title: Sirolimus for progressive neurofibromatosis type 1-associated plexiform neurofibromas: a neurofibromatosis Clinical Trials Consortium phase II study.
abstract: BACKGROUND
  Plexiform neurofibromas (PNs) are benign peripheral nerve sheath tumors that arise in one-third of individuals with neurofibromatosis type 1 (NF1). They may cause significant disfigurement, compression of vital structures, neurologic dysfunction, and/or pain. Currently, the only effective management strategy is surgical resection. Converging evidence has demonstrated that the NF1 tumor suppressor protein, neurofibromin, negatively regulates activity in the mammalian Target of Rapamycin pathway.
  
  
  METHODS
  We employed a 2-strata clinical trial design. Stratum 1 included subjects with inoperable, NF1-associated progressive PN and sought to determine whether sirolimus safely and tolerably increases time to progression (TTP). Volumetric MRI analysis conducted at regular intervals was used to determine TTP relative to baseline imaging.
  
  
  RESULTS
  The estimated median TTP of subjects receiving sirolimus was 15.4 months (95% CI: 14.3-23.7 mo), which was significantly longer than 11.9 months (P < .001), the median TTP of the placebo arm of a previous PN clinical trial with similar eligibility criteria.
  
  
  CONCLUSIONS
  This study demonstrated that sirolimus prolongs TTP by almost 4 months in patients with NF1-associated progressive PN. Although the improvement in TTP is modest, given the lack of significant or frequent toxicity and the availability of few other treatment options, the use of sirolimus to slow the growth of progressive PN could be considered in select patients.
authors.affiliation: Division of Oncology, Cincinnati Children's Hospital Medical Center, Cancer and Blood Diseases Institute, Cincinnati, Ohio (B.W., J.P.); Division of Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio (E.S.); Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio (A.V.); National Cancer Institute, Pediatric Oncology Branch, Bethesda, Maryland (B.C.W, E.D., P.W.); Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama (B.K.); Department of Preventitive Medicine, University of Alabama at Birmingham, Birmingham, Alabama (A.C.); Department of Neurology, Boston Children's Hospital, Boston, Massachusetts (N.U.); Department of Neurology, Washington University, St. Louis, Missouri (D.H.G.); Children's National Health System, Center for Neuroscience and Behavioral Medicine, Washington, DC (R.J.P.); Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania (M.J.F.); Division of Genetics, Primary Children's Hospital, Salt Lake City, Utah (D.V.); Division of Neurology, The University of Chicago Medicine Comer Children's Hospital, Chicago, Illinois (J.T.).
authors.forename: Brian
authors.initials: B
authors.lastname: Weiss
authors.affiliation: Division of Oncology, Cincinnati Children's Hospital Medical Center, Cancer and Blood Diseases Institute, Cincinnati, Ohio (B.W., J.P.); Division of Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio (E.S.); Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio (A.V.); National Cancer Institute, Pediatric Oncology Branch, Bethesda, Maryland (B.C.W, E.D., P.W.); Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama (B.K.); Department of Preventitive Medicine, University of Alabama at Birmingham, Birmingham, Alabama (A.C.); Department of Neurology, Boston Children's Hospital, Boston, Massachusetts (N.U.); Department of Neurology, Washington University, St. Louis, Missouri (D.H.G.); Children's National Health System, Center for Neuroscience and Behavioral Medicine, Washington, DC (R.J.P.); Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania (M.J.F.); Division of Genetics, Primary Children's Hospital, Salt Lake City, Utah (D.V.); Division of Neurology, The University of Chicago Medicine Comer Children's Hospital, Chicago, Illinois (J.T.).
authors.forename: Brigitte C
authors.initials: BC
authors.lastname: Widemann
authors.affiliation: Division of Oncology, Cincinnati Children's Hospital Medical Center, Cancer and Blood Diseases Institute, Cincinnati, Ohio (B.W., J.P.); Division of Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio (E.S.); Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio (A.V.); National Cancer Institute, Pediatric Oncology Branch, Bethesda, Maryland (B.C.W, E.D., P.W.); Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama (B.K.); Department of Preventitive Medicine, University of Alabama at Birmingham, Birmingham, Alabama (A.C.); Department of Neurology, Boston Children's Hospital, Boston, Massachusetts (N.U.); Department of Neurology, Washington University, St. Louis, Missouri (D.H.G.); Children's National Health System, Center for Neuroscience and Behavioral Medicine, Washington, DC (R.J.P.); Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania (M.J.F.); Division of Genetics, Primary Children's Hospital, Salt Lake City, Utah (D.V.); Division of Neurology, The University of Chicago Medicine Comer Children's Hospital, Chicago, Illinois (J.T.).
authors.forename: Pamela
authors.initials: P
authors.lastname: Wolters
authors.affiliation: Division of Oncology, Cincinnati Children's Hospital Medical Center, Cancer and Blood Diseases Institute, Cincinnati, Ohio (B.W., J.P.); Division of Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio (E.S.); Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio (A.V.); National Cancer Institute, Pediatric Oncology Branch, Bethesda, Maryland (B.C.W, E.D., P.W.); Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama (B.K.); Department of Preventitive Medicine, University of Alabama at Birmingham, Birmingham, Alabama (A.C.); Department of Neurology, Boston Children's Hospital, Boston, Massachusetts (N.U.); Department of Neurology, Washington University, St. Louis, Missouri (D.H.G.); Children's National Health System, Center for Neuroscience and Behavioral Medicine, Washington, DC (R.J.P.); Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania (M.J.F.); Division of Genetics, Primary Children's Hospital, Salt Lake City, Utah (D.V.); Division of Neurology, The University of Chicago Medicine Comer Children's Hospital, Chicago, Illinois (J.T.).
authors.forename: Eva
authors.initials: E
authors.lastname: Dombi
authors.affiliation: Division of Oncology, Cincinnati Children's Hospital Medical Center, Cancer and Blood Diseases Institute, Cincinnati, Ohio (B.W., J.P.); Division of Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio (E.S.); Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio (A.V.); National Cancer Institute, Pediatric Oncology Branch, Bethesda, Maryland (B.C.W, E.D., P.W.); Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama (B.K.); Department of Preventitive Medicine, University of Alabama at Birmingham, Birmingham, Alabama (A.C.); Department of Neurology, Boston Children's Hospital, Boston, Massachusetts (N.U.); Department of Neurology, Washington University, St. Louis, Missouri (D.H.G.); Children's National Health System, Center for Neuroscience and Behavioral Medicine, Washington, DC (R.J.P.); Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania (M.J.F.); Division of Genetics, Primary Children's Hospital, Salt Lake City, Utah (D.V.); Division of Neurology, The University of Chicago Medicine Comer Children's Hospital, Chicago, Illinois (J.T.).
authors.forename: Alexander
authors.initials: A
authors.lastname: Vinks
authors.affiliation: Division of Oncology, Cincinnati Children's Hospital Medical Center, Cancer and Blood Diseases Institute, Cincinnati, Ohio (B.W., J.P.); Division of Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio (E.S.); Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio (A.V.); National Cancer Institute, Pediatric Oncology Branch, Bethesda, Maryland (B.C.W, E.D., P.W.); Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama (B.K.); Department of Preventitive Medicine, University of Alabama at Birmingham, Birmingham, Alabama (A.C.); Department of Neurology, Boston Children's Hospital, Boston, Massachusetts (N.U.); Department of Neurology, Washington University, St. Louis, Missouri (D.H.G.); Children's National Health System, Center for Neuroscience and Behavioral Medicine, Washington, DC (R.J.P.); Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania (M.J.F.); Division of Genetics, Primary Children's Hospital, Salt Lake City, Utah (D.V.); Division of Neurology, The University of Chicago Medicine Comer Children's Hospital, Chicago, Illinois (J.T.).
authors.forename: Alan
authors.initials: A
authors.lastname: Cantor
authors.affiliation: Division of Oncology, Cincinnati Children's Hospital Medical Center, Cancer and Blood Diseases Institute, Cincinnati, Ohio (B.W., J.P.); Division of Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio (E.S.); Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio (A.V.); National Cancer Institute, Pediatric Oncology Branch, Bethesda, Maryland (B.C.W, E.D., P.W.); Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama (B.K.); Department of Preventitive Medicine, University of Alabama at Birmingham, Birmingham, Alabama (A.C.); Department of Neurology, Boston Children's Hospital, Boston, Massachusetts (N.U.); Department of Neurology, Washington University, St. Louis, Missouri (D.H.G.); Children's National Health System, Center for Neuroscience and Behavioral Medicine, Washington, DC (R.J.P.); Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania (M.J.F.); Division of Genetics, Primary Children's Hospital, Salt Lake City, Utah (D.V.); Division of Neurology, The University of Chicago Medicine Comer Children's Hospital, Chicago, Illinois (J.T.).
authors.forename: John
authors.initials: J
authors.lastname: Perentesis
authors.affiliation: Division of Oncology, Cincinnati Children's Hospital Medical Center, Cancer and Blood Diseases Institute, Cincinnati, Ohio (B.W., J.P.); Division of Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio (E.S.); Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio (A.V.); National Cancer Institute, Pediatric Oncology Branch, Bethesda, Maryland (B.C.W, E.D., P.W.); Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama (B.K.); Department of Preventitive Medicine, University of Alabama at Birmingham, Birmingham, Alabama (A.C.); Department of Neurology, Boston Children's Hospital, Boston, Massachusetts (N.U.); Department of Neurology, Washington University, St. Louis, Missouri (D.H.G.); Children's National Health System, Center for Neuroscience and Behavioral Medicine, Washington, DC (R.J.P.); Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania (M.J.F.); Division of Genetics, Primary Children's Hospital, Salt Lake City, Utah (D.V.); Division of Neurology, The University of Chicago Medicine Comer Children's Hospital, Chicago, Illinois (J.T.).
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Schorry
authors.affiliation: Division of Oncology, Cincinnati Children's Hospital Medical Center, Cancer and Blood Diseases Institute, Cincinnati, Ohio (B.W., J.P.); Division of Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio (E.S.); Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio (A.V.); National Cancer Institute, Pediatric Oncology Branch, Bethesda, Maryland (B.C.W, E.D., P.W.); Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama (B.K.); Department of Preventitive Medicine, University of Alabama at Birmingham, Birmingham, Alabama (A.C.); Department of Neurology, Boston Children's Hospital, Boston, Massachusetts (N.U.); Department of Neurology, Washington University, St. Louis, Missouri (D.H.G.); Children's National Health System, Center for Neuroscience and Behavioral Medicine, Washington, DC (R.J.P.); Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania (M.J.F.); Division of Genetics, Primary Children's Hospital, Salt Lake City, Utah (D.V.); Division of Neurology, The University of Chicago Medicine Comer Children's Hospital, Chicago, Illinois (J.T.).
authors.forename: Nicole
authors.initials: N
authors.lastname: Ullrich
authors.affiliation: Division of Oncology, Cincinnati Children's Hospital Medical Center, Cancer and Blood Diseases Institute, Cincinnati, Ohio (B.W., J.P.); Division of Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio (E.S.); Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio (A.V.); National Cancer Institute, Pediatric Oncology Branch, Bethesda, Maryland (B.C.W, E.D., P.W.); Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama (B.K.); Department of Preventitive Medicine, University of Alabama at Birmingham, Birmingham, Alabama (A.C.); Department of Neurology, Boston Children's Hospital, Boston, Massachusetts (N.U.); Department of Neurology, Washington University, St. Louis, Missouri (D.H.G.); Children's National Health System, Center for Neuroscience and Behavioral Medicine, Washington, DC (R.J.P.); Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania (M.J.F.); Division of Genetics, Primary Children's Hospital, Salt Lake City, Utah (D.V.); Division of Neurology, The University of Chicago Medicine Comer Children's Hospital, Chicago, Illinois (J.T.).
authors.forename: David H
authors.initials: DH
authors.lastname: Gutmann
authors.affiliation: Division of Oncology, Cincinnati Children's Hospital Medical Center, Cancer and Blood Diseases Institute, Cincinnati, Ohio (B.W., J.P.); Division of Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio (E.S.); Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio (A.V.); National Cancer Institute, Pediatric Oncology Branch, Bethesda, Maryland (B.C.W, E.D., P.W.); Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama (B.K.); Department of Preventitive Medicine, University of Alabama at Birmingham, Birmingham, Alabama (A.C.); Department of Neurology, Boston Children's Hospital, Boston, Massachusetts (N.U.); Department of Neurology, Washington University, St. Louis, Missouri (D.H.G.); Children's National Health System, Center for Neuroscience and Behavioral Medicine, Washington, DC (R.J.P.); Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania (M.J.F.); Division of Genetics, Primary Children's Hospital, Salt Lake City, Utah (D.V.); Division of Neurology, The University of Chicago Medicine Comer Children's Hospital, Chicago, Illinois (J.T.).
authors.forename: James
authors.initials: J
authors.lastname: Tonsgard
authors.affiliation: Division of Oncology, Cincinnati Children's Hospital Medical Center, Cancer and Blood Diseases Institute, Cincinnati, Ohio (B.W., J.P.); Division of Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio (E.S.); Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio (A.V.); National Cancer Institute, Pediatric Oncology Branch, Bethesda, Maryland (B.C.W, E.D., P.W.); Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama (B.K.); Department of Preventitive Medicine, University of Alabama at Birmingham, Birmingham, Alabama (A.C.); Department of Neurology, Boston Children's Hospital, Boston, Massachusetts (N.U.); Department of Neurology, Washington University, St. Louis, Missouri (D.H.G.); Children's National Health System, Center for Neuroscience and Behavioral Medicine, Washington, DC (R.J.P.); Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania (M.J.F.); Division of Genetics, Primary Children's Hospital, Salt Lake City, Utah (D.V.); Division of Neurology, The University of Chicago Medicine Comer Children's Hospital, Chicago, Illinois (J.T.).
authors.forename: David
authors.initials: D
authors.lastname: Viskochil
authors.affiliation: Division of Oncology, Cincinnati Children's Hospital Medical Center, Cancer and Blood Diseases Institute, Cincinnati, Ohio (B.W., J.P.); Division of Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio (E.S.); Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio (A.V.); National Cancer Institute, Pediatric Oncology Branch, Bethesda, Maryland (B.C.W, E.D., P.W.); Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama (B.K.); Department of Preventitive Medicine, University of Alabama at Birmingham, Birmingham, Alabama (A.C.); Department of Neurology, Boston Children's Hospital, Boston, Massachusetts (N.U.); Department of Neurology, Washington University, St. Louis, Missouri (D.H.G.); Children's National Health System, Center for Neuroscience and Behavioral Medicine, Washington, DC (R.J.P.); Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania (M.J.F.); Division of Genetics, Primary Children's Hospital, Salt Lake City, Utah (D.V.); Division of Neurology, The University of Chicago Medicine Comer Children's Hospital, Chicago, Illinois (J.T.).
authors.forename: Bruce
authors.initials: B
authors.lastname: Korf
authors.affiliation: Division of Oncology, Cincinnati Children's Hospital Medical Center, Cancer and Blood Diseases Institute, Cincinnati, Ohio (B.W., J.P.); Division of Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio (E.S.); Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio (A.V.); National Cancer Institute, Pediatric Oncology Branch, Bethesda, Maryland (B.C.W, E.D., P.W.); Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama (B.K.); Department of Preventitive Medicine, University of Alabama at Birmingham, Birmingham, Alabama (A.C.); Department of Neurology, Boston Children's Hospital, Boston, Massachusetts (N.U.); Department of Neurology, Washington University, St. Louis, Missouri (D.H.G.); Children's National Health System, Center for Neuroscience and Behavioral Medicine, Washington, DC (R.J.P.); Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania (M.J.F.); Division of Genetics, Primary Children's Hospital, Salt Lake City, Utah (D.V.); Division of Neurology, The University of Chicago Medicine Comer Children's Hospital, Chicago, Illinois (J.T.).
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Packer
authors.affiliation: Division of Oncology, Cincinnati Children's Hospital Medical Center, Cancer and Blood Diseases Institute, Cincinnati, Ohio (B.W., J.P.); Division of Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio (E.S.); Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio (A.V.); National Cancer Institute, Pediatric Oncology Branch, Bethesda, Maryland (B.C.W, E.D., P.W.); Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama (B.K.); Department of Preventitive Medicine, University of Alabama at Birmingham, Birmingham, Alabama (A.C.); Department of Neurology, Boston Children's Hospital, Boston, Massachusetts (N.U.); Department of Neurology, Washington University, St. Louis, Missouri (D.H.G.); Children's National Health System, Center for Neuroscience and Behavioral Medicine, Washington, DC (R.J.P.); Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania (M.J.F.); Division of Genetics, Primary Children's Hospital, Salt Lake City, Utah (D.V.); Division of Neurology, The University of Chicago Medicine Comer Children's Hospital, Chicago, Illinois (J.T.).
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Fisher
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D018318:Neurofibroma, Plexiform / Q000188:drug therapy*; D009456:Neurofibromatosis 1 / Q000188:drug therapy*; D020123:Sirolimus / Q000009:adverse effects / Q000627:therapeutic use*; D013125:Spinal Neoplasms / Q000188:drug therapy*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D020123:Sirolimus
keywords: NF1; mTOR; neurofibromatosis; plexiform neurofibroma; rapamycin; sirolimus