title: Leptomeningeal metastasis: a Response Assessment in Neuro-Oncology critical review of endpoints and response criteria of published randomized clinical trials.
abstract: OBJECTIVE
  To date, response criteria and optimal methods for assessment of outcome have not been standardized in patients with leptomeningeal metastasis (LM).
  
  
  METHODS
  A Response Assessment in Neuro-Oncology working group of experts in LM critically reviewed published literature regarding randomized clinical trials (RCTs) and trial design in patients with LM.
  
  
  RESULTS
  A literature review determined that 6 RCTs regarding the treatment of LM have been published, all of which assessed the response to intra-CSF based chemotherapy. Amongst these RCTs, only a single trial attempted to determine whether intra-CSF chemotherapy was of benefit compared with systemic therapy. Otherwise, this pragmatic question has not been formally addressed in patients with solid cancers and LM. The methodology of the 6 RCTs varied widely with respect to pretreatment evaluation, type of treatment, and response to treatment. Additionally there was little uniformity in reporting of treatment-related toxicity. One RCT suggests no advantage of combined versus single-agent intra-CSF chemotherapy in patients with LM. No specific intra-CSF regimen has shown superior efficacy in the treatment of LM, with the exception of liposomal cytarabine in patients with lymphomatous meningitis. Problematic with all RCTs is the lack of standardization with respect to response criteria. There was considerable variation in definitions of response by clinical examination, neuroimaging, and CSF analysis.
  
  
  CONCLUSIONS
  Based upon a review of published RCTs in LM, there exists a significant unmet need for guidelines for evaluating patients with LM in clinical practice as well as for response assessment in clinical trials.
authors.affiliation: Department of Neurology, Fred Hutchinson Cancer Research Center, University of Washington, Seattle, Washington (M.C.); Department of Neuroscience, Division of Neuro-Oncology, University Hospital, Torino, Italy (R.S., R.R.); Department of Neurology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, Illinois (J.R.); Department of Neuro-Oncology, Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, Netherlands (D.B., W.B.); Departments of Neuro-Oncology Mazarin and Radiation Oncology, Pitie-Salpetriere Hospital and University Pierre et Marie Curie, Paris VI, Paris, France (S.T.); Austin Brain Tumor Center, Texas Oncology/US Oncology Research, Austin, Texas (M.D.G.); Department of Neuro-Oncology, University Hospital, Lille, France (E.L.R.); Department of Neurology, Oscar Lambret Center, Lille, France (E.L.R.); Department of Neurology, University of Michigan, Ann Arbor, Michigan (L.J.); Department of Neuro-oncology, Erasmus MC-Daniel den Hoed Cancer Center, Rotterdam, Netherlands (M.v.d.B.); Department of Neurology, Dana-Farber Cancer Institute, Massachusetts General Hospital, Boston, Massachusetts (P.Y.W.); Department of Neurology and Oncology, Mayo Clinic Florida, Jacksonville, Florida (K.A.J.).
authors.forename: Marc
authors.initials: M
authors.lastname: Chamberlain
authors.affiliation: Department of Neurology, Fred Hutchinson Cancer Research Center, University of Washington, Seattle, Washington (M.C.); Department of Neuroscience, Division of Neuro-Oncology, University Hospital, Torino, Italy (R.S., R.R.); Department of Neurology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, Illinois (J.R.); Department of Neuro-Oncology, Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, Netherlands (D.B., W.B.); Departments of Neuro-Oncology Mazarin and Radiation Oncology, Pitie-Salpetriere Hospital and University Pierre et Marie Curie, Paris VI, Paris, France (S.T.); Austin Brain Tumor Center, Texas Oncology/US Oncology Research, Austin, Texas (M.D.G.); Department of Neuro-Oncology, University Hospital, Lille, France (E.L.R.); Department of Neurology, Oscar Lambret Center, Lille, France (E.L.R.); Department of Neurology, University of Michigan, Ann Arbor, Michigan (L.J.); Department of Neuro-oncology, Erasmus MC-Daniel den Hoed Cancer Center, Rotterdam, Netherlands (M.v.d.B.); Department of Neurology, Dana-Farber Cancer Institute, Massachusetts General Hospital, Boston, Massachusetts (P.Y.W.); Department of Neurology and Oncology, Mayo Clinic Florida, Jacksonville, Florida (K.A.J.).
authors.forename: Riccardo
authors.initials: R
authors.lastname: Soffietti
authors.affiliation: Department of Neurology, Fred Hutchinson Cancer Research Center, University of Washington, Seattle, Washington (M.C.); Department of Neuroscience, Division of Neuro-Oncology, University Hospital, Torino, Italy (R.S., R.R.); Department of Neurology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, Illinois (J.R.); Department of Neuro-Oncology, Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, Netherlands (D.B., W.B.); Departments of Neuro-Oncology Mazarin and Radiation Oncology, Pitie-Salpetriere Hospital and University Pierre et Marie Curie, Paris VI, Paris, France (S.T.); Austin Brain Tumor Center, Texas Oncology/US Oncology Research, Austin, Texas (M.D.G.); Department of Neuro-Oncology, University Hospital, Lille, France (E.L.R.); Department of Neurology, Oscar Lambret Center, Lille, France (E.L.R.); Department of Neurology, University of Michigan, Ann Arbor, Michigan (L.J.); Department of Neuro-oncology, Erasmus MC-Daniel den Hoed Cancer Center, Rotterdam, Netherlands (M.v.d.B.); Department of Neurology, Dana-Farber Cancer Institute, Massachusetts General Hospital, Boston, Massachusetts (P.Y.W.); Department of Neurology and Oncology, Mayo Clinic Florida, Jacksonville, Florida (K.A.J.).
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Raizer
authors.affiliation: Department of Neurology, Fred Hutchinson Cancer Research Center, University of Washington, Seattle, Washington (M.C.); Department of Neuroscience, Division of Neuro-Oncology, University Hospital, Torino, Italy (R.S., R.R.); Department of Neurology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, Illinois (J.R.); Department of Neuro-Oncology, Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, Netherlands (D.B., W.B.); Departments of Neuro-Oncology Mazarin and Radiation Oncology, Pitie-Salpetriere Hospital and University Pierre et Marie Curie, Paris VI, Paris, France (S.T.); Austin Brain Tumor Center, Texas Oncology/US Oncology Research, Austin, Texas (M.D.G.); Department of Neuro-Oncology, University Hospital, Lille, France (E.L.R.); Department of Neurology, Oscar Lambret Center, Lille, France (E.L.R.); Department of Neurology, University of Michigan, Ann Arbor, Michigan (L.J.); Department of Neuro-oncology, Erasmus MC-Daniel den Hoed Cancer Center, Rotterdam, Netherlands (M.v.d.B.); Department of Neurology, Dana-Farber Cancer Institute, Massachusetts General Hospital, Boston, Massachusetts (P.Y.W.); Department of Neurology and Oncology, Mayo Clinic Florida, Jacksonville, Florida (K.A.J.).
authors.forename: Roberta
authors.initials: R
authors.lastname: Rudà
authors.affiliation: Department of Neurology, Fred Hutchinson Cancer Research Center, University of Washington, Seattle, Washington (M.C.); Department of Neuroscience, Division of Neuro-Oncology, University Hospital, Torino, Italy (R.S., R.R.); Department of Neurology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, Illinois (J.R.); Department of Neuro-Oncology, Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, Netherlands (D.B., W.B.); Departments of Neuro-Oncology Mazarin and Radiation Oncology, Pitie-Salpetriere Hospital and University Pierre et Marie Curie, Paris VI, Paris, France (S.T.); Austin Brain Tumor Center, Texas Oncology/US Oncology Research, Austin, Texas (M.D.G.); Department of Neuro-Oncology, University Hospital, Lille, France (E.L.R.); Department of Neurology, Oscar Lambret Center, Lille, France (E.L.R.); Department of Neurology, University of Michigan, Ann Arbor, Michigan (L.J.); Department of Neuro-oncology, Erasmus MC-Daniel den Hoed Cancer Center, Rotterdam, Netherlands (M.v.d.B.); Department of Neurology, Dana-Farber Cancer Institute, Massachusetts General Hospital, Boston, Massachusetts (P.Y.W.); Department of Neurology and Oncology, Mayo Clinic Florida, Jacksonville, Florida (K.A.J.).
authors.forename: Dieta
authors.initials: D
authors.lastname: Brandsma
authors.affiliation: Department of Neurology, Fred Hutchinson Cancer Research Center, University of Washington, Seattle, Washington (M.C.); Department of Neuroscience, Division of Neuro-Oncology, University Hospital, Torino, Italy (R.S., R.R.); Department of Neurology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, Illinois (J.R.); Department of Neuro-Oncology, Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, Netherlands (D.B., W.B.); Departments of Neuro-Oncology Mazarin and Radiation Oncology, Pitie-Salpetriere Hospital and University Pierre et Marie Curie, Paris VI, Paris, France (S.T.); Austin Brain Tumor Center, Texas Oncology/US Oncology Research, Austin, Texas (M.D.G.); Department of Neuro-Oncology, University Hospital, Lille, France (E.L.R.); Department of Neurology, Oscar Lambret Center, Lille, France (E.L.R.); Department of Neurology, University of Michigan, Ann Arbor, Michigan (L.J.); Department of Neuro-oncology, Erasmus MC-Daniel den Hoed Cancer Center, Rotterdam, Netherlands (M.v.d.B.); Department of Neurology, Dana-Farber Cancer Institute, Massachusetts General Hospital, Boston, Massachusetts (P.Y.W.); Department of Neurology and Oncology, Mayo Clinic Florida, Jacksonville, Florida (K.A.J.).
authors.forename: Willem
authors.initials: W
authors.lastname: Boogerd
authors.affiliation: Department of Neurology, Fred Hutchinson Cancer Research Center, University of Washington, Seattle, Washington (M.C.); Department of Neuroscience, Division of Neuro-Oncology, University Hospital, Torino, Italy (R.S., R.R.); Department of Neurology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, Illinois (J.R.); Department of Neuro-Oncology, Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, Netherlands (D.B., W.B.); Departments of Neuro-Oncology Mazarin and Radiation Oncology, Pitie-Salpetriere Hospital and University Pierre et Marie Curie, Paris VI, Paris, France (S.T.); Austin Brain Tumor Center, Texas Oncology/US Oncology Research, Austin, Texas (M.D.G.); Department of Neuro-Oncology, University Hospital, Lille, France (E.L.R.); Department of Neurology, Oscar Lambret Center, Lille, France (E.L.R.); Department of Neurology, University of Michigan, Ann Arbor, Michigan (L.J.); Department of Neuro-oncology, Erasmus MC-Daniel den Hoed Cancer Center, Rotterdam, Netherlands (M.v.d.B.); Department of Neurology, Dana-Farber Cancer Institute, Massachusetts General Hospital, Boston, Massachusetts (P.Y.W.); Department of Neurology and Oncology, Mayo Clinic Florida, Jacksonville, Florida (K.A.J.).
authors.forename: Sophie
authors.initials: S
authors.lastname: Taillibert
authors.affiliation: Department of Neurology, Fred Hutchinson Cancer Research Center, University of Washington, Seattle, Washington (M.C.); Department of Neuroscience, Division of Neuro-Oncology, University Hospital, Torino, Italy (R.S., R.R.); Department of Neurology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, Illinois (J.R.); Department of Neuro-Oncology, Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, Netherlands (D.B., W.B.); Departments of Neuro-Oncology Mazarin and Radiation Oncology, Pitie-Salpetriere Hospital and University Pierre et Marie Curie, Paris VI, Paris, France (S.T.); Austin Brain Tumor Center, Texas Oncology/US Oncology Research, Austin, Texas (M.D.G.); Department of Neuro-Oncology, University Hospital, Lille, France (E.L.R.); Department of Neurology, Oscar Lambret Center, Lille, France (E.L.R.); Department of Neurology, University of Michigan, Ann Arbor, Michigan (L.J.); Department of Neuro-oncology, Erasmus MC-Daniel den Hoed Cancer Center, Rotterdam, Netherlands (M.v.d.B.); Department of Neurology, Dana-Farber Cancer Institute, Massachusetts General Hospital, Boston, Massachusetts (P.Y.W.); Department of Neurology and Oncology, Mayo Clinic Florida, Jacksonville, Florida (K.A.J.).
authors.forename: Morris D
authors.initials: MD
authors.lastname: Groves
authors.affiliation: Department of Neurology, Fred Hutchinson Cancer Research Center, University of Washington, Seattle, Washington (M.C.); Department of Neuroscience, Division of Neuro-Oncology, University Hospital, Torino, Italy (R.S., R.R.); Department of Neurology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, Illinois (J.R.); Department of Neuro-Oncology, Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, Netherlands (D.B., W.B.); Departments of Neuro-Oncology Mazarin and Radiation Oncology, Pitie-Salpetriere Hospital and University Pierre et Marie Curie, Paris VI, Paris, France (S.T.); Austin Brain Tumor Center, Texas Oncology/US Oncology Research, Austin, Texas (M.D.G.); Department of Neuro-Oncology, University Hospital, Lille, France (E.L.R.); Department of Neurology, Oscar Lambret Center, Lille, France (E.L.R.); Department of Neurology, University of Michigan, Ann Arbor, Michigan (L.J.); Department of Neuro-oncology, Erasmus MC-Daniel den Hoed Cancer Center, Rotterdam, Netherlands (M.v.d.B.); Department of Neurology, Dana-Farber Cancer Institute, Massachusetts General Hospital, Boston, Massachusetts (P.Y.W.); Department of Neurology and Oncology, Mayo Clinic Florida, Jacksonville, Florida (K.A.J.).
authors.forename: Emilie
authors.initials: E
authors.lastname: Le Rhun
authors.affiliation: Department of Neurology, Fred Hutchinson Cancer Research Center, University of Washington, Seattle, Washington (M.C.); Department of Neuroscience, Division of Neuro-Oncology, University Hospital, Torino, Italy (R.S., R.R.); Department of Neurology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, Illinois (J.R.); Department of Neuro-Oncology, Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, Netherlands (D.B., W.B.); Departments of Neuro-Oncology Mazarin and Radiation Oncology, Pitie-Salpetriere Hospital and University Pierre et Marie Curie, Paris VI, Paris, France (S.T.); Austin Brain Tumor Center, Texas Oncology/US Oncology Research, Austin, Texas (M.D.G.); Department of Neuro-Oncology, University Hospital, Lille, France (E.L.R.); Department of Neurology, Oscar Lambret Center, Lille, France (E.L.R.); Department of Neurology, University of Michigan, Ann Arbor, Michigan (L.J.); Department of Neuro-oncology, Erasmus MC-Daniel den Hoed Cancer Center, Rotterdam, Netherlands (M.v.d.B.); Department of Neurology, Dana-Farber Cancer Institute, Massachusetts General Hospital, Boston, Massachusetts (P.Y.W.); Department of Neurology and Oncology, Mayo Clinic Florida, Jacksonville, Florida (K.A.J.).
authors.forename: Larry
authors.initials: L
authors.lastname: Junck
authors.affiliation: Department of Neurology, Fred Hutchinson Cancer Research Center, University of Washington, Seattle, Washington (M.C.); Department of Neuroscience, Division of Neuro-Oncology, University Hospital, Torino, Italy (R.S., R.R.); Department of Neurology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, Illinois (J.R.); Department of Neuro-Oncology, Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, Netherlands (D.B., W.B.); Departments of Neuro-Oncology Mazarin and Radiation Oncology, Pitie-Salpetriere Hospital and University Pierre et Marie Curie, Paris VI, Paris, France (S.T.); Austin Brain Tumor Center, Texas Oncology/US Oncology Research, Austin, Texas (M.D.G.); Department of Neuro-Oncology, University Hospital, Lille, France (E.L.R.); Department of Neurology, Oscar Lambret Center, Lille, France (E.L.R.); Department of Neurology, University of Michigan, Ann Arbor, Michigan (L.J.); Department of Neuro-oncology, Erasmus MC-Daniel den Hoed Cancer Center, Rotterdam, Netherlands (M.v.d.B.); Department of Neurology, Dana-Farber Cancer Institute, Massachusetts General Hospital, Boston, Massachusetts (P.Y.W.); Department of Neurology and Oncology, Mayo Clinic Florida, Jacksonville, Florida (K.A.J.).
authors.forename: Martin
authors.initials: M
authors.lastname: van den Bent
authors.affiliation: Department of Neurology, Fred Hutchinson Cancer Research Center, University of Washington, Seattle, Washington (M.C.); Department of Neuroscience, Division of Neuro-Oncology, University Hospital, Torino, Italy (R.S., R.R.); Department of Neurology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, Illinois (J.R.); Department of Neuro-Oncology, Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, Netherlands (D.B., W.B.); Departments of Neuro-Oncology Mazarin and Radiation Oncology, Pitie-Salpetriere Hospital and University Pierre et Marie Curie, Paris VI, Paris, France (S.T.); Austin Brain Tumor Center, Texas Oncology/US Oncology Research, Austin, Texas (M.D.G.); Department of Neuro-Oncology, University Hospital, Lille, France (E.L.R.); Department of Neurology, Oscar Lambret Center, Lille, France (E.L.R.); Department of Neurology, University of Michigan, Ann Arbor, Michigan (L.J.); Department of Neuro-oncology, Erasmus MC-Daniel den Hoed Cancer Center, Rotterdam, Netherlands (M.v.d.B.); Department of Neurology, Dana-Farber Cancer Institute, Massachusetts General Hospital, Boston, Massachusetts (P.Y.W.); Department of Neurology and Oncology, Mayo Clinic Florida, Jacksonville, Florida (K.A.J.).
authors.forename: Patrick Y
authors.initials: PY
authors.lastname: Wen
authors.affiliation: Department of Neurology, Fred Hutchinson Cancer Research Center, University of Washington, Seattle, Washington (M.C.); Department of Neuroscience, Division of Neuro-Oncology, University Hospital, Torino, Italy (R.S., R.R.); Department of Neurology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, Illinois (J.R.); Department of Neuro-Oncology, Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, Netherlands (D.B., W.B.); Departments of Neuro-Oncology Mazarin and Radiation Oncology, Pitie-Salpetriere Hospital and University Pierre et Marie Curie, Paris VI, Paris, France (S.T.); Austin Brain Tumor Center, Texas Oncology/US Oncology Research, Austin, Texas (M.D.G.); Department of Neuro-Oncology, University Hospital, Lille, France (E.L.R.); Department of Neurology, Oscar Lambret Center, Lille, France (E.L.R.); Department of Neurology, University of Michigan, Ann Arbor, Michigan (L.J.); Department of Neuro-oncology, Erasmus MC-Daniel den Hoed Cancer Center, Rotterdam, Netherlands (M.v.d.B.); Department of Neurology, Dana-Farber Cancer Institute, Massachusetts General Hospital, Boston, Massachusetts (P.Y.W.); Department of Neurology and Oncology, Mayo Clinic Florida, Jacksonville, Florida (K.A.J.).
authors.forename: Kurt A
authors.initials: KA
authors.lastname: Jaeckle
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017322:Clinical Trials, Phase II as Topic / Q000592:standards; D023381:Endpoint Determination; D006801:Humans; D008577:Meningeal Neoplasms / Q000188:drug therapy* / Q000556:secondary; D063868:Patient Outcome Assessment; D016032:Randomized Controlled Trials as Topic / Q000592:standards*; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents