meningitis.
A. Shaw (2011)
Methotrexate: distribution in cerebrospinal fluid after intravenous, ventricular and lumbar injections.
W. Shapiro (1975)
Targeted delivery of antitumoral therapy to glioma and other malignancies with synthetic chlorotoxin (TM-601)
A. Mamelak (2007)
• First use of intra-cerebrospinal fluid trastuzumab in humans
Convection-enhanced delivery: neurosurgical issues.
W. Hall (2009)
Prognostic significance of human epidermal growth factor receptor positivity for the development of brain metastasis after newly diagnosed breast cancer.
Z. Gabos (2006)
Patterns of relapse of N2 nonsmall‐cell lung carcinoma patients treated with preoperative chemotherapy
F. André (2001)
Methotrexate cerebrospinal fluid and serum concentrations after intermediate‐dose methotrexate infusion
W. Evans (1983)
Natural history of CNS relapse in patients with aggressive non-Hodgkin's lymphoma: a 20-year follow-up analysis of SWOG 8516 -- the Southwest Oncology Group.
S. Bernstein (2009)
Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer (The IDEAL 1 Trial) [corrected].
M. Fukuoka (2003)
Are EGFR antagonists associated with increased central nervous system metastases in non-small-cell lung cancer?
M. Chamberlain (2006)
Phase I clinical trial of intrathecal gemcitabine in patients with neoplastic meningitis
R. J. Bernardi (2007)
Metastatic pattern of malignant melanoma. A study of 216 autopsy cases.
J. Patel (1978)
Seizure‐Promoting Effect of Blood–Brain Barrier Disruption
Nicola Marchi (2007)
Papers of special note have been highlighted as: • of interest therapy for metastatic breast carcinoma
Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer.
E. H. Romond (2005)
High-dose intrathecal trastuzumab for leptomeningeal metastases secondary to HER-2 overexpressing breast cancer.
O. Mir (2008)
Antitenascin-C monoclonal antibody radioimmunotherapy for malignant glioma patients
D. Reardon (2007)
An Unexpected Synergist Role of P-Glycoprotein and Breast Cancer Resistance Protein on the Central Nervous System Penetration of the Tyrosine Kinase Inhibitor Lapatinib (N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methylsulfonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine; GW572016)
J. Polli (2009)
Topotecan central nervous system penetration is altered by a tyrosine kinase inhibitor.
Yanli Zhuang (2006)
Phase I/II trial of tremelimumab in patients with metastatic melanoma.
L. Camacho (2009)
Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: a randomized trial.
M. Kris (2003)
Characteristics of patients with brain metastases receiving trastuzumab for HER2 overexpressing metastatic breast cancer.
H. Stemmler (2006)
A phase III randomized comparison of lapatinib plus capecitabine versus capecitabine alone in women with advanced breast cancer that has progressed on trastuzumab: updated efficacy and biomarker analyses
D. Cameron (2007)
Website 201 National Cancer Institute www
Enhanced chemotherapy delivery by intraarterial infusion and blood‐brain barrier disruption in the treatment of cerebral metastasis
D. Fortin (2007)
Diffuse large B-cell lymphoma with central nervous system relapse: prognosis and risk factors according to retrospective analysis from a single-center experience
Y. Shimazu (2009)
Emergence of increased cerebral metastasis after high‐dose preoperative radiotherapy with chemotherapy in patients with locally advanced nonsmall cell lung carcinoma
A. Law (2001)
Lapatinib plus capecitabine resolved human epidermal growth factor receptor 2-positive brain metastases.
Stefan Glück (2009)
Randomized trial of a slow-release versus a standard formulation of cytarabine for the intrathecal treatment of lymphomatous meningitis.
M. Glantz (1999)
CSF flow cytometry greatly improves diagnostic accuracy in CNS hematologic malignancies
J. Bromberg (2007)
• Documents, for the first time, the utility of cerebrospinal fluid flow cytometry in newly diagnosed non-Hodgkin's lymphoma patients
Intracranial metastases from systemic cancer.
J. Posner (1978)
Human epidermal growth factor receptor 2-positive breast cancer and central nervous system metastases.
B. Leyland-Jones (2009)
Etoposide achieves potentially cytotoxic concentrations in CSF of children with acute lymphoblastic leukemia.
M. Relling (1996)
Lymphomatous meningitis: early diagnosis and treatment.
Alixis Van Horn (2009)
Effect of intravenous dose and schedule on cerebrospinal fluid pharmacokinetics of 5-fluorouracil in the monkey.
I. Kerr (1984)
Time from treatment to subsequent diagnosis of brain metastases in stage III non-small-cell lung cancer: a retrospective review by the Southwest Oncology Group.
L. Gaspar (2005)
Cerebrospinal fluid and plasma methotrexate levels following high-dose regimen given as a 3-hour intravenous infusion in children with nonHodgkin's lymphoma.
G. Vassal (1990)
Trastuzumab in CSF.
B. Pestalozzi (2000)
The relevance of intraventricular chemotherapy for leptomeningeal metastasis in breast cancer: a randomised study.
W. Boogerd (2004)
Intrathecal Thiotepa: Reappraisal of an Established Therapy
P. Fisher (2002)
Prognostic factors and clinical outcomes in patients with leptomeningeal metastasis from solid tumors
Fusako Waki (2008)
Effect of dose and repeat intravenous 24 hr infusions of methotrexate on cerebrospinal fluid availability in children with hematological malignancies.
A. Thyss (1987)
Identifying breast cancer patients at risk for Central Nervous System (CNS) metastases in trials of the International Breast Cancer Study Group (IBCSG).
B. Pestalozzi (2006)
Unusual cervical spinal cord toxicity associated with intra-arterial carboplatin, intra-arterial or intravenous etoposide phosphate, and intravenous cyclophosphamide in conjunction with osmotic blood brain-barrier disruption in the vertebral artery.
D. Fortin (1999)
Dasatinib crosses the blood-brain barrier and is an efficient therapy for central nervous system Philadelphia chromosome-positive leukemia.
K. Porkka (2008)
Strategies to advance translational research into brain barriers
E. Neuwelt (2008)
Eastern Cooperative Oncology Group. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer
JH Schiller (2002)
randomized study to evaluate the utility of intra-cerebrospinal fluid chemotherapy in patients with breast cancer and leptomeningeal metastases
• First
Multicenter Phase II Study of Lapatinib in Patients with Brain Metastases from HER2-Positive Breast Cancer
N. Lin (2009)
Prognostic significance of HER-2 oncoprotein expression in breast cancer: a 30-year follow-up.
S. Toikkanen (1992)
Preclinical pharmacology of arabinosyl-5-azacytidine in nonhuman primates.
R. Heideman (1988)
The Biology of Metastasis to a Sanctuary Site
D. Palmieri (2007)
Incidence of cerebral metastases in patients treated with trastuzumab for metastatic breast cancer
A. Clayton (2004)
Cognitive sequelae of brain radiation in adults.
N. Laack (2004)
Randomized prospective comparison of intraventricular methotrexate and thiotepa in patients with previously untreated neoplastic meningitis. Eastern Cooperative Oncology Group.
S. Grossman (1993)
Incidence, pattern and timing of brain metastases among patients with advanced breast cancer treated with trastuzumab
T. Yau (2006)
Trastuzumab treatment improves brain metastasis outcomes through control and durable prolongation of systemic extracranial disease in HER2-overexpressing breast cancer patients
R. Jankowitz (2009)
Brain drug delivery of small molecules using immunoliposomes.
J. Huwyler (1996)
Intracranial metastases from systemic cancer.
Posner Jb (1978)
First human treatment of resistant neoplastic meningitis by intrathecal administration of MTX Plus 125IUdR
C. Rebischung (2008)
Phase I study of intraventricular administration of rituximab in patients with recurrent CNS and intraocular lymphoma.
J. Rubenstein (2007)
Renal dysfunction during and after high-dose methotrexate
Myke R. Green (2008)
Risk of brain metastases in HER2/neu-positive breast cancer.
R. Altaha (2004)
• Excellent summary of the anatomy and physiology of the BBB
Chief, Division of Neuro-Oncology
• Affiliation
Drug streaming during intra-arterial chemotherapy.
J. B. Blacklock (1986)
Neoplastic meningitis (Journal of Clinical Oncology (2005) 23 (3605-3613))
M. Chamberlain (2010)
Erlotinib in previously treated non-small-cell lung cancer.
F. Shepherd (2005)
Pharmacokinetics of 3-methyl-(triazen-1-yl)imidazole-4-carboximide following administration of temozolomide to patients with advanced cancer.
J. Reid (1997)
Factors affecting the risk of brain metastases after definitive chemoradiation for locally advanced non-small-cell lung carcinoma.
T. J. Robnett (2001)
Route of intra-CSF chemotherapy administration and efficacy of therapy in neoplastic meningitis
MJ Glantz (2009)
Chemotherapy plus Rituximab versus chemotherapy alone for B-cell non-Hodgkin's lymphoma.
H. Schulz (2007)
Blood–brain barrier and chemotherapeutic treatment of brain tumors
N. D. de Vries (2006)
Phase II randomized trial of temozolomide and concurrent radiotherapy in patients with brain metastases.
D. Antonadou (2002)
Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer.
A. Sandler (2006)
Route of intracerebrospinal fluid chemotherapy administration and efficacy of therapy in neoplastic meningitis
M. Glantz (2010)
Characteristics of patients with brain metastases receiving trastuzumab for HER 2 overexpressing metastatic
HJ Stemmler (2004)
Plasma and cerebrospinal fluid pharmacokinetics of imatinib after administration to nonhuman primates
K. Neville (2004)
Treatment of acute lymphocytic leukemia by high-dose intravenous methotrexate.
J. J. Wang (1976)
Methotrexate injection USP, package insert
Brain metastases in locally advanced nonsmall cell lung carcinoma after multimodality treatment
Giovanni Luca Ceresoli (2002)
Fusion antibody for Alzheimer's disease with bidirectional transport across the blood-brain barrier and abeta fibril disaggregation.
R. Boado (2007)
A Phase I study using intralumbar injection of I-131 sodium iodide to treat leptomeningeal metastases (LM)
F Wong
Rituximab therapy for CNS lymphomas: targeting the leptomeningeal compartment.
J. Rubenstein (2003)
Plasma and cerebrospinal fluid pharmacokinetics of recombinant interferon alpha A in monkeys: comparison of intravenous, intramuscular, and intraventricular delivery.
J. Collins (1985)
High dose methotrexate with leucovorin rescue. Rationale and spectrum of antitumor activity.
E. Frei (1980)
Complement Activation in Circulation and Central Nervous System after Rituximab (Anti-CD20) Treatment of B-Cell Lymphoma
A. Harjunpää (2001)
CNS Metastasis: An Old Problem in a New Guise
J. Aragon-Ching (2007)
Leukemic and lymphomatous meningitis: incidence, prognosis and treatment
Marc C. Chamberlain (2004)
Central nervous system metastases in women who receive trastuzumab‐based therapy for metastatic breast carcinoma
J. Bendell (2003)
Quality‐of‐life–adjusted survival comparison of sustained‐release cytosine arabinoside versus intrathecal methotrexate for treatment of solid tumor neoplastic meningitis
B. Cole (2003)
Phase II trial of patupilone in patients (pts) with breast cancer brain metastases (BCBM) progressing or recurring after whole brain radiation therapy (WBXRT)
A. Conlin (2008)
Phase I and pharmacokinetic evaluation of thiotepa in the cerebrospinal fluid and plasma of pediatric patients: evidence for dose-dependent plasma clearance of thiotepa.
R. Heideman (1989)
Zachary Hall (1906)
Intracranial dural metastases
L. Nayak (2009)
• First trial of intra-cerebrospinal fluid rituximab in humans
High dose methotrexate with leucovorin rescue. Rationale and spectrum of anti-tumor activity
E 3rdFrei (1980)
Lapatinib plus capecitabine for HER2-positive advanced breast cancer.
C. Geyer (2006)

This paper is referenced by
Novel Use of Dual Anti-Inflammatory Therapy to Overcome Drug Resistance and Improve Functional Recovery Following Spinal Cord Injury
Jennifer N. Dulin (2012)
Intestinal receptor targeting for peptide delivery: an expert's personal perspective on reasons for failure and new opportunities.
G. Russell-Jones (2011)
Liposomal Carrier Conjugated to APP-Derived Peptide for Brain Cancer Treatment.
Martin Gabay (2020)
Integrated Systems and Technologies Apoptosis Imaging for Monitoring DR 5 Antibody Accumulation and Pharmacodynamics in Brain Tumors Noninvasively
Thomas G. Weber (2014)
Treatment of Experimental Brain Metastasis with MTO-Liposomes: Impact of Fluidity and LRP-Targeting on the Therapeutic Result
Andrea Orthmann (2012)
Molecular imaging of drug transit through the blood-brain barrier with MALDI mass spectrometry imaging
X. Liu (2013)
Brain Exposure of Two Selective Dual CDK4 and CDK6 Inhibitors and the Antitumor Activity of CDK4 and CDK6 Inhibition in Combination with Temozolomide in an Intracranial Glioblastoma Xenograft
Thomas J. Raub (2015)
NBGNU: a hypoxia-activated tripartite combi-nitrosourea prodrug overcoming AGT-mediated chemoresistance.
Yao Ge (2018)
Current chemotherapeutic regimens for brain metastases treatment
J. Y. Nam (2017)
Neoplastic Meningitis: How MRI and CSF Cytology Are Influenced by CSF Cell Count and Tumor Type
P. Proemmel (2013)
Lactoferrin-conjugated biodegradable polymersome holding doxorubicin and tetrandrine for chemotherapy of glioma rats.
Zhiqing Pang (2010)
Computational Study on Novel Natural Inhibitors Targeting O6-Methylguanine-DNA Methyltransferase (MGMT).
Y. Liu (2019)
CDK 6 Inhibitors and the Antitumor Activity of CDK 4 and 6 Inhibition in Combination with Temozolomide in an Intracranial Glioblastoma Xenograft
Thomas J. Raub (2015)
Therapy and prophylaxis of brain metastases
Y. Kienast (2010)
Functional and Molecular Mechanisms of Hypertensive Brain Damage
S. Nag (2015)
Profound Prevention of Experimental Brain Metastases of Breast Cancer by Temozolomide in an MGMT-Dependent Manner
D. Palmieri (2014)
Improving delivery of molecularly targeted agents to glioma
Sagar Agarwal (2011)
Gliadel for brain metastasis
T. Abel (2013)
Matrix-assisted laser desorption/ionization imaging mass spectrometry of intraperitoneally injected danegaptide (ZP1609) for treatment of stroke-reperfusion injury in mice.
J. Wang (2018)
Breast cancer resistance protein and P-glycoprotein in brain cancer: two gatekeepers team up.
Sagar Agarwal (2011)
Apoptosis imaging for monitoring DR5 antibody accumulation and pharmacodynamics in brain tumors noninvasively.
Thomas G. Weber (2014)
Leptomeningeal Carcinomatosis in Non–Small-Cell Lung Cancer Patients: Impact on Survival and Correlated Prognostic Factors
S. Lee (2013)
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