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@ARTICLE{Herrlinger:860831,
      author       = {Herrlinger, Ulrich and Tzaridis, Theophilos and Mack,
                      Frederic and Steinbach, Joachim Peter and Schlegel, Uwe and
                      Sabel, Michael and Hau, Peter and Kortmann, Rolf-Dieter and
                      Krex, Dietmar and Grauer, Oliver and Goldbrunner, Roland and
                      Schnell, Oliver and Bähr, Oliver and Uhl, Martin and
                      Seidel, Clemens and Tabatabai, Ghazaleh and Kowalski, Thomas
                      and Ringel, Florian and Schmidt-Graf, Friederike and
                      Suchorska, Bogdana and Brehmer, Stefanie and Weyerbrock,
                      Astrid and Renovanz, Miriam and Bullinger, Lars and
                      Galldiks, Norbert and Vajkoczy, Peter and Misch, Martin and
                      Vatter, Hartmut and Stuplich, Moritz and Schäfer, Niklas
                      and Kebir, Sied and Weller, Johannes and Schaub, Christina
                      and Stummer, Walter and Tonn, Jörg-Christian and Simon,
                      Matthias and Keil, Vera C and Nelles, Michael and Urbach,
                      Horst and Coenen, Martin and Wick, Wolfgang and Weller,
                      Michael and Fimmers, Rolf and Schmid, Matthias and
                      Hattingen, Elke and Pietsch, Torsten and Coch, Christoph and
                      Glas, Martin},
      title        = {{L}omustine-temozolomide combination therapy versus
                      standard temozolomide therapy in patients with newly
                      diagnosed glioblastoma with methylated {MGMT} promoter
                      ({C}e{T}e{G}/{NOA}–09): a randomised, open-label, phase 3
                      trial},
      journal      = {The lancet},
      volume       = {393},
      number       = {10172},
      issn         = {0140-6736},
      address      = {London [u.a.]},
      publisher    = {Elsevier},
      reportid     = {FZJ-2019-01486},
      pages        = {678 - 688},
      year         = {2019},
      abstract     = {BackgroundThere is an urgent need for more effective
                      therapies for glioblastoma. Data from a previous
                      unrandomised phase 2 trial suggested that
                      lomustine-temozolomide plus radiotherapy might be superior
                      to temozolomide chemoradiotherapy in newly diagnosed
                      glioblastoma with methylation of the MGMT promoter. In the
                      CeTeG/NOA-09 trial, we aimed to further investigate the
                      effect of lomustine-temozolomide therapy in the setting of a
                      randomised phase 3 trial.MethodsIn this open-label,
                      randomised, phase 3 trial, we enrolled patients from 17
                      German university hospitals who were aged 18–70 years,
                      with newly diagnosed glioblastoma with methylated MGMT
                      promoter, and a Karnofsky Performance Score of $70\%$ and
                      higher. Patients were randomly assigned (1:1) with a
                      predefined SAS-generated randomisation list to standard
                      temozolomide chemoradiotherapy (75 mg/m2 per day concomitant
                      to radiotherapy [59–60 Gy] followed by six courses of
                      temozolomide 150–200 mg/m2 per day on the first 5 days of
                      the 4-week course) or to up to six courses of lomustine (100
                      mg/m2 on day 1) plus temozolomide (100–200 mg/m2 per day
                      on days 2–6 of the 6-week course) in addition to
                      radiotherapy (59–60 Gy). Because of the different
                      schedules, patients and physicians were not masked to
                      treatment groups. The primary endpoint was overall survival
                      in the modified intention-to-treat population, comprising
                      all randomly assigned patients who started their allocated
                      chemotherapy. The prespecified test for overall survival
                      differences was a log-rank test stratified for centre and
                      recursive partitioning analysis class. The trial is
                      registered with ClinicalTrials.gov, number
                      NCT01149109.FindingsBetween June 17, 2011, and April 8,
                      2014, 141 patients were randomly assigned to the treatment
                      groups; 129 patients (63 in the temozolomide and 66 in the
                      lomustine-temozolomide group) constituted the modified
                      intention-to-treat population. Median overall survival was
                      improved from 31·4 months $(95\%$ CI 27·7–47·1) with
                      temozolomide to 48·1 months (32·6 months–not assessable)
                      with lomustine-temozolomide (hazard ratio [HR] 0·60, $95\%$
                      CI 0·35–1·03; p=0·0492 for log-rank analysis). A
                      significant overall survival difference between groups was
                      also found in a secondary analysis of the intention-to-treat
                      population (n=141, HR 0·60, $95\%$ CI 0·35–1·03;
                      p=0·0432 for log-rank analysis). Adverse events of grade 3
                      or higher were observed in 32 $(51\%)$ of 63 patients in the
                      temozolomide group and 39 $(59\%)$ of 66 patients in the
                      lomustine-temozolomide group. There were no
                      treatment-related deaths.InterpretationOur results suggest
                      that lomustine-temozolomide chemotherapy might improve
                      survival compared with temozolomide standard therapy in
                      patients with newly diagnosed glioblastoma with methylated
                      MGMT promoter. The findings should be interpreted with
                      caution, owing to the small size of the trial.},
      cin          = {INM-3},
      ddc          = {610},
      cid          = {I:(DE-Juel1)INM-3-20090406},
      pnm          = {572 - (Dys-)function and Plasticity (POF3-572)},
      pid          = {G:(DE-HGF)POF3-572},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:30782343},
      UT           = {WOS:000458817300026},
      doi          = {10.1016/S0140-6736(18)31791-4},
      url          = {https://juser.fz-juelich.de/record/860831},
}