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      Neurocognitive functioning and health-related quality of life in adult medulloblastoma patients: long-term outcomes of the NOA-07 study

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          Abstract

          Background

          Combined radiochemotherapy followed by maintenance chemotherapy with cisplatin, lomustine and vincristine within the NOA-07 study resulted in considerable short-term toxicity in adult medulloblastoma patients. Here we investigated the long-term impact of this treatment, focusing on neurocognitive functioning and health-related quality of life (HRQoL).

          Methods

          Neurocognitive functioning and HRQoL scores over time were determined, and differences between the post-treatment and follow-up assessments were calculated up to 18 months for neurocognition and 60 months for HRQoL.

          Results

          28/30 patients were analyzed. The three preselected HRQoL scales (role, social and cognitive functioning) showed improved scores, to a clinically relevant extent (≥ 10 points), compared to post-treatment levels up to 30 months, but decreased afterwards. Z-scores for verbal working memory were worse during follow-up compared to post-treatment scores and remained impaired during 18 months follow-up (i.e. z-score below − 1 standard deviation). Attention was impaired post-treatment, and remained impaired to a clinically relevant extent during follow-up. Coordination/processing speed and lexical verbal fluency improved compared to post-treatment scores, and remained within the normal range thereafter. Other tests of verbal fluency were stable over time, with z-scores within the normal range.

          Conclusions

          This long-term follow-up study showed that the NOA-07 treatment regimen was not associated with a deterioration in HRQoL in the post-treatment period. Verbal working memory deteriorated, while other neurocognitive domains did not seem to be impacted negatively by the treatment.

          Electronic supplementary material

          The online version of this article (10.1007/s11060-020-03502-y) contains supplementary material, which is available to authorized users.

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          Most cited references47

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          Interpreting the significance of changes in health-related quality-of-life scores.

          To determine the significance to patients of changes in health-related quality-of-life (HLQ) scores assessed by the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30). A subjective significance questionnaire (SSQ), which asks patients about perceived changes in physical, emotional, and social functioning and in global quality of life (global QL) and the QLQ-C30 were completed by patients who received chemotherapy for either breast cancer or small-cell lung cancer (SCLC). In the SSQ, patients rated their perception of change since the last time they completed the QLQ-C30 using a 7-category scale that ranged from "much worse" through "no change" to "much better." For each category of change in the SSQ, the corresponding differences were calculated in QLQ-C30 mean scores and effect sizes were determined. For patients who indicated "no change" in the SSQ, the mean change in scores in the corresponding QLQ-C30 domains was not significantly different from 0. For patients who indicated "a little" change either for better or for worse, the mean change in scores was about 5 to 10; for "moderate" change, about 10 to 20; and for "very much" change, greater than 20. Effect sizes increased in concordance with increasing changes in SSQ ratings and QLQ-C30 scores. The significance of changes in QLQ-C30 scores can be interpreted in terms of small, moderate, or large changes in quality of life as reported by patients in the SSQ. The magnitude of these changes also can be used to calculate the sample sizes required to detect a specified change in clinical trials.
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            Phase III study of craniospinal radiation therapy followed by adjuvant chemotherapy for newly diagnosed average-risk medulloblastoma.

            To determine the event-free survival (EFS) and overall survival of children with average-risk medulloblastoma and treated with reduced-dose craniospinal radiotherapy (CSRT) and one of two postradiotherapy chemotherapies. Four hundred twenty-one patients between 3 years and 21 years of age with nondisseminated medulloblastoma (MB) were prospectively randomly assigned to treatment with 23.4 Gy of CSRT, 55.8 Gy of posterior fossa RT, plus one of two adjuvant chemotherapy regimens: lomustine (CCNU), cisplatin, and vincristine; or cyclophosphamide, cisplatin, and vincristine. Results Forty-two of 421 patients enrolled were excluded from analysis. Sixty-six of the remaining 379 patients had incompletely assessable postoperative studies. Five-year EFS and survival for the cohort of 379 patients was 81% +/- 2.1% and 86% +/- 9%, respectively (median follow-up over 5 years). EFS was unaffected by sex, race, age, treatment regimen, brainstem involvement, or excessive anaplasia. EFS was detrimentally affected by neuroradiographic unassessability. Patients with areas of frank dissemination had a 5-year EFS of 36% +/- 15%. Sixty-seven percent of progressions had some component of dissemination. There were seven second malignancies. Infections occurred more frequently on the cyclophosphamide arm and electrolyte abnormalities were more common on the CCNU regimen. This study discloses an encouraging EFS rate for children with nondisseminated MB treated with reduced-dose craniospinal radiation and chemotherapy. Additional, careful, step-wise reductions in CSRT in adequately staged patients may be possible.
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              Cognitive and radiological effects of radiotherapy in patients with low-grade glioma: long-term follow-up.

              Our previous study on cognitive functioning among 195 patients with low-grade glioma (LGG) a mean of 6 years after diagnosis suggested that the tumour itself, rather than the radiotherapy used to treat it, has the most deleterious effect on cognitive functioning; only high fraction dose radiotherapy (>2 Gy) resulted in significant added cognitive deterioration. The present study assesses the radiological and cognitive abnormalities in survivors of LGG at a mean of 12 years after first diagnosis. Patients who have had stable disease since the first assessment were invited for follow-up cognitive assessment (letter-digit substitution test, concept shifting test, Stroop colour-word test, visual verbal learning test, memory comparison test, and categoric word fluency). Compound scores in six cognitive domains (attention, executive functioning, verbal memory, working memory, psychomotor functioning, and information processing speed) were calculated to detect differences between patients who had radiotherapy and patients who did not have radiotherapy. White-matter hyperintensities and global cortical atrophy were rated on MRI scans. 65 patients completed neuropsychological follow-up at a mean of 12 years (range 6-28 years). 32 (49%) patients had received radiotherapy (three had fraction doses >2 Gy). The patients who had radiotherapy had more deficits that affected attentional functioning at the second follow-up, regardless of fraction dose, than those who did not have radiotherapy (-1.6 [SD 2.4] vs -0.1 [1.3], p=0.003; mean difference 1.4, 95% CI 0.5-2.4). The patients who had radiotherapy also did worse in measures of executive functioning (-2.0 [3.7] vs -0.5 [1.2], p=0.03; mean difference 1.5, 0.2-2.9) and information processing speed (-2.0 [3.7] vs -0.6 [1.5], p=0.05; mean difference 0.8, 0.009-1.6]) between the two assessments. Furthermore, attentional functioning deteriorated significantly between the first and second assessments in patients who had radiotherapy (p=0.25). In total, 17 (53%) patients who had radiotherapy developed cognitive disabilities deficits in at least five of 18 neuropsychological test parameters compared with four (27%) patients who were radiotherapy naive. White-matter hyperintensities and global cortical atrophy were associated with worse cognitive functioning in several domains. Long-term survivors of LGG who did not have radiotherapy had stable radiological and cognitive status. By contrast, patients with low-grade glioma who received radiotherapy showed a progressive decline in attentional functioning, even those who received fraction doses that are regarded as safe (
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                Author and article information

                Contributors
                l.dirven@lumc.nl
                ralf.luerding@medbo.de
                dagmar.beier@rsyd.dk
                elisabeth.bumes@ukr.de
                Christiane.Reinert@barmherzige-regensburg.de
                clemens.seidel@medizin.uni-leipzig.de
                matteo.bonsanto@uksh.de
                bremer.michael@mh-hannover.de
                stefan.rieken@med.uni-goettingen.de
                Stephanie.Combs@tum.de
                ulrich.herrlinger@ukb.uni-bonn.de
                Corinna.Seliger@klinik.uni-regensburg.de , corinna.seliger-behme@med.uni-heidelberg.de
                holger.kuntze@unimedizin-mainz.de
                regine.mayer-steinacker@uniklinik-ulm.de
                annette.dieing@vivantes.de
                claudius.bartels@med.ovgu.de
                oliver.schnell@uniklinik-freiburg.de
                Astrid.weyerbrock@uniklinik-freiburg.de
                sabine.seidel@kk-bochum.de
                oliver.grauer@ukmuenster.de
                m.nadji-ohl@klinikum-stuttgart.de
                frank.paulsen@med.uni-tuebingen.de
                michael.weller@usz.ch
                wolfgang.wick@med.uni-heidelberg.de
                peter.hau@ukr.de
                Journal
                J Neurooncol
                J. Neurooncol
                Journal of Neuro-Oncology
                Springer US (New York )
                0167-594X
                1573-7373
                4 May 2020
                4 May 2020
                2020
                : 148
                : 1
                : 117-130
                Affiliations
                [1 ]GRID grid.10419.3d, ISNI 0000000089452978, Department of Neurology, , Leiden University Medical Center, ; Leiden, The Netherlands
                [2 ]GRID grid.414842.f, ISNI 0000 0004 0395 6796, Department of Neurology, , Haaglanden Medical Center, ; The Hague, The Netherlands
                [3 ]GRID grid.7727.5, ISNI 0000 0001 2190 5763, Wilhelm Sander-NeuroOncology Unit and Department of Neurology, , University of Regensburg, ; Regensburg, Germany
                [4 ]GRID grid.10825.3e, ISNI 0000 0001 0728 0170, Department of Neurology, University Hospital Odense and Clinical Institute, , University of Southern Denmark, ; Odense, Denmark
                [5 ]Department of Oncology, Krankenhaus der Barmherzigen Brüder Regensburg, Regensburg, Germany
                [6 ]GRID grid.411339.d, ISNI 0000 0000 8517 9062, Department of Radiation Oncology, , University Hospital Leipzig, ; Leipzig, Germany
                [7 ]GRID grid.412468.d, ISNI 0000 0004 0646 2097, Department of Neurosurgery, , University Hospital, ; Lübeck, Germany
                [8 ]GRID grid.10423.34, ISNI 0000 0000 9529 9877, Department of Radiation Oncology, , Medical School Hannover, ; Hannover, Germany
                [9 ]GRID grid.411984.1, ISNI 0000 0001 0482 5331, Department of Radiotherapy and Radiation Oncology, , University Hospital Göttingen, ; Göttingen, Germany
                [10 ]GRID grid.6936.a, ISNI 0000000123222966, Department of Radiation Oncology, , Technical University of Munich, ; Munich, Germany
                [11 ]Institute of Radiation Medicine, Helmholtz Zentrum Münche, Oberschleißheim, Germany
                [12 ]Deutsches Konsortium für Translationale Krebsforschung (DKTK), Partner Site Munich, Munich, Germany
                [13 ]GRID grid.15090.3d, ISNI 0000 0000 8786 803X, Division of Neurooncology, , University of Bonn Medical Center, ; Bonn, Germany
                [14 ]GRID grid.5253.1, ISNI 0000 0001 0328 4908, Department of Neurology, , University Hospital Heidelberg, ; Heidelberg, Germany
                [15 ]GRID grid.7497.d, ISNI 0000 0004 0492 0584, Neurooncology Program at the National Center for Tumor Diseases, , German Cancer Research Center (DKFZ)/DKTK, ; Heidelberg, Germany
                [16 ]GRID grid.410607.4, Department of Neurology, , University Hospital Mainz, ; Mainz, Germany
                [17 ]GRID grid.410712.1, Department of Medical Oncology, , University Hospital Ulm, ; Ulm, Germany
                [18 ]GRID grid.415085.d, Department of Internal Medicine, Hematology and Oncology, , Vivantes Klinikum am Friedrichshain, ; Berlin, Germany
                [19 ]GRID grid.411559.d, ISNI 0000 0000 9592 4695, Department of Neurosurgery, , University Hospital Magdeburg, ; Magdeburg, Germany
                [20 ]GRID grid.7708.8, ISNI 0000 0000 9428 7911, Department of Neurosurgery, , University Hospital Freiburg, ; Freiburg, Germany
                [21 ]GRID grid.5570.7, ISNI 0000 0004 0490 981X, Department of Neurology, Knappschaftskrankenhaus, , University of Bochum, ; Bochum, Germany
                [22 ]GRID grid.16149.3b, ISNI 0000 0004 0551 4246, Department of Neurology with Institute of Translational Neurology, , University Hospital Münster, ; Münster, Germany
                [23 ]GRID grid.419842.2, ISNI 0000 0001 0341 9964, Department of Radiation Oncology, , Klinikum Stuttgart, ; Stuttgart, Germany
                [24 ]GRID grid.411544.1, ISNI 0000 0001 0196 8249, Department of Radiation Oncology, , University Hospital Tübingen, ; Tübingen, Germany
                [25 ]GRID grid.7400.3, ISNI 0000 0004 1937 0650, Department of Neurology, , University Hospital and University of Zurich, ; Zurich, Switzerland
                Article
                3502
                10.1007/s11060-020-03502-y
                7280359
                32367436
                2234ced7-218d-4f1d-a0f7-8d63fae9c5de
                © The Author(s) 2020

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 11 January 2020
                : 9 April 2020
                Funding
                Funded by: German Neuro-Oncology Society (NOA)
                Funded by: medac GmbH
                Categories
                Clinical Study
                Custom metadata
                © Springer Science+Business Media, LLC, part of Springer Nature 2020

                Oncology & Radiotherapy
                brain tumor,medulloblastoma,cognition,quality of life,patient-reported outcome,toxicity

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