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@ARTICLE{Robinson:135968,
      author       = {G. W. Robinson and V. A. Rudneva and I. Buchhalter$^*$ and
                      C. A. Billups and S. M. Waszak and K. S. Smith and D. C.
                      Bowers and A. Bendel and P. G. Fisher and S. Partap and J.
                      R. Crawford and T. Hassall and D. J. Indelicato and F. Boop
                      and P. Klimo and N. D. Sabin and Z. Patay and T. E. Merchant
                      and C. F. Stewart and B. A. Orr and J. O. Korbel and D.
                      Jones$^*$ and T. Sharma$^*$ and P. Lichter$^*$ and M.
                      Kool$^*$ and A. Korshunov$^*$ and S. Pfister$^*$ and R. J.
                      Gilbertson and R. P. Sanders and A. Onar-Thomas and D. W.
                      Ellison and A. Gajjar and P. A. Northcott},
      title        = {{R}isk-adapted therapy for young children with
                      medulloblastoma ({SJYC}07): therapeutic and molecular
                      outcomes from a multicentre, phase 2 trial.},
      journal      = {The lancet / Oncology},
      volume       = {19},
      number       = {6},
      issn         = {1470-2045},
      address      = {London},
      publisher    = {The Lancet Publ. Group},
      reportid     = {DKFZ-2018-00705},
      pages        = {768 - 784},
      year         = {2018},
      abstract     = {Young children with medulloblastoma have a poor overall
                      survival compared with older children, due to use of
                      radiation-sparing therapy in young children. Radiotherapy is
                      omitted or reduced in these young patients to spare them
                      from debilitating long-term side-effects. We aimed to
                      estimate event-free survival and define the molecular
                      characteristics associated with progression-free survival in
                      young patients with medulloblastoma using a risk-stratified
                      treatment strategy designed to defer, reduce, or delay
                      radiation exposure.In this multicentre, phase 2 trial, we
                      enrolled children younger than 3 years with newly diagnosed
                      medulloblastoma at six centres in the USA and Australia.
                      Children aged 3-5 years with newly diagnosed, non-metastatic
                      medulloblastoma without any high-risk features were also
                      eligible. Eligible patients were required to start therapy
                      within 31 days from definitive surgery, had a Lansky
                      performance score of at least 30, and did not receive
                      previous radiotherapy or chemotherapy. Patients were
                      stratified postoperatively by clinical and histological
                      criteria into low-risk, intermediate-risk, and high-risk
                      treatment groups. All patients received identical induction
                      chemotherapy (methotrexate, vincristine, cisplatin, and
                      cyclophosphamide), with high-risk patients also receiving an
                      additional five doses of vinblastine. Induction was followed
                      by risk-adapted consolidation therapy: low-risk patients
                      received cyclophosphamide (1500 mg/m2 on day 1), etoposide
                      (100 mg/m2 on days 1 and 2), and carboplatin (area under the
                      curve 5 mg/mL per min on day 2) for two 4-week cycles;
                      intermediate-risk patients received focal radiation therapy
                      (54 Gy with a clinical target volume of 5 mm over 6 weeks)
                      to the tumour bed; and high-risk patients received
                      chemotherapy with targeted intravenous topotecan (area under
                      the curve 120-160 ng-h/mL intravenously on days 1-5) and
                      cyclophosphamide (600 mg/m2 intravenously on days 1-5).
                      After consolidation, all patients received maintenance
                      chemotherapy with cyclophosphamide, topotecan, and
                      erlotinib. The coprimary endpoints were event-free survival
                      and patterns of methylation profiling associated with
                      progression-free survival. Outcome and safety analyses were
                      per protocol (all patients who received at least one dose of
                      induction chemotherapy); biological analyses included all
                      patients with tissue available for methylation profiling.
                      This trial is registered with ClinicalTrials.gov, number
                      NCT00602667, and was closed to accrual on April 19,
                      2017.Between Nov 27, 2007, and April 19, 2017, we enrolled
                      81 patients with histologically confirmed medulloblastoma.
                      Accrual to the low-risk group was suspended after an interim
                      analysis on Dec 2, 2015, when the 1-year event-free survival
                      was estimated to be below the stopping rule boundary. After
                      a median follow-up of 5·5 years (IQR 2·7-7·3), 5-year
                      event-free survival was $31·3\%$ $(95\%$ CI 19·3-43·3)
                      for the whole cohort, $55·3\%$ $(95\%$ CI 33·3-77·3) in
                      the low-risk cohort (n=23) versus $24·6\%$ (3·6-45·6) in
                      the intermediate-risk cohort (n=32; hazard ratio 2·50,
                      $95\%$ CI 1·19-5·27; p=0·016) and $16·7\%$ (3·4-30·0)
                      in the high-risk cohort (n=26; 3·55, 1·66-7·59;
                      p=0·0011; overall p=0·0021). 5-year progression-free
                      survival by methylation subgroup was $51·1\%$ $(95\%$ CI
                      34·6-67·6) in the sonic hedgehog (SHH) subgroup (n=42),
                      $8·3\%$ $(95\%$ CI $0·0-24·0\%)$ in the group 3 subgroup
                      (n=24), and $13·3\%$ $(95\%$ CI $0·0-37·6\%)$ in the
                      group 4 subgroup (n=10). Within the SHH subgroup, two
                      distinct methylation subtypes were identified and named
                      iSHH-I and iSHH-II. 5-year progression-free survival was
                      $27·8\%$ $(95\%$ CI 9·0-46·6; n=21) for iSHH-I and
                      $75·4\%$ (55·0-95·8; n=21) for iSHH-II. The most common
                      adverse events were grade 3-4 febrile neutropenia (48
                      patients $[59\%]),$ neutropenia (21 $[26\%]),$ infection
                      with neutropenia (20 $[25\%]),$ leucopenia (15 $[19\%]),$
                      vomiting (15 $[19\%]),$ and anorexia (13 $[16\%]).$ No
                      treatment-related deaths occurred.The risk-adapted approach
                      did not improve event-free survival in young children with
                      medulloblastoma. However, the methylation subgroup analyses
                      showed that the SHH subgroup had improved progression-free
                      survival compared with the group 3 subgroup. Moreover,
                      within the SHH subgroup, the iSHH-II subtype had improved
                      progression-free survival in the absence of radiation,
                      intraventricular chemotherapy, or high-dose chemotherapy
                      compared with the iSHH-I subtype. These findings support the
                      development of a molecularly driven, risk-adapted, treatment
                      approach in future trials in young children with
                      medulloblastoma.American Lebanese Syrian Associated
                      Charities, St Jude Children's Research Hospital, NCI Cancer
                      Center, Alexander and Margaret Stewart Trust, Sontag
                      Foundation, and American Association for Cancer Research.},
      cin          = {G200 / B062 / L101 / B060 / G380},
      ddc          = {610},
      cid          = {I:(DE-He78)G200-20160331 / I:(DE-He78)B062-20160331 /
                      I:(DE-He78)L101-20160331 / I:(DE-He78)B060-20160331 /
                      I:(DE-He78)G380-20160331},
      pnm          = {319H - Addenda (POF3-319H)},
      pid          = {G:(DE-HGF)POF3-319H},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:29778738},
      doi          = {10.1016/S1470-2045(18)30204-3},
      url          = {https://inrepo02.dkfz.de/record/135968},
}