- Email: [email protected]
Strategies to improve the quality of survival for childhood brain tumour survivors
Accepted Manuscript Strategies to improve the Quality of Survival for Childhood Brain Tumour Survivors PD Dr. med. Gesche Tallen, Anika Resch, Gabriele Calaminus, Andreas Wiener, Ulrike Leiss, Thomas Pletschko, Carsten Friedrich, Thorsten Langer, Desiree Grabow, Pablo Hernáiz Driever, Rolf-Dieter Kortmann, Beate Timmermann, Torsten Pietsch, Monika Warmuth-Metz, Brigitte Bison, Ulrich-Wilhelm Thomale, Jürgen Krauss, Martin Mynarek, Katja von Hoff, Holger Ottensmeier, Michael Frühwald, Christof M. Kramm, Petra Temming, Hermann L. Müller, Olaf Witt, Uwe Kordes, Gudrun Fleischhack, Astrid Gnekow, Stefan Rutkowski
PII:
S1090-3798(15)00139-7
DOI:
10.1016/j.ejpn.2015.07.011
Reference:
YEJPN 1935
To appear in:
European Journal of Paediatric Neurology
Received Date: 28 April 2015 Accepted Date: 5 July 2015
Please cite this article as: Tallen G, Resch A, Calaminus G, Wiener A, Leiss U, Pletschko T, Friedrich C, Langer T, Grabow D, Driever PH, Kortmann R-D, Timmermann B, Pietsch T, Warmuth-Metz M, Bison B, Thomale U-W, Krauss J, Mynarek M, von Hoff K, Ottensmeier H, Frühwald M, Kramm CM, Temming P, Müller HL, Witt O, Kordes U, Fleischhack G, Gnekow A, Rutkowski S, on behalf of the German Paediatric Brain Tumour Consortium (HIT-Network), Strategies to improve the Quality of Survival for Childhood Brain Tumour Survivors, European Journal of Paediatric Neurology (2015), doi: 10.1016/ j.ejpn.2015.07.011. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT 1
Strategies to improve the Quality of Survival
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for Childhood Brain Tumour Survivors
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Gesche Tallena, Anika Reschb, Gabriele Calaminusc, Andreas Wienerc, Ulrike Leissd, Thomas Pletschkod, Carsten Friedrichb,e, Thorsten Langerf, Desiree Grabowg, Pablo Hernáiz Drievera, Rolf-Dieter Kortmannh, Beate Timmermanni, Torsten Pietschj, Monika Warmuth-Metzk, Brigitte Bisonk, Ulrich-Wilhelm Thomalel, Jürgen Kraussm, Martin Mynarekb, Katja von Hoffb, Holger Ottensmeiern, Michael Frühwaldo, Christof M. Krammp, Petra Temmingq, Hermann L. Müllerr, Olaf Witts, Uwe Kordesb, Gudrun Fleischhackq, Astrid Gnekowo, Stefan Rutkowskib on behalf of the German Paediatric Brain Tumour Consortium (HIT-Network) a
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Department of Paediatric Oncology/Haematology, Charité-Universitätsmedizin Berlin, Campus Virchow, Augustenburger Platz 1, 13353 Berlin, Germany ([email protected], [email protected]) b Department of Paediatric Haematology and Oncology, University Medical Centre Hamburg-Eppendorf (UKE), Martinistr. 52, 20246 Hamburg, Germany ([email protected], [email protected], [email protected], [email protected], [email protected], [email protected]) c Department of Paediatric Haematology and Oncology, University Hospital Münster, Albert-Schweitzer-Campus 1, 48149 Münster, Germany ([email protected], [email protected]) d Medical University Vienna, Department of Paediatric and Adolescent Medicine, Währinger Gürtel 18-20, 1090 Vienna, Austria ([email protected], [email protected]) e Division of Paediatric Oncology, Haematology and Haemostaseology, Department of Woman´s and Children´s Health, University Hospital Leipzig, Liebigstr. 20a, 04103 Leipzig, Germany ([email protected]) f Department of Paediatric Oncology/Haematology, University of Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany ([email protected]) g German Childhood Cancer Registry (GCCR), Institute of Medical Biostatistics, Epidemiology, and Informatics (IMBEI), University Medical Center, University of Mainz, Gebäude 902, Obere Zahlbacher Straße 69, 55131 Mainz, Germany ([email protected]) h Department of Radiation Oncology, University of Leipzig, Stephanstr. 9a, 04103 Leipzig, Germany ([email protected]) i Particle Therapy Clinic at West German Proton Therapy Centre Essen, University Hospital Essen, Hufelandstr. 55, 45147 Essen, Germany ([email protected]) j Institute of Neuropathology, University of Bonn, Sigmund-Freud-Str. 25, 53105 Bonn, Germany ([email protected]) k Dept. of Neuroradiology, University of Würzburg, Josef-Schneider-Str. 11, 97080 Würzburg, Germany ([email protected], [email protected]) l Department of Paediatric Neurosurgery, Charité-Universitätsmedizin Berlin, Campus Virchow, Augustenburger Platz 1, 13353 Berlin, Germany ([email protected]) m Department of Neurosurgery, Head Clinic, University of Würzburg, Josef-Schneider-Str. 11, 97080 Würzburg, Germany ([email protected]) n University Children’s Hospital Würzburg, Dept. of Paed. Haematology, Oncology, Josef-Schneider-Str. 2, 97080 Würzburg, Germany ([email protected]) o Department of Paediatric Oncology/Haematology, Klinikum Augsburg, Stenglinstr. 2, 86156 Augsburg, Germany ([email protected], [email protected]) p Division of Paediatric Haematology and Oncology, University of Göttingen, Robert-Koch-Str. 40, 37075 Göttingen, Germany ([email protected]) q Paediatric Haematology/Oncology, Paediatrics III, University of Essen, Hufelandstr. 55, 45147 Essen, Germany ([email protected], [email protected]) r Paediatric Oncology/Haematology, Klinikum Oldenburg, Medical Campus University Oldenburg, Rahel-Straus-Str. 10, 26133 Oldenburg, Germany ([email protected]) s German Cancer Research Centre (DKFZ) and Department of Paediatric Oncology/Haematology, University of Heidelberg, Heidelberg, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany ([email protected]) Corresponding author: PD Dr. med. Gesche Tallen Department of Paediatric Oncology/Haematology Charité-Universitätsmedizin Berlin Campus Virchow, Augustenburger Platz 1, 13353 Berlin, Germany Tel.:++49 (0)30-450-566032 | Fax:++49 (0)30-450-566906 email: [email protected]
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ABSTRACT
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second most frequent type of cancer in children and adolescents. Overall survival has
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continuously improved in Germany, since an increasing number of patients has been treated
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according to standardized, multicentric, multimodal treatment recommendations, trials of the
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German Paediatric Brain Tumour Consortium (HIT-Network) or the International Society of
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Paediatric Oncology-Europe (SIOP-E) during the last decades. Today, two out of three patients
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survive. At least 8000 long-term childhood brain tumour survivors (CBTS) are currently living
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in Germany. They face lifelong disease- and treatment-related late effects (LE) and associated
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Tumours of the central nervous system (CNS) are the most frequent solid tumours and the
socioeconomic problems more than many other childhood cancer survivors (CCS).
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We review the LE and resulting special needs of this particular group of CCS. Despite their
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increasing relevance for future treatment optimisation, neither the diversity of chronic and
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cumulative LE nor their pertinent risk factors and subsequent impact on quality of survival have
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yet been comprehensively addressed for CBTS treated according to HIT- or SIOP-E-protocols.
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Evidence-based information to empower survivors and stakeholders, as well as medical
16
expertise to manage their individual health care, psychosocial and educational/vocational needs
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must still be generated and established.
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In conclusion, the establishment of a long-term research- and care network in Germany shall
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contribute to a European platform, that aims at optimising CBTS' transition into adulthood as
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resilient individuals with high quality of survival including optimal levels of activity,
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participation and acceptance by society.
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Key-words: Childhood Brain Tumor - Childhood Cancer Survivor - Late Effects - Quality of Survival -
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Long-Term Care
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1.1 The Background: Increasing "Quantity of Survival" for patients with the diagnosis "Childhood Primary Brain Tumour". Accounting for about 24% of childhood cancers, primary central nervous system (CNS)* tumours are the most frequent solid tumours and second most frequent
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malignancies in childhood and adolescence [1,2]. More than 400 children and
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adolescents are diagnosed with a CNS tumour in Germany each year. About 95% of
8
them receive treatment according to prospective, multi-centre therapy optimisation
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studies or non-interventional registries, respectively, conducted by the German
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Paediatric Brain Tumour Consortium (HIT-Network) and the European branch of the
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International Society of Paediatric Oncology (SIOP-E) (table 1). HIT and SIOP-E
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collaboratively unite and coordinate trials and reference centres for different childhood
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brain tumour (CBT) entities, thereby promoting national and international
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implementation and continuous optimisation of treatment concepts with quality-
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controlled standards for diagnosis, treatment and supportive care (figure 1).
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The overall survival (OS) rates for CBT patients continuously improved over the
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past three decades from below 50% to over 70% (figure 2A, B), varying based upon
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tumour type, site, response to treatment and late effects (LE) [3-28]. CBT survivors
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(CBTS) suffer from LE even more than any other childhood cancer survivors (CCS)
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[29-31]. However, evidence-based LE management still needs development.
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1.2 The Goal: Maximizing "Quality of Survival" towards the diagnosis "Future".
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An estimated 8000 CBTS are currently living in Germany and numbers have been rising in many parts of Europe [32]. So have LE prevalence and the need for an adequate
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outcome measure.
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Two major outcome measures are currently applied to summarize the efficacy of
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paediatric cancer treatment: "health related QoL" (HRQoL) [33,34] and "quality of
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cure" [35]. Besides health, various host-related factors, including socioeconomic status * The following abbreviations will be used more than once in this review: CBT-childhood brain tumour, CBTS-childhood brain tumour survivor, CCS-childhood cancer survivor, CIPN - chemotherapyinduced peripheral neuropathy, CNS-central nervous system, CT-chemotherapy, CRT-cranial radiotherapy, CSI-craniospinal irradiation, FO-functional outcome, GPOH-German Society of Paediatric Oncology/Haematology, HGG-high grade glioma, HITHirntumor (German for "brain tumour"), HIT-Network - Research and Treatment Consortium consisting of all German study coordination- and reference centers for the treatment of children and adolescents with primary brain tumours (supported by the German Childhood Cancer Foundation/Deutsche Kinderkrebsstiftung), HRQoL-health-related quality of life, LE-late effect(s), LGGlow grade glioma, LTFU - long-term follow-up, MB-medulloblastoma, NCF-neurocognitive functioning, NO-neuropsychological outcome, NS-neurosurgery, OS-overall survival, PF-posterior fossa, PFS-posterior fossa syndrome, PNET-primitive neuroectodermal tumour, QoL-quality of life, QoS-quality of survival, RT-radiotherapy, SES-socioeconomic status, SIOPInternational Society of Paediatric Oncology, SIOP-E - SIOP Europe; SMN-secondary malignant neoplasm, WBRT-whole brain RT.
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ACCEPTED MANUSCRIPT (SES), individual levels of activity and participation add to the complexity of QoL-
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measurement. Large population-based studies show that the overall HRQoL of many
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CCS is compromised compared to the healthy population [36-40], while QoL-analyses
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of smaller CBTS subgroups [41-43] are partially controversial. Overall, the classical
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(HR)QoL framework did not prove adequate for CCS [44]. Particularly during QoL-
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assessment in survivors of medulloblastoma (MB), the most frequent malignant CBT,
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regular conceptual broadening was imperative [45] owing to continuous treatment
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optimisations and subsequent increases in both OS and LE.
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In European paediatric oncology, "quality of cure" is defined by the "presence
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and intensity of treatment complications in a long-term survivor" [35]. This concept
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may not completely cover the situation of CBTS either, because in addition to
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treatment-related LE, they typically suffer frequently from those caused by the tumour
13
itself. Taken together, a measure addressing the "quality of survival" (QoS) with all its
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relevant treatment-, tumour- and host-related factors may be more accurate for CBTS
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[46].
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1.3 The Facts: Multifactorial Late Effects.
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To assess the present needs of CBTS, we reviewed the international literature based on
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Medline-searches and textbooks in paediatric oncology. We included all reports
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published between 01/2009 and 01/2015 (aside from single earlier, basic reviews and
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large-cohort studies), that provided comprehensive information on type, incidence,
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causes, risk factors, current management of LE and QoL in CBTS. Because of the
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conceptual and clinical heterogeneity as well as the diversity of the major foci in these
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articles, statistic pooling of the information was not performed.
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1.3.1 Not only somatic: Tumour-related late effects.
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Tumour-related LE largely depend on CBT-type, anatomic localisation, incidence,
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extent and duration of peritumoural edema, hydrocephalus and age at diagnosis.
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Seizures, focal palsies, ataxia, visual impairment, endocrinopathies [47-52] and
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sometimes reduced neurocognitive functioning (NCF) [53] are common and require
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systematic assessment.
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1.3.2 "Surgical neurotoxicity": Neurosurgery-related late effects. Neurosurgery (NS) remains a mainstay of therapy, both for reducing tumour
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burden and obtaining histology. Careful balance must be kept between extent of
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resection and preservation of eloquent structures. While for many CBT, including high-
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grade glioma (HGG), cerebellar low-grade glioma (LGG) and ependymoma, failure to
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achieve gross radiographic resection is associated with poorer outcome [54,55], subtotal
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resection (for reducing the risk of LE) proved feasible for selective patients with MB
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(<1.5cm2 of residual tumour, followed by chemo- (CT) and radiotherapy (RT)),
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visual pathway glioma and craniopharyngioma [4,6,12,47,56-61]. Whether continuously
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advancing techniques such as intraoperative magnetic resonance imaging (MRI),
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neurofunctional monitoring, intraoperative tumour staining [62-68] may impact on
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options of complete resection, but not LE prevalence, needs assessment.
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Functional outcome (FO) after NS depends on tumour site, surgical approach,
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neurosurgeon's experience, patient's age and presurgical performance status [47-50].
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Postoperative impairments may include stroke, seizures, palsies, central oculomotor
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deficits, ataxia, vision loss as well as hypothalamic damage resulting in endocrinopathy
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and reduced NCF [51-53] and may be enhanced by adjuvant therapy. Hydrocephalus requiring shunt surgery often negatively influences FO as well
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[69-74]. Potential covariates like the degree and duration of ventricular dilatation,
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shunting technique and adjuvant therapy still need evaluation.
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A prime example of "surgical neurotoxicity" is cerebellar mutism- or posterior
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fossa (PF) syndrome (CMS/PFS). It occurs in 15%-25% of patients with fourth
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ventricular tumours, bilateral inferior olivary nucleus abnormalities [74,75], left-
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handedness, large PF tumours [76] and vermian splitting during NS [77]. The onset is
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usually within the first postoperative week presenting with speech impairments,
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followed by pseudobulbar palsy, ataxia, cognitive, behavioural and emotional disorders.
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These may be progressive and irreversible or take months to years to recover [78,79]. In
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addition to NS, other treatment- and also host-related factors may contribute to
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developing PFS, particularly to the behavioural changes [80,81]. Careful distinction
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between CMS/PFS and "real" brainstem damage is necessary to frame effective
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interventional concepts. This distinction requires standardised diagnostic tools
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developed in prospective analyses based on incidence, aetiological role of a disrupted
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fronto-cerebellar circuit, severity of PFS and development of long-term cerebellar
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cognitive affective syndrome [75,81-85].
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1.3.4 Changing patterns due to technical advancements: Radiotherapy
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(RT)-related late effects
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Like neurosurgery, cranial RT (CRT) and craniospinal irradiation (CSI) are well-proven
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backbones of local CBT control. Standard approaches include CRT and/or CSI either as
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adjuvant or single local therapy. However, the developing CNS is vulnerable to
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irradiation, particularly in very young children. CRT-related LE range from transient
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and treatable to permanent and progressive impairments [86]. The risk of many LE is, as
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shown in table 2 [87-145], dependent of CRT-region, -dose, -technique and multiple
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covariates. The role of the CRT-dose-volume-ratio still needs validation for already
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examined entities such as ependymoma and LGG [70,146] and also further analysis for
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other CBT-subgroups and different CRT techniques. Currently conflicting results may
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be due to small, heterogeneous cohorts and the multiple covariates, that have only been
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incompletely assessed for CBTS, thus only been incompletely considered in many
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analyses so far.
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1.3.4.1 Neurovascular disease
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CRT-induced neurovascular damage leads to artherosclerosis with risk of stroke and
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development of malformations (table 2A). Covariates for most neurovascular
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complications, except stroke, have not yet been reported (table 2A). Multi-centre
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prospective studies are required to identify both risk factors and imaging tools to
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recognize high-risk survivors early.
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1.3.4.2 Radiation-induced brain injury.
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Radiation necrosis radiographically presents as white matter lesions (WML,
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leukencephalopathy). Compared to RT-vasculopathy, WML are rare, particularly after
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fractionated CRT. Whole brain RT (WBRT) and intrathecal methotrexate (MTX)
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present enhancing factors (table 2A).
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1.3.4.3 Neurocognitive and behavioural impairments
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Reduced NCF after CRT is progressive, often associated with behavioural difficulties
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and promoted by various factors (table 2B). CRT involving the temporal region
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increases the risk in a dose-dependent manner, since the normal function of
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subventricular and hippocampal neural stem cells is required for normal NCF, but
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particularly vulnerable to RT-induced damage. Therefore, both proton-beam-therapy vs
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fractionation schemes applying lower single doses should be evaluated prospectively.
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1.3.4.4 Endocrinopathies
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Endocrine functions are strongly influenced by the CRT-dose to the hypothalamic-
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pituitary (hp-)axis. In CBTS without pre-CRT endocrinopathy, growth hormone (GH)
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secretion is affected most frequently and first, followed by thyroid stimulating hormone,
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adrenocorticotropic
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replacement therapy, many CBTS suffer from growth failure and/or disproportional
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spinal growth, partially due to CSI-related damage of vertebral growth plates (table 2B).
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Future studies should validate the contributory role of CT, which is currently discussed.
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Overall, it remains unclear, why, for a given critical CRT-dose to the hp-axis, some
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patients develop an endocrinopathy, while others do not.
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1.3.4.5 Ototoxicity
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CRT-related ototoxicity is mainly dependent on the cochlear dose. It mostly affects high
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frequency thresholds (table 2B). Some reports on CRT-related hearing loss, in particular
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regarding its degrees, long-term prognosis and synergistic effects of CT are
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controversial [43,70]. This may be a result of both a lack of uniform grading systems
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and different treatment concepts of the national study groups. Therefore, large-cohort
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analyses based on universal classifications should be conducted.
gonadotropins.
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Current concepts of CRT/CSI specifically focus on fine-tuning target volume- and dose
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reductions and will most likely result in positive changes of LE patterns. Multi-centre
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prospective analyses are now required, that compare QoS of CBTS after WBRT alone (-
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/+ CT), WBRT + boost to tumour site/PF (-/+ CT), or partial CRT/CSI alone (“local
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field”) (-/+ CT), respectively, and evaluate the dose-effect dependency with respect to
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dose distribution within the CNS.
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1.3.5 Late effects of chemotherapy (CT): demanding trade-offs between
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quantity and quality of survival?
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The role of CT has become increasingly important over the past decades, especially for
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very young patients, for whom CRT is not yet an option [61], and LGG patients [147].
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Both systemic and intrathecal CT can cause various LE. These are specifically observed
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after intensified therapy and concomitant CRT, thus as a result of damage to neural stem
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cells and subsequently disrupted white matter integrity. Type, cumulative dose of the
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agents as well as timing within the treatment schedule (e.g. before or after CRT) and
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route of administration are major determining factors. Although a promising option for
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younger children with MB or primitive neuroectodermal tumour of the CNS (CNS-
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PNET)
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cardiovascular LE [149]. These still need assessment for CBTS, since they may
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necessitate conceptual compromises to balance highest possible treatment intensity with
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optimal FO.
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1.3.5.1 Chemotherapy-induced peripheral neuropathy (CIPN)
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[148],
CIPN is well described after treatment with cisplatin, carboplatin, vinca-alkaloids and
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thalidomide [150-154]. Vincristine impairs sensory and motor function dependent on
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the cumulative dose [154] by disrupting axonal microtubules. The result is CIPN that, in
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children, mostly presents as pain first, followed by decreased deep tendon reflex
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responses, peripheral motor and distal sensory deficits, and sometimes visceral
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neuropathy with gastrointestinal complications. Motor deficits may persist in
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susceptible patients and often require long-term orthotic support. Older age, gender,
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ethnicity, inherited neuropathies, certain drug-drug interactions are among the risk
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factors reported so far [155-159]. Neuroprotective interventions are now required
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for prevention, because withdrawal of the agent usually does not halt CIPN.
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1.3.5.2 Encephalopathy and neurocognitive decline
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Encephalopathy can be caused by both systemic and intrathecal CT as well as
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supportive care involving glucocorticoids. MTX-related encephalopathy occurs in about
23
3% of CCS [160]. Symptoms may include headaches, neuropsychological impairments
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and seizures. Chronic forms have been associated with leukencephalopathy, especially
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in conjunction with WBRT (table 2). CT can also decrease neo- and subcortical grey
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matter volume and proliferation of hippocampal neural stem cells, thereby progressively
27
reducing NCF [159]. Reduced NCF after CT without concomitant CRT particularly
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occurs in survivors, who were very young at diagnosis [111,161] and/or who
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experienced severe ototoxicity [80]. While a recently validated neuropsychological test
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battery enables health care providers to assess the specific needs of CBTS in their daily
31
lives and to optimise parent counselling [162], other current measurement tools [154-
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155] may still need broadening regarding their feasibility, particularly for CBTS with
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visual loss [165-167] or different ethnic and language backgrounds, respectively.
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ACCEPTED MANUSCRIPT 1.3.5.3 Ototoxicity
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Ototoxicity is associated with high cumulative doses, high doses per course and bolus
3
applications of cis- and carboplatin [9], which damage cochlear hair-, spiral ganglion
4
cells and the stria vascularis - processes triggering the production of reactive oxygen
5
species, thereby promoting cell death, thus hearing loss [168]. Contributory covariates
6
are concomitant treatment with other ototoxic agents, such as aminoglycosides,
7
furosemide and CRT (table 2). As a major component of MB-treatment [7], cisplatin
8
induces ototoxicity in 28%-68% of MB-patients who received CRT [131,169]. These
9
observations were confirmed by data from trial HIT-SIOP PNET 4 [6] using the HIT-
10
and Brock classification [170]. Since 10% of the patients later on needed a hearing aid,
11
ototoxicity was declared a severe LE of this protocol. The risk of hearing loss correlates
12
with younger age at diagnosis [131]. Besides, there is promising evidence, that using
13
carboplatin instead of cisplatin may reduce ototoxicity [131]. Overall, the correlation of
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the degree of hearing loss after CT and CRT vs CT or CRT alone needs analysis.
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Genetic predisposition to ototoxicity has been reported [171-174] and discussed
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[175,176]. Also, early alteration of high-frequency thresholds may has been associated
17
with the later need of a hearing aid [177]. Many reports, including those addressing the
18
communicative, educational and psychosocial significance of high-frequency hearing
19
loss [80] may require validation, since they are based on different treatment protocols
20
and ototoxicity grading systems as well as non-randomised or retrospective in nature.
21
1.3.6 Premature aging and secondary malignant neoplasms: sharing risk
22
factors?
23
According to the North American Childhood Cancer Survivor Study, 1.3 % of CBTS
24
develop a secondary malignancy (SMN) including different CNS- and other tumour
25
types [145]. The excess absolute risk for developing a glioma rose from 8.05 in the
26
1970ies to 28.9 in the 1980ies while following a dose-response relationship. In younger
27
children, the interval is shorter after CT with a cumulative risk of 11% at 8 years after
28
CRT. Major causes of this high SMN rate may include intensified CT with high
29
cumulative doses of platinum derivates, alkylators and topoisomerase-II-inhibitors. In
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general, CRT coupled with CT increases the risk of SMN from 1.4 (CRT alone) to 4.9
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(CRT+CT) [116,127,139,141-145] (table 2B).
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Cancer is known as an aging-related disease with telomere loss as a well-
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established contributor [178]. Telomere loss can be accelerated by DNA damage, 9
ACCEPTED MANUSCRIPT thereby inducing premature aging [178], signs of which, including cancer (alias SMNs),
2
were recently reported for many CCS [179-182]. This cancer-aging interface needs
3
further analysis in CBTS. Last but not least, there is increasing evidence, that clinically
4
unrecognized hereditary cancer predisposition syndromes are genetic causes for
5
what we presently think of as SMNs [183].
6
1.4 The Challenge: Back to normal Life.
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The broad spectrum of LE may impact the psychological outcome of CBTS.
8
Posttraumatic stress, depression, anxiety, compromised coping-strategies and reduced
9
social competence have been reported [184-190]. The different measurement tools
10
applied in these studies may require harmonisation in order to establish standardized
11
long-term follow-up (LTFU)- and interventional concepts for supporting re-integration,
12
which is challenging for many survivors [191,192]. Others may face their cancer
13
experience
14
coordination of services between academic, employment and healthcare systems,
15
medical teams and social agencies is needed to maximize the survivor’s potential for
16
activity and participation in everyday life. Promising models exist for CCS [189,194],
17
but require feasibility-assessment for CBTS' special needs.
18
1.5 The Need: Empowerment for the People.
19
Paediatric Neurooncologists are currently still unable to predict the types and severity of
20
LE at the time of CBT diagnosis. Instead, only general assumptions can be disclosed for
21
informed consent in the context of multimodal treatment recommendations owing to the
22
broad interindividual range of both LE and predictive markers. Although parents’
23
decision-making behaviour when juggling the balance of least LE-risk and highest
24
survival advantage varies remarkably, many of them may feel empowered to decide
25
rather in favour of less LE if they were better informed. Hence, evidence-based
26
information should be generated to develop risk-adapted strategies for therapy
27
assignment. In addition, most survivors and their parents desire information regarding
28
their overall health and health maintenance, including their medical history and future
29
[195-197]. In fact, one-third of them are not confident in their primary care physician’s
30
competence of managing their issues [198-201]. Also, not much is known yet about
31
how they are coping with their transition from one age-group to the next. Combined
32
with their specific neuropsychological issues, this maturational process may be
optimism,
demonstrating
resilience
[193,194].
Nevertheless,
AC C
EP
TE D
with
M AN U
SC
RI PT
1
10
ACCEPTED MANUSCRIPT particularly challenging, thereby requiring quality-assured, standardized LTFU
2
guidelines not only for educating the survivors and health care professionals, but also
3
for academic staff, employers, counsellors and insurance policies.
4
1.6 The Plan: Generating evidence-based information &
5
distributing harmonised guidelines for holistic long-term care
6
concepts.
7
Quality-assured LTFU care of CCS is one of SIOP's major missions [35]. Several
8
national guidelines already exist [202,203]. However, due to a rather non-integrated
9
approach, they may require harmonisation.
SC
RI PT
1
New initiatives (PanCareSurFup, PanCareLife, VIVE [204]) use a pan-European or
11
pan-German, respectively, approach in collaboration with partners, such as the Late-
12
Effects-Study-Group/Late-Effects-Surveillance-System (LESS) and the Cardiac and
13
Vascular Late Sequelae in long-term survivors of childhood cancer (CVSS)-Study
14
Group, to develop better harmonised LFTU guidelines. Additionally, they collaborate to
15
evaluate the risks of SMN, late mortality, cardiovascular damage, infertility, ototoxicity,
16
and compromised HRQoL. However, these initiatives deal with CCS in general, not
17
with CBTS' unique needs in particular.
18
1.7 The Conclusion: A new science has emerged.
19
An important step for research towards better understanding and improving the current
20
situation of CBTS is to collaborate on national levels and in larger-scale studies, that
21
provide sufficient statistical power for a) analysing the relative contributions of host-,
22
tumour- and treatment-related variables, b) identifying risk factors, c) characterising the
23
mechanisms underlying each of the LE and d) how these may impact a CBTS's QoS.
24
The HIT-network provides favourable preconditions to conduct these studies.
TE D
EP
AC C
25
M AN U
10
26 27 28 29 30
11
ACCEPTED MANUSCRIPT 1
ACKNOWLEDGEMENTS
2
We would like to thank the German Childhood Cancer Foundation for supporting the
3
HIT-Network, including all study- and reference centres since 2000. We also thank the
4
Fördergemeinschaft
5
neuropsychological evaluations by A.R. within the HIT-MED trials. Our thanks also go
6
to PD Dr. Claudia Spix, deputy head of the German Childhood Cancer Registry
7
(GCCR), University Medical Centre, University of Mainz, Germany, for providing
8
Figure 2A and B.
9
CONFLICT OF INTEREST STATEMENT
Hamburg
e.V.
for
support
of
RI PT
Kinderkrebs-Zentrum
None.
11 12
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DEFINITIONS
29
The following terms (listed in alphabetical order) will be used more than once in this
30
review in the context of childhood brain tumour survival. They are based on the
31
following definitions of the World Health Organization (WHO) Quality of Life
32
Assessment Group, the International Classification of functioning, disability and health
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ACCEPTED MANUSCRIPT according to the WHO [33,34] and the International Society of Paediatric Oncology
2
(Europe) (SIOP-E) [205]:
3
Activity
4
Relating to the execution of a task or action by a childhood brain tumour survivor
5
(CBTS). Activity limitations comprise problems a CBTS may have in executing
6
activities.
7
Functional outcome (FO)
8
Summarizes all aspects of a CBTS's physiological functions of body systems, including
9
neurocognitive function as well as neuropsychological and psychooncological outcomes
SC
RI PT
1
(see below).
11
Environmental factors
12
Relating to the physical, social and attitudinal environment in which the survivor lives
13
and conducts her/his life as well as to the survivor's individual internal influences, such
14
as socio-economic status (SES), ethnic and cultural heritage, religion and spirituality. In
15
this review also referred to as "host-related factors".
16
Impairment
17
Relating to a CBTS's problems in body function or structure such as a significant
18
deviation or loss.
19
Neurocognitive functioning (NCF)
20
Relating to a CBTS's central nervous system (CNS) function and structure as it relates
21
to her/his cognitive (i.e. relating to, or being conscious intellectual activity such as
22
thinking, reasoning, remembering, imagining, or learning words) functions associated
23
with particular areas, neural pathways and cortical networks of the CNS.
24
Neuropsychological outcome
25
A CBTS's CNS function and structure as it relates to her/his neurologic, emotional,
26
behavioural and neurocognitive functioning (see above) and related physical abilities.
AC C
EP
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10
30
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2
Relating to the CBTS's involvement in a life situation. Participation restrictions are
3
difficulties a CBTS may have in involvement in life situations.
4
Psychooncological outcome (PO)
5
Referring to the survivors' psychological health and the social and behavioural factors
6
that may affect the disease process as well as the development in, and interaction with a
7
social environment.
8
Quality of Life (QoL), Health-related QOL (HRQoL)
9
QoL is a broad multidimensional concept that mainly addresses the subjective indicators
10
of the wellbeing of an individual, i.e. everyday emotional experiences as well as life in
11
general. In contrast, HRQoL is a concept (including physical, social, emotional,
12
cognitive, work-/role-related, spiritual aspects) that focuses on this wellbeing with
13
respect to a disability, disorder or underlying disease like a primary childhood brain
14
tumour (CBT). Using self-reporting questionnaires, subjects describe their individual
15
situation in the context of their personal expectations and goals.
16
Quality of Survival (QoS)
17
In this review: includes long-term neurocognitive, endocrine and other medical,
18
behavioural, emotional and adaptive functional sequelae of CBT and environmental
19
(host-related) factors (see above).
SC
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EP
21
AC C
20
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1
31
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Table 1. Trials/registries of the German Paediatric Brain Tumour Consortium (HIT-Network) for treatment/registration of children and adolescents with primary central nervous system (CNS) tumours.
intracerebral and spinal Ependymoma (WHO°II, III)
HIT-2000 (01/2012-12/14: HIT-2000-Interim-Registry) (ClinicalTrials.gov Identifier: NCT02238899) SIOP-PNET5 MB (ClinicalTrials.gov Identifier: NCT02066220) low and standard risk MB I-HIT-MED registry (since 1/2015)
Major Objectives
interventional & registry multicentre, prospective, randomised, therapy optimisation clinical phase III & II/III (SIOP-PNET5 MB)
Recurrent/refractory: MB Supratentorial CNSPNET Ependymoma (WHO°II, III)
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Pineoblastoma
Study Type Design
SC
MB Medulloepithelioma CNS-PNET
Acronym of trial/registry (ClinicalTrials.gov Identifier, EudraCT)
HIT-REZ 2005 (ClinicalTrials.gov Identifier: NCT00749723)
1) increasing the probability of survival rates using intensified CT and/or RT, risk-stratification and improved quality controls of surgery, CT and RT
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CNS tumour
interventional multicentre, prospective non-randomised, therapy optimisation clinical phase II
Activity/Recruitment
HIT 2000: 01/2001 - 12/11 HIT 2000-Interim-Reg.: 01/2012-12/2014 I-HIT-MED Registry: 01/15ongoing SIOP-PNET5 MB: 06/2014ongoing
2) reducing late effects by using less craniospinal and or no cranial RT-doses in children < 4y 3) acquiring epidemiological data, reference results, tumour-, CSF- and blood samples for current and future clinical and biological studies patients: 0 - 21 y 1) increasing probability of survival with adequate QoL
2) studying safety and efficacy of new agents: a) P-HIT-REZ 2005: oral temozolomide vs carboplatin/VP16 P-HIT)
02/2006-02/2013 (end of recruitment) 02/2016 (end of P- and EHIT-REZ 2005) 04/2014 (end of phase II intraventricular VP16)
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Brain stem gliomas WHO°°III/IV
without NF1 or other phacomatosis)
Astrocytoma Ganglioglioma Oligodendroglioma
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Gliomatosis cerebri
LGG WHO°°I/II (with or
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HIT-HGG 2007: interventional multicentre prospective, therapy optimisation clinical phase II HIT-HGG-CilMetro: interventional safety/efficacy, treatment clinical phase II
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DIPG
HIT-HGG 2007 (primary) (EudraCT: 2007-000128-42) HIT-HGG-CilMetro (recurrent) (ClinicalTrials.gov Identifier: NCT01517776)
HIT-HGG 2007: 07/2009 ongoing HIT-HGG-CilMetro: 01/2012 - ongoing
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Primary/recurrent malignant glioma WHO°°III/IV
b) E-HIT-REZ 2005: neuro(radio)logical and CSF-response to temozolamide on d 60 c) intraventricular VP16 patients: >3m - <30y 1) HIT-HGG 2007: assessing treatment efficacy (defined as 6m EFS after diagnosis) of oral temozolomide and RT for induction and oral temozolomide for consolidation in order to justify subsequent phase III trial with oral temozolomide for the same cohort (patients >3y-<18y)
SIOP-LGG 2004 (ClinicalTrials.gov Identifier: NCT00276640) SIOP-LGG 2004 Interim Registry
SIOP-LGG 2004: interventional, multicentre randomised, safety/efficacy, therapy optimisation SIOP-LGG 2004 Interim Registry:
2) HIT-HGG-CilMetro: evaluating the efficacy of a combined treatment with cilengitide and metronomic oral temozolomide as measured by 6m OS after diagnosis of relapse or tumour progression patients with relapsed or refractory HGG and DIPG (patients >3y-<18y) 1) comparing efficacy (defined as PFS) of/response to standard induction with carboplatin and VCR vs intensified induction with additional
SIOP-LGG 2004: 04/2004 04/2012 SIOP-LGG 2004-InterimReg.: 04/2012-04/2014
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2) acquiring epidemiological data, reference results, tumour-, CSF- and blood samples for current and future clinical and biological studies (patients 0-<18 y) 1) maintaining current EFS a) by applying risk-adapted treatment strategies/CSI (localized germinoma) b) by treatment as of localized germinoma and by replacement of CSI by combined CT and ventricular RT (bifocal germinoma) c) by replacement of CSI by combined CT and ventricular RT (metastasized germinoma) d) by dose-escalating CT (HR-non-germinoma) e) by standardizing surgical approach (residual malignant non-germinoma)
interventional multicentre, prospective non-randomised, therapy optimisation efficacy
EP
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SIOP CNS GCT II (ClinicalTrials.gov Identifier: NCT01424839)
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Intracranial germ cell tumours
VP16
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registry multicentre, prospective non-randomised, safety/efficacy
Oligoastrocytoma Dysembryoblastic neuroepithelial tumour
2) patient registration and data acquisition on diagnosis, treatment strategies and -efficacy for development of future protocols (teratoma)
10/2011 - 10/2016
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Pituitary adenoma
KRANIOPHARYNGEOM 2007 (ClinicalTrials.gov Identifier: NCT01272622)
interventional & registry/observatory multicentre, prospective, randomised, therapy optimisation, efficacy
Meningioma
2) assessment of different treatment strategies and evaluation of remission status (craniopharygioma) 3) assessment of QoL (> 3y after randomisation; incompletely resected craniopharyngioma) 4) assessment of PFS and OS depending on timepoint of postoperative RT (incompletely resected craniopharyngioma) patients 0 - 18y 1) evaluation of epidemiological and clinical data of patients with CPT 2) developing infrastructure for reference centers (pathology, genetics, radiology, RT) 3) improving understanding of tumour biology and genetics 4) supporting tumourbanking 5) conducting biological studies 6) comparing safety/efficacy of 4 chemotherapy regimens
interventional & registry multicentre, prospective, randomised, therapy optimisation safety/efficacy clinical phase III
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CPT-SIOP-2000 CPT-SIOP-2009 (ClinicalTrials.gov Identifier: NCT01014767)
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Cysts of Rathke Pouch
Choroid plexus tumours (APP, CPP, CPC)
10/2007-ongoing
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Xanthogranuloma
1) acquisition of epidemiological, diagnostic, treatment and response data (all tumour types)
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Craniopharyngioma
11/2009-11/2017 temporarily closed
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RB-Registry
RI PT
Retinoblastoma
registry
start: 07/2010
SC
European Rhabdoid Registry (EUR-RHAB)
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EP
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Atypical teratoid/rhabdoid tumours of the brain (AR/RT)
7) development of future treatment strategies/clinical phase I/II studies 8) establishing panEuropean and other international collaborations 1) evaluation of all patients with AT/RT (EFS, PFS after different treatment approaches, efficacy of surgery, RT) 2) developing infrastructure for reference centres (pathology, genetics, radiology, RT) 3) improving understanding of tumour biology and genetics 4) supporting tumourbanking - conducting biological studies 5) development of future treatment strategies/clinical phase I/II studies 6) establishing panEuropean and other international collaborations 1) evaluation of epidemiological and clinical data of patients (0 - < 18y) with RB 2) establishing reference centres (pathology,
registry
start: 11/2013
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neuroradiology) Abbreviations: APP-atypical plexus papilloma, AT/RT-atypical teratoid/rhabdoid tumour, CNS-central nervous system, CNS-PNET-primitive neuroectodermal tumour of the CNS, CPC-choroid plexus carcinoma, CPP-choroid plexus papilloma, CPT-choroid plexus tumour, CSF-craniospinal fluid, CSI-craniospinal irradiation, CT-chemotherapy, d-day, DIPG-diffuse intrinsic pons glioma, EFS-event free survival, GCT-germ cell tumour, HGG-high grade glioma, HIT-Hirntumor (German for "brain tumour"), HR - high-risk, LGG-low grade glioma, m-months, MB-medulloblastoma, NF1Neurofibromatosis Type 1, PFS-progression free survival, (p)OS-(probability of) overall survival, QoL-quality of life, RB-retinoblastoma, RTradiotherapy, SIOP-International Society of Paediatric Oncology, VCR-vincristine, VP16-Etoposide, WHO-World Health Organization, y-years.
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Table 2: Multifactorial radiotherapy-related late effects (LE) and reported synergistic covariates in survivors of childhood primary central nervous system tumours: A) by pathogenesis and B) by impairment. A) ONSET
SYNERGISTIC COVARIATES
[mean y post RT]
Tx-related
Stroke/TIA
100-fold ↑
headaches, focal deficits, seizures
(all CBTS compared to healthy paediatric population)
cognitive NCF*↓
endocrine (s. table 2B)
4.7-4.9
field CRT (COW)/cervical CSI dose: >30 Gy
40-fold ↑
CRT)
NCF*↓
CCM ICA HM-AP FHD
headaches, focal deficits, seizures
cognitive
NCF*↓ (HM-AP)
neurologic recurrent complex migraine attacks (SMART)
nr
nr
(NF1patients)
cognitive
neurologic
field WBRT/ CRT (COW) cervical CSI dose: >45 Gy
4.6 3.2
3.4% (CCM, post CRT) 20% (HM-AP, post CRT) 80% (FHD post CRT)
3.1-19.5
field
(CCM)
CRT/WBRT/CSI
random MRI findings
AP: nr SMART: rare
NS
nr
(systemic)
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3.5% (post
headaches, focal deficits, seizures
CT
+
EP
neurologic
nr
TMrelated
site ST type ni
Host-related coexisting health conditions NF1, MMS, metabolic (DM, endocrine LE: s. table 2B), macro-/micro-AP, HTN gender male age at dx ni other: sedentary lifestyle
site PS, SS
coexisting health conditions NF1
gender male age at RT <5y nr
dose
site ST (HMAP/FHD)
>30 Gy (CCM; HM-AP/FHD: ni)
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MMS
(post CRT)
Mineralising MicroAP/SMART
NEUROVASCULAR DAMAGE
RT neurologic
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PATHOGENESIS
INCIDENCE
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CHARACTERISTICS OF LATE EFFECT CHRONIC HEALTH CONDITION
coexisting health conditions
PROGNOSIS/ COMPLICA-TIONS
recurrent events
(↑ with time after 1st RT), ICH,
irreversible chronic health conditions progessive NCF*decline stroke/TIA, ICH irreversible chronic health conditions progessive NCF*decline ICB, symptomatic epilepsy (CCM, ICA)
genetic predisposition age at RT <10y (CCM), >7y (HM-AP/FHD)
REF.
87-92
93-98
99105
(other)
2-10
field
CRT (SMART: PF, ST/TL) WBRT(AP) dose: >15 Gy (AP; SMART: nr)
nr
+
nr
gender male age at dx: young
self-limiting (within days to weeks)
106109
anosmia, sensorineural hearing loss, optic neuropathy, nystagmus, cerebellar ataxia, dysarthria, myelopathic syndrome
rare (post CRT & NS)
8-22
nr
nr
IT (PF) IS
cognitive NCF*↓
CRT)
cognitive
3m-5y
field WBRT > localized CRT (when including BS, CC: risk↑), CSI dose/fs
endocrine
72 Gy/<2.5 Gy: incidence=5% 90 Gy/<2.5 Gy: incidence=10% fs >2.5 Gy: nr other low conformality index
EP
(s. table 2B)
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NCF*↓
+ (HD-CT, MTX)
nr
nr
SC
5%-10% (post
headaches, focal deficits, symptoms of increased ICP
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neurologic
site
+
coexisting health conditions
progressive symptoms
110
CCM, ICA
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neurologic
AC C
Necrosis/WML/WMV/Leuken cephalopathy
WHITE MATTER LOSS
Superficial Siderosis
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coexisting health conditions DM
gender male age at dx conflicting data (younger vs older children) other shorter overall Tx-time
nr
111114
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B)
CHARACTERISTICS OF LATE EFFECT INCIDENCE
ONSET
SYNERGISTIC COVARIATES
[mean y post RT]
Tx-related RT
up to 80%
1-5
(increases with time post CRT) GHD: 50-80% GnD: 20-50% TSHD: 3-6% primary ovarian insufficiency: 83% precocious puberty: 11.1% delayed puberty: 11.8%
(biphasic , GHD earliest)
hypothyroidism, hypogonadism (delayed puberty, permanent amenorrhoe, azoospermia), primary ovarian insufficiency, infertility, precocious puberty, hyperprolactinemia low HDL, insulin resistance, adrenal insufficiency
timepoi nt
busulfan, cis/carboplatin, cyclophosphamide, ifosfamide, etoposide, procarbacine, melphalan (dose dependent)
NS prior to CRT
coexisting health conditions pre-CRT endocrinopathy gender male (RE: growth failure) age at dx prepubertal stage at CRT (RE: infertility)
progressive and irreversible impairments*, dysproportional growth (after CSI), osteoporosis, osteopenia, obesity
30,41, 43, 47,57, 59, 70,115 -121
(controversial reports), stroke
risk↑
TSHD, ACTHD: nr
EP
social withdrawal, depression
nr
AC C
psychooncological*
Dysproportional Growth
site PS, SS, P, HT
combined PB+conventional CRT >PB alone (earlier onset of impairments*)
NCF*↓
SPINE GROWTH
GnD:
site PS, SS, P, HT
Host-related
REF.
technique
cognitive
reduced sitting heigth (damaged vertebral growth plates)
dose GHD: >18 Gy: risk ↑, 30-50 Gy: 50100% risk ACTHD, GnD: > 30 Gy TSHD: >50 Gy (no TSHD post low-dose CRT or TBI) precautious puberty: 18-24 Gy (females), 2550 Gy (both genders)
metabolic
musculoskeletal
GHD: data controversial
TMrelated
PROGNOSIS/ COMPLICA-TIONS
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GH-/TSH-/ ACTH-/ GnD
ENDOCRINOPATHY
endocrine
field CRT (including hpaxis)/CSI
NS
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musculoskeletal growth failure, reduced bone mineral density, lean muscle mass
CT
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IMPAIRMENT*
CHRONIC HEALTH CONDITION
nr
field CSI>CRT dose >18 Gy CSI
+
nr
nr
gender male age at RT young (<6y) at CSI
short adult height
116,12 2, 123
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36 Gy >24 Gy>18Gy (CRT)
14% (post CRT including cochlea, not treated with platinum-based CT) 28-68% (in combination with CT)
3-5
field CRT (including cochlea/PF) dose
low incidence after mean cochlear dose <30 Gy, risk↑: 4045 Gy & >50 Gy to PF
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Sensorineural Hearing Loss
hearing loss (high (68 kHz) > low frequencies) cognitive NCF*↓
dose
technique extent of resection
other hydrocephalus, shuntsurgery
site ST, PF riskstratification HR
coexisting health conditions
progressive NCF* decline
43,70, 86, 112,12 4-129
progressive hearing loss, permanent need for hearing aids
43,57, 70, 130133
exposure to glucocorticoids, and/or antiepileptic agents and/or opioids, homozygous GSTM1 deletion (MB-patients), perioperative morbidity (e.g.PFS), NF1, reduced WMV, WML, cerebrovascular disease (stroke, MMS) (s. table 2A), serious hearing loss (s. below) age at dx young other low baseline performance level at dx
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+ (MTX)
(MBpatients)
SC
attention deficits, impaired psychological development in, and interaction with social environment, inactive lifestyle/reduced participation in physical activities
field
RE NCF*↓: CRT (TL), conformal CRT (3D)>intensitymodulated CRT (HC-sparing) >proton-Tx (spot scanned), WBRT >local CRT, CSI >ventricular CRT, conven-tional > fractio-nated CRT; RE motor skills↓: CRT (including frontal regions)
M AN U
nr
psychosocial/ behavioural
neurosensory
AUDIOLOGICAL
40-100% (↑ post CRT)
+
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NEUROPSYCHOLOGICAL*
compromised physical performance, reduced everyday life activity cognitive NCF*↓ (RE: memory, attention, executive function, IQscores/academic achievements, everyday life participation)
EP
motor skills
(platinumagents)
nr
site PF, BS
coexisting health conditions genetic predisposition age at dx young other ethnic background
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legal blindness: CI = 1.8% (20 y post dx) cataract: CI = 2.1% (20 y post dx)
taste/smell disturbances
smell ca. 90% taste ca. 70%
during CRT or ca. 36w post start of CRT
nr
site HT, CO, DE
dry eyes: >2 Gy CRT to eye, >30 Gy to TL; double vision: >5 Gy to eye, >30 Gy to TL or PF; legal blindness (1 or both eyes): all doses to PF, >5 Gy CRT to eye, >30 Gy to TL; cataract: all doses to PF, TL, >2 Gy to eye, CI↑ with >5 Gy to eye retinal condition: >20 Gy to eye
field CRT/WBRT/RT (including nasopharyngeal region)
dose
60 Gy (median dose to tumor volume)
coexisting health conditions exposure to dexamethasone (RE dry eyes)/prednisone (RE cataract) other risk of double vision and legal blindness↓ after exposure to prednisone
dose
EP
neurosensory
nr
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5.7% (20y post dx)
(dry eyes/ double vision/ legal blindness/ cataract, post dx)
field CRT (including orbita/eye, TL, PF)
persistent need of eye medication/servic es for the visual impaired
133,13 4
altered dietary habits/malnutritio n
135137
SC
double vision: CI =
7.2/2.2 / 1/4.7
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dry eyes: CI = 5.3% (20 y post dx)
nr
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amblyopia, legal blindness, double vision, cataract, kerato-conjunctivitis sicca (dry eyes)
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OLFACTORY
OCULAR / VISUAL
neurosensory
nr
site TL
nr
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ORN
dose/ volume developmental: >10 Gy to teeth >24 Gy CRT; xerostomia, caries: single dose and fractionated CRT >24 Gy; craniofacial deformities: >30 Gy with increased volumes; trismus: >40 Gy to pterygoid muscle
+ (high cumulative doses of alkylating agents/cyclophosphamide, HSCTconditioning regimens including cyclophosphamide/ busulfan)
nr
nr
coexisting health conditions invasive dental therapy in the former RT field (RE ORN risk), poor pre-RT dental/peridontal status age < 5y at cancer-Tx (RE developmental) gender female other low SES
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(ORN)
TBI/CRT (including oral cavity)/cervical CSI
SC
1-5
field
M AN U
peridontal disease, impaired salivary gland function/xerostomia/ caries, oral infections, impaired temporomandibular joint function, trismus/ speech difficulties
2 (xerostomia)
TE D
ORAL / DENTAL
compromised oral/dental health
microdontia: 9.2% vs 3.3% hypodontia: 8.2 vs 5.3% root malformation : 5.4% vs 1.9% enamel hypoplasia: 11.7% vs 5.3% severe gingivitis: 6.7% vs 5.7% loss of > 6 teeth due to decay or gum disease: 4.8% vs 1.8% xerostomia: 2.8 % vs 0.3% craniofacial deformities: 35-90% (CBTS vs healthy controls)
EP
micro-/hypodontia, craniofacial abnormalities, root stunting, enamel defects
AC C
developmental
increased need for dental care (including dentures), for reconstructive surgery, facial/dental cosmetic concerns, speech delay, increased cardiac late morbidity (due recurrent oral infections)
138140
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field CRT/WBRT/TBI CSI
dose meningioma, glioma: mean of 1.5 Gy CRT (range 1-6 Gy)
other lower risk of breast cancer post PB-CSI
+ alkylating agents, platinum agents, topoisomerase II inhibitors (risk↑ compared to RT alone)
nr
nr
coexisting health conditions
nr
cancer predisposition syndromes (e.g. Li-Fraumeni-, Turcot-, Gorlin-Syndrome, NF1, NF2, von Hippel-Lindau disease, MES), alcohol and/or tobacco abuse (RE oral SMN) age young (< 5y) at tx (except for MB as primary dx: ni)
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CNS lymphoma, intracranial fibrosarcoma, oral carcinoma, osteosarcoma (skull), thyroid carcinoma, MDS, breast cancer
5-10y post CRT (median for MBpatients: 5.8y, range 31.-16.8y post dx)
SC
secondary nonprimary intracranial tumours and other SMN
(meningioma > HGG>LGG> CNS-PNET) 4.2% (MB, CI at 10y)
EP
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Abbreviations and symbols: ACTHD-adrenocorticotropic hormone deficiency, AP-angiopathy, BS-brain stem, CBTS-childhood brain tumour survivor, CC-corpus callosum, CCM-cerebral cavernous malformation, CI-cumulative incidence, CNS-central nervous system, CNS-PNET-primitive neuroectodermal tumour of the CNS, CO-chiasma opticum, COW-circle of Willis, CT-chemotherapy, CRT-cranial RT, CSI-craniospinal irradiation, DEdiencephalon, DM-diabetes mellitus, dx-diagnosis, FHD-focal haemosiderin deposition, fs-fraction size, GHD-growth hormone deficiency, GnDgonadotropin deficiency, Gy-Gray, HC-hippocampus, HD-high dose, HDL-high density lipoprotein, HGG-high-grade glioma, HM-AP-haemorrhagic microangiopathy, hp-axis-hypothalamic-pituitary axis, HR-high risk, HSCT-haematopoietic stem cell transplantation, HT-hypothalamic, HTNhypertension, ICA-intracranial aneurysm, ICH-intracerebral haemorrhage, ICP-intracranial pressure, IQ-intelligence quotient, IT-infratentorial, ISintraspinal, LE-late effect, LGG-low grade glioma, m-month(s), MB-medulloblastoma, MDS-myelodysplastic syndrome, MES-multiple endocrine neoplasia, MMS-Moyamoya Syndrome, MRI-magnetic resonance imaging, MTX-methotrexate, NCF-neurocognitive functioning*, NF1(2)neurofibromatosis type I (II), ni-no impact on LE/pathology/impairment, nr-not reported for CBTS, NS-neurosurgery, ORN-osteoradionecrosis of facial bones, P-pineal, PB-proton beam, PF-posterior fossa, PFS-posterior fossa syndrome, PS-parasellar, QoL-quality of life*, RE-regarding, RT-radiotherapy, SES-socioeconomic status, SMART-stroke-like migraine attacks after CRT, S(M)N-secondary (malignant) neoplasm, SS-suprasellar, ST-supratentorial, TBI-total body irradiation, TIA-transient ischaemic attack, TL-temporal lobe, TM-tumour, TSHD-thyroid stimulating hormone deficiency, Tx-treatment, vs-versus, w-week(s), WBRT-whole brain RT, WML - white matter lesions, WMV - white matter volume, y-year(s); *: see definitions in main text, ↑: increased, ↓ : reduced/impaired, + : "yes".
AC C
S(M)N
meningioma, glioma, CNS-- PNET, MB
1.3%
M AN U
secondary primary CNS tumours
116,12 7, 139,14 1-145
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LEGENDS TO FIGURES Figure 1. Organisation of multicentre, standardised therapy optimising studies and
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associated registries of the HIT-Network and SIOP-E. Abbreviations: CSF-craniospinal fluid, HIT-"HirnTumor" (German for "brain tumour"), SAE-severe adverse event, SIOP-E - International Society of Paediatric Oncology, European branch; for details regarding late effect- and biological studies: see main text.
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Figure 2. Increase in A) 10-, B) 15-year overall survival rates by year of diagnosis in 3-year groups of children with primary CNS tumours and other malignancies in Germany between 1981 and 2010 (estimation according to Brenner and Spix [206].
Oncology/Haematology (KPOH);
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Sources: German Childhood Cancer Registry (GCCR), Competence Network Paediatric
Abbreviations: ALL-acute lymphoblastic leukemia, AML-acute myeloid leukemia, CNS-
AC C
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central nervous system, NHL-non-Hodgkin lymphoma.
AC C
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Tallen et al._EJC_03/2015_Highlights
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Highlights/Bullet Points
1) For many childhood brain tumour survivors, survival means chronic disease.
2) For CBTS, QoS assessment should include tumour-, treatment- and host-related
SC
factors.
3) Many CBTSs' dilemma: Treatment takes CNS tumour, but bates CNS function.
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4) Predictive markers of LE-risks are needed for individual treatment planning.
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5) Empowering survivors and stakeholders: a new mission in Paediatric Neurooncology.
PII:
S1090-3798(15)00139-7
DOI:
10.1016/j.ejpn.2015.07.011
Reference:
YEJPN 1935
To appear in:
European Journal of Paediatric Neurology
Received Date: 28 April 2015 Accepted Date: 5 July 2015
Please cite this article as: Tallen G, Resch A, Calaminus G, Wiener A, Leiss U, Pletschko T, Friedrich C, Langer T, Grabow D, Driever PH, Kortmann R-D, Timmermann B, Pietsch T, Warmuth-Metz M, Bison B, Thomale U-W, Krauss J, Mynarek M, von Hoff K, Ottensmeier H, Frühwald M, Kramm CM, Temming P, Müller HL, Witt O, Kordes U, Fleischhack G, Gnekow A, Rutkowski S, on behalf of the German Paediatric Brain Tumour Consortium (HIT-Network), Strategies to improve the Quality of Survival for Childhood Brain Tumour Survivors, European Journal of Paediatric Neurology (2015), doi: 10.1016/ j.ejpn.2015.07.011. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT 1
Strategies to improve the Quality of Survival
2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49
for Childhood Brain Tumour Survivors
50 51 52 53 54 55 56
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Gesche Tallena, Anika Reschb, Gabriele Calaminusc, Andreas Wienerc, Ulrike Leissd, Thomas Pletschkod, Carsten Friedrichb,e, Thorsten Langerf, Desiree Grabowg, Pablo Hernáiz Drievera, Rolf-Dieter Kortmannh, Beate Timmermanni, Torsten Pietschj, Monika Warmuth-Metzk, Brigitte Bisonk, Ulrich-Wilhelm Thomalel, Jürgen Kraussm, Martin Mynarekb, Katja von Hoffb, Holger Ottensmeiern, Michael Frühwaldo, Christof M. Krammp, Petra Temmingq, Hermann L. Müllerr, Olaf Witts, Uwe Kordesb, Gudrun Fleischhackq, Astrid Gnekowo, Stefan Rutkowskib on behalf of the German Paediatric Brain Tumour Consortium (HIT-Network) a
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Department of Paediatric Oncology/Haematology, Charité-Universitätsmedizin Berlin, Campus Virchow, Augustenburger Platz 1, 13353 Berlin, Germany ([email protected], [email protected]) b Department of Paediatric Haematology and Oncology, University Medical Centre Hamburg-Eppendorf (UKE), Martinistr. 52, 20246 Hamburg, Germany ([email protected], [email protected], [email protected], [email protected], [email protected], [email protected]) c Department of Paediatric Haematology and Oncology, University Hospital Münster, Albert-Schweitzer-Campus 1, 48149 Münster, Germany ([email protected], [email protected]) d Medical University Vienna, Department of Paediatric and Adolescent Medicine, Währinger Gürtel 18-20, 1090 Vienna, Austria ([email protected], [email protected]) e Division of Paediatric Oncology, Haematology and Haemostaseology, Department of Woman´s and Children´s Health, University Hospital Leipzig, Liebigstr. 20a, 04103 Leipzig, Germany ([email protected]) f Department of Paediatric Oncology/Haematology, University of Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany ([email protected]) g German Childhood Cancer Registry (GCCR), Institute of Medical Biostatistics, Epidemiology, and Informatics (IMBEI), University Medical Center, University of Mainz, Gebäude 902, Obere Zahlbacher Straße 69, 55131 Mainz, Germany ([email protected]) h Department of Radiation Oncology, University of Leipzig, Stephanstr. 9a, 04103 Leipzig, Germany ([email protected]) i Particle Therapy Clinic at West German Proton Therapy Centre Essen, University Hospital Essen, Hufelandstr. 55, 45147 Essen, Germany ([email protected]) j Institute of Neuropathology, University of Bonn, Sigmund-Freud-Str. 25, 53105 Bonn, Germany ([email protected]) k Dept. of Neuroradiology, University of Würzburg, Josef-Schneider-Str. 11, 97080 Würzburg, Germany ([email protected], [email protected]) l Department of Paediatric Neurosurgery, Charité-Universitätsmedizin Berlin, Campus Virchow, Augustenburger Platz 1, 13353 Berlin, Germany ([email protected]) m Department of Neurosurgery, Head Clinic, University of Würzburg, Josef-Schneider-Str. 11, 97080 Würzburg, Germany ([email protected]) n University Children’s Hospital Würzburg, Dept. of Paed. Haematology, Oncology, Josef-Schneider-Str. 2, 97080 Würzburg, Germany ([email protected]) o Department of Paediatric Oncology/Haematology, Klinikum Augsburg, Stenglinstr. 2, 86156 Augsburg, Germany ([email protected], [email protected]) p Division of Paediatric Haematology and Oncology, University of Göttingen, Robert-Koch-Str. 40, 37075 Göttingen, Germany ([email protected]) q Paediatric Haematology/Oncology, Paediatrics III, University of Essen, Hufelandstr. 55, 45147 Essen, Germany ([email protected], [email protected]) r Paediatric Oncology/Haematology, Klinikum Oldenburg, Medical Campus University Oldenburg, Rahel-Straus-Str. 10, 26133 Oldenburg, Germany ([email protected]) s German Cancer Research Centre (DKFZ) and Department of Paediatric Oncology/Haematology, University of Heidelberg, Heidelberg, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany ([email protected]) Corresponding author: PD Dr. med. Gesche Tallen Department of Paediatric Oncology/Haematology Charité-Universitätsmedizin Berlin Campus Virchow, Augustenburger Platz 1, 13353 Berlin, Germany Tel.:++49 (0)30-450-566032 | Fax:++49 (0)30-450-566906 email: [email protected]
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ABSTRACT
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second most frequent type of cancer in children and adolescents. Overall survival has
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continuously improved in Germany, since an increasing number of patients has been treated
5
according to standardized, multicentric, multimodal treatment recommendations, trials of the
6
German Paediatric Brain Tumour Consortium (HIT-Network) or the International Society of
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Paediatric Oncology-Europe (SIOP-E) during the last decades. Today, two out of three patients
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survive. At least 8000 long-term childhood brain tumour survivors (CBTS) are currently living
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in Germany. They face lifelong disease- and treatment-related late effects (LE) and associated
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Tumours of the central nervous system (CNS) are the most frequent solid tumours and the
socioeconomic problems more than many other childhood cancer survivors (CCS).
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We review the LE and resulting special needs of this particular group of CCS. Despite their
12
increasing relevance for future treatment optimisation, neither the diversity of chronic and
13
cumulative LE nor their pertinent risk factors and subsequent impact on quality of survival have
14
yet been comprehensively addressed for CBTS treated according to HIT- or SIOP-E-protocols.
15
Evidence-based information to empower survivors and stakeholders, as well as medical
16
expertise to manage their individual health care, psychosocial and educational/vocational needs
17
must still be generated and established.
18
In conclusion, the establishment of a long-term research- and care network in Germany shall
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contribute to a European platform, that aims at optimising CBTS' transition into adulthood as
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resilient individuals with high quality of survival including optimal levels of activity,
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participation and acceptance by society.
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Key-words: Childhood Brain Tumor - Childhood Cancer Survivor - Late Effects - Quality of Survival -
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Long-Term Care
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1.1 The Background: Increasing "Quantity of Survival" for patients with the diagnosis "Childhood Primary Brain Tumour". Accounting for about 24% of childhood cancers, primary central nervous system (CNS)* tumours are the most frequent solid tumours and second most frequent
6
malignancies in childhood and adolescence [1,2]. More than 400 children and
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adolescents are diagnosed with a CNS tumour in Germany each year. About 95% of
8
them receive treatment according to prospective, multi-centre therapy optimisation
9
studies or non-interventional registries, respectively, conducted by the German
10
Paediatric Brain Tumour Consortium (HIT-Network) and the European branch of the
11
International Society of Paediatric Oncology (SIOP-E) (table 1). HIT and SIOP-E
12
collaboratively unite and coordinate trials and reference centres for different childhood
13
brain tumour (CBT) entities, thereby promoting national and international
14
implementation and continuous optimisation of treatment concepts with quality-
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controlled standards for diagnosis, treatment and supportive care (figure 1).
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The overall survival (OS) rates for CBT patients continuously improved over the
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past three decades from below 50% to over 70% (figure 2A, B), varying based upon
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tumour type, site, response to treatment and late effects (LE) [3-28]. CBT survivors
19
(CBTS) suffer from LE even more than any other childhood cancer survivors (CCS)
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[29-31]. However, evidence-based LE management still needs development.
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1.2 The Goal: Maximizing "Quality of Survival" towards the diagnosis "Future".
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An estimated 8000 CBTS are currently living in Germany and numbers have been rising in many parts of Europe [32]. So have LE prevalence and the need for an adequate
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outcome measure.
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Two major outcome measures are currently applied to summarize the efficacy of
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paediatric cancer treatment: "health related QoL" (HRQoL) [33,34] and "quality of
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cure" [35]. Besides health, various host-related factors, including socioeconomic status * The following abbreviations will be used more than once in this review: CBT-childhood brain tumour, CBTS-childhood brain tumour survivor, CCS-childhood cancer survivor, CIPN - chemotherapyinduced peripheral neuropathy, CNS-central nervous system, CT-chemotherapy, CRT-cranial radiotherapy, CSI-craniospinal irradiation, FO-functional outcome, GPOH-German Society of Paediatric Oncology/Haematology, HGG-high grade glioma, HITHirntumor (German for "brain tumour"), HIT-Network - Research and Treatment Consortium consisting of all German study coordination- and reference centers for the treatment of children and adolescents with primary brain tumours (supported by the German Childhood Cancer Foundation/Deutsche Kinderkrebsstiftung), HRQoL-health-related quality of life, LE-late effect(s), LGGlow grade glioma, LTFU - long-term follow-up, MB-medulloblastoma, NCF-neurocognitive functioning, NO-neuropsychological outcome, NS-neurosurgery, OS-overall survival, PF-posterior fossa, PFS-posterior fossa syndrome, PNET-primitive neuroectodermal tumour, QoL-quality of life, QoS-quality of survival, RT-radiotherapy, SES-socioeconomic status, SIOPInternational Society of Paediatric Oncology, SIOP-E - SIOP Europe; SMN-secondary malignant neoplasm, WBRT-whole brain RT.
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ACCEPTED MANUSCRIPT (SES), individual levels of activity and participation add to the complexity of QoL-
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measurement. Large population-based studies show that the overall HRQoL of many
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CCS is compromised compared to the healthy population [36-40], while QoL-analyses
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of smaller CBTS subgroups [41-43] are partially controversial. Overall, the classical
5
(HR)QoL framework did not prove adequate for CCS [44]. Particularly during QoL-
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assessment in survivors of medulloblastoma (MB), the most frequent malignant CBT,
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regular conceptual broadening was imperative [45] owing to continuous treatment
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optimisations and subsequent increases in both OS and LE.
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In European paediatric oncology, "quality of cure" is defined by the "presence
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and intensity of treatment complications in a long-term survivor" [35]. This concept
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may not completely cover the situation of CBTS either, because in addition to
12
treatment-related LE, they typically suffer frequently from those caused by the tumour
13
itself. Taken together, a measure addressing the "quality of survival" (QoS) with all its
14
relevant treatment-, tumour- and host-related factors may be more accurate for CBTS
15
[46].
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1.3 The Facts: Multifactorial Late Effects.
17
To assess the present needs of CBTS, we reviewed the international literature based on
18
Medline-searches and textbooks in paediatric oncology. We included all reports
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published between 01/2009 and 01/2015 (aside from single earlier, basic reviews and
20
large-cohort studies), that provided comprehensive information on type, incidence,
21
causes, risk factors, current management of LE and QoL in CBTS. Because of the
22
conceptual and clinical heterogeneity as well as the diversity of the major foci in these
23
articles, statistic pooling of the information was not performed.
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1.3.1 Not only somatic: Tumour-related late effects.
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Tumour-related LE largely depend on CBT-type, anatomic localisation, incidence,
26
extent and duration of peritumoural edema, hydrocephalus and age at diagnosis.
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Seizures, focal palsies, ataxia, visual impairment, endocrinopathies [47-52] and
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sometimes reduced neurocognitive functioning (NCF) [53] are common and require
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systematic assessment.
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1.3.2 "Surgical neurotoxicity": Neurosurgery-related late effects. Neurosurgery (NS) remains a mainstay of therapy, both for reducing tumour
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burden and obtaining histology. Careful balance must be kept between extent of
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resection and preservation of eloquent structures. While for many CBT, including high-
5
grade glioma (HGG), cerebellar low-grade glioma (LGG) and ependymoma, failure to
6
achieve gross radiographic resection is associated with poorer outcome [54,55], subtotal
7
resection (for reducing the risk of LE) proved feasible for selective patients with MB
8
(<1.5cm2 of residual tumour, followed by chemo- (CT) and radiotherapy (RT)),
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visual pathway glioma and craniopharyngioma [4,6,12,47,56-61]. Whether continuously
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advancing techniques such as intraoperative magnetic resonance imaging (MRI),
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neurofunctional monitoring, intraoperative tumour staining [62-68] may impact on
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options of complete resection, but not LE prevalence, needs assessment.
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Functional outcome (FO) after NS depends on tumour site, surgical approach,
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neurosurgeon's experience, patient's age and presurgical performance status [47-50].
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Postoperative impairments may include stroke, seizures, palsies, central oculomotor
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deficits, ataxia, vision loss as well as hypothalamic damage resulting in endocrinopathy
17
and reduced NCF [51-53] and may be enhanced by adjuvant therapy. Hydrocephalus requiring shunt surgery often negatively influences FO as well
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[69-74]. Potential covariates like the degree and duration of ventricular dilatation,
20
shunting technique and adjuvant therapy still need evaluation.
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A prime example of "surgical neurotoxicity" is cerebellar mutism- or posterior
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fossa (PF) syndrome (CMS/PFS). It occurs in 15%-25% of patients with fourth
23
ventricular tumours, bilateral inferior olivary nucleus abnormalities [74,75], left-
24
handedness, large PF tumours [76] and vermian splitting during NS [77]. The onset is
25
usually within the first postoperative week presenting with speech impairments,
26
followed by pseudobulbar palsy, ataxia, cognitive, behavioural and emotional disorders.
27
These may be progressive and irreversible or take months to years to recover [78,79]. In
28
addition to NS, other treatment- and also host-related factors may contribute to
29
developing PFS, particularly to the behavioural changes [80,81]. Careful distinction
30
between CMS/PFS and "real" brainstem damage is necessary to frame effective
31
interventional concepts. This distinction requires standardised diagnostic tools
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developed in prospective analyses based on incidence, aetiological role of a disrupted
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fronto-cerebellar circuit, severity of PFS and development of long-term cerebellar
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cognitive affective syndrome [75,81-85].
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1.3.4 Changing patterns due to technical advancements: Radiotherapy
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(RT)-related late effects
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Like neurosurgery, cranial RT (CRT) and craniospinal irradiation (CSI) are well-proven
4
backbones of local CBT control. Standard approaches include CRT and/or CSI either as
5
adjuvant or single local therapy. However, the developing CNS is vulnerable to
6
irradiation, particularly in very young children. CRT-related LE range from transient
7
and treatable to permanent and progressive impairments [86]. The risk of many LE is, as
8
shown in table 2 [87-145], dependent of CRT-region, -dose, -technique and multiple
9
covariates. The role of the CRT-dose-volume-ratio still needs validation for already
10
examined entities such as ependymoma and LGG [70,146] and also further analysis for
11
other CBT-subgroups and different CRT techniques. Currently conflicting results may
12
be due to small, heterogeneous cohorts and the multiple covariates, that have only been
13
incompletely assessed for CBTS, thus only been incompletely considered in many
14
analyses so far.
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1.3.4.1 Neurovascular disease
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CRT-induced neurovascular damage leads to artherosclerosis with risk of stroke and
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development of malformations (table 2A). Covariates for most neurovascular
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complications, except stroke, have not yet been reported (table 2A). Multi-centre
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prospective studies are required to identify both risk factors and imaging tools to
20
recognize high-risk survivors early.
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1.3.4.2 Radiation-induced brain injury.
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Radiation necrosis radiographically presents as white matter lesions (WML,
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leukencephalopathy). Compared to RT-vasculopathy, WML are rare, particularly after
24
fractionated CRT. Whole brain RT (WBRT) and intrathecal methotrexate (MTX)
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present enhancing factors (table 2A).
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1.3.4.3 Neurocognitive and behavioural impairments
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Reduced NCF after CRT is progressive, often associated with behavioural difficulties
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and promoted by various factors (table 2B). CRT involving the temporal region
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increases the risk in a dose-dependent manner, since the normal function of
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subventricular and hippocampal neural stem cells is required for normal NCF, but
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particularly vulnerable to RT-induced damage. Therefore, both proton-beam-therapy vs
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fractionation schemes applying lower single doses should be evaluated prospectively.
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1.3.4.4 Endocrinopathies
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Endocrine functions are strongly influenced by the CRT-dose to the hypothalamic-
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pituitary (hp-)axis. In CBTS without pre-CRT endocrinopathy, growth hormone (GH)
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secretion is affected most frequently and first, followed by thyroid stimulating hormone,
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adrenocorticotropic
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replacement therapy, many CBTS suffer from growth failure and/or disproportional
9
spinal growth, partially due to CSI-related damage of vertebral growth plates (table 2B).
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Future studies should validate the contributory role of CT, which is currently discussed.
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Overall, it remains unclear, why, for a given critical CRT-dose to the hp-axis, some
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patients develop an endocrinopathy, while others do not.
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1.3.4.5 Ototoxicity
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CRT-related ototoxicity is mainly dependent on the cochlear dose. It mostly affects high
15
frequency thresholds (table 2B). Some reports on CRT-related hearing loss, in particular
16
regarding its degrees, long-term prognosis and synergistic effects of CT are
17
controversial [43,70]. This may be a result of both a lack of uniform grading systems
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and different treatment concepts of the national study groups. Therefore, large-cohort
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analyses based on universal classifications should be conducted.
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Current concepts of CRT/CSI specifically focus on fine-tuning target volume- and dose
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reductions and will most likely result in positive changes of LE patterns. Multi-centre
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prospective analyses are now required, that compare QoS of CBTS after WBRT alone (-
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/+ CT), WBRT + boost to tumour site/PF (-/+ CT), or partial CRT/CSI alone (“local
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field”) (-/+ CT), respectively, and evaluate the dose-effect dependency with respect to
26
dose distribution within the CNS.
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1.3.5 Late effects of chemotherapy (CT): demanding trade-offs between
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quantity and quality of survival?
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The role of CT has become increasingly important over the past decades, especially for
30
very young patients, for whom CRT is not yet an option [61], and LGG patients [147].
31
Both systemic and intrathecal CT can cause various LE. These are specifically observed
32
after intensified therapy and concomitant CRT, thus as a result of damage to neural stem
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ACCEPTED MANUSCRIPT 1
cells and subsequently disrupted white matter integrity. Type, cumulative dose of the
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agents as well as timing within the treatment schedule (e.g. before or after CRT) and
3
route of administration are major determining factors. Although a promising option for
4
younger children with MB or primitive neuroectodermal tumour of the CNS (CNS-
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PNET)
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cardiovascular LE [149]. These still need assessment for CBTS, since they may
7
necessitate conceptual compromises to balance highest possible treatment intensity with
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optimal FO.
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1.3.5.1 Chemotherapy-induced peripheral neuropathy (CIPN)
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[148],
CIPN is well described after treatment with cisplatin, carboplatin, vinca-alkaloids and
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thalidomide [150-154]. Vincristine impairs sensory and motor function dependent on
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the cumulative dose [154] by disrupting axonal microtubules. The result is CIPN that, in
13
children, mostly presents as pain first, followed by decreased deep tendon reflex
14
responses, peripheral motor and distal sensory deficits, and sometimes visceral
15
neuropathy with gastrointestinal complications. Motor deficits may persist in
16
susceptible patients and often require long-term orthotic support. Older age, gender,
17
ethnicity, inherited neuropathies, certain drug-drug interactions are among the risk
18
factors reported so far [155-159]. Neuroprotective interventions are now required
19
for prevention, because withdrawal of the agent usually does not halt CIPN.
20
1.3.5.2 Encephalopathy and neurocognitive decline
21
Encephalopathy can be caused by both systemic and intrathecal CT as well as
22
supportive care involving glucocorticoids. MTX-related encephalopathy occurs in about
23
3% of CCS [160]. Symptoms may include headaches, neuropsychological impairments
24
and seizures. Chronic forms have been associated with leukencephalopathy, especially
25
in conjunction with WBRT (table 2). CT can also decrease neo- and subcortical grey
26
matter volume and proliferation of hippocampal neural stem cells, thereby progressively
27
reducing NCF [159]. Reduced NCF after CT without concomitant CRT particularly
28
occurs in survivors, who were very young at diagnosis [111,161] and/or who
29
experienced severe ototoxicity [80]. While a recently validated neuropsychological test
30
battery enables health care providers to assess the specific needs of CBTS in their daily
31
lives and to optimise parent counselling [162], other current measurement tools [154-
32
155] may still need broadening regarding their feasibility, particularly for CBTS with
33
visual loss [165-167] or different ethnic and language backgrounds, respectively.
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Ototoxicity is associated with high cumulative doses, high doses per course and bolus
3
applications of cis- and carboplatin [9], which damage cochlear hair-, spiral ganglion
4
cells and the stria vascularis - processes triggering the production of reactive oxygen
5
species, thereby promoting cell death, thus hearing loss [168]. Contributory covariates
6
are concomitant treatment with other ototoxic agents, such as aminoglycosides,
7
furosemide and CRT (table 2). As a major component of MB-treatment [7], cisplatin
8
induces ototoxicity in 28%-68% of MB-patients who received CRT [131,169]. These
9
observations were confirmed by data from trial HIT-SIOP PNET 4 [6] using the HIT-
10
and Brock classification [170]. Since 10% of the patients later on needed a hearing aid,
11
ototoxicity was declared a severe LE of this protocol. The risk of hearing loss correlates
12
with younger age at diagnosis [131]. Besides, there is promising evidence, that using
13
carboplatin instead of cisplatin may reduce ototoxicity [131]. Overall, the correlation of
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the degree of hearing loss after CT and CRT vs CT or CRT alone needs analysis.
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Genetic predisposition to ototoxicity has been reported [171-174] and discussed
16
[175,176]. Also, early alteration of high-frequency thresholds may has been associated
17
with the later need of a hearing aid [177]. Many reports, including those addressing the
18
communicative, educational and psychosocial significance of high-frequency hearing
19
loss [80] may require validation, since they are based on different treatment protocols
20
and ototoxicity grading systems as well as non-randomised or retrospective in nature.
21
1.3.6 Premature aging and secondary malignant neoplasms: sharing risk
22
factors?
23
According to the North American Childhood Cancer Survivor Study, 1.3 % of CBTS
24
develop a secondary malignancy (SMN) including different CNS- and other tumour
25
types [145]. The excess absolute risk for developing a glioma rose from 8.05 in the
26
1970ies to 28.9 in the 1980ies while following a dose-response relationship. In younger
27
children, the interval is shorter after CT with a cumulative risk of 11% at 8 years after
28
CRT. Major causes of this high SMN rate may include intensified CT with high
29
cumulative doses of platinum derivates, alkylators and topoisomerase-II-inhibitors. In
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general, CRT coupled with CT increases the risk of SMN from 1.4 (CRT alone) to 4.9
31
(CRT+CT) [116,127,139,141-145] (table 2B).
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Cancer is known as an aging-related disease with telomere loss as a well-
33
established contributor [178]. Telomere loss can be accelerated by DNA damage, 9
ACCEPTED MANUSCRIPT thereby inducing premature aging [178], signs of which, including cancer (alias SMNs),
2
were recently reported for many CCS [179-182]. This cancer-aging interface needs
3
further analysis in CBTS. Last but not least, there is increasing evidence, that clinically
4
unrecognized hereditary cancer predisposition syndromes are genetic causes for
5
what we presently think of as SMNs [183].
6
1.4 The Challenge: Back to normal Life.
7
The broad spectrum of LE may impact the psychological outcome of CBTS.
8
Posttraumatic stress, depression, anxiety, compromised coping-strategies and reduced
9
social competence have been reported [184-190]. The different measurement tools
10
applied in these studies may require harmonisation in order to establish standardized
11
long-term follow-up (LTFU)- and interventional concepts for supporting re-integration,
12
which is challenging for many survivors [191,192]. Others may face their cancer
13
experience
14
coordination of services between academic, employment and healthcare systems,
15
medical teams and social agencies is needed to maximize the survivor’s potential for
16
activity and participation in everyday life. Promising models exist for CCS [189,194],
17
but require feasibility-assessment for CBTS' special needs.
18
1.5 The Need: Empowerment for the People.
19
Paediatric Neurooncologists are currently still unable to predict the types and severity of
20
LE at the time of CBT diagnosis. Instead, only general assumptions can be disclosed for
21
informed consent in the context of multimodal treatment recommendations owing to the
22
broad interindividual range of both LE and predictive markers. Although parents’
23
decision-making behaviour when juggling the balance of least LE-risk and highest
24
survival advantage varies remarkably, many of them may feel empowered to decide
25
rather in favour of less LE if they were better informed. Hence, evidence-based
26
information should be generated to develop risk-adapted strategies for therapy
27
assignment. In addition, most survivors and their parents desire information regarding
28
their overall health and health maintenance, including their medical history and future
29
[195-197]. In fact, one-third of them are not confident in their primary care physician’s
30
competence of managing their issues [198-201]. Also, not much is known yet about
31
how they are coping with their transition from one age-group to the next. Combined
32
with their specific neuropsychological issues, this maturational process may be
optimism,
demonstrating
resilience
[193,194].
Nevertheless,
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2
guidelines not only for educating the survivors and health care professionals, but also
3
for academic staff, employers, counsellors and insurance policies.
4
1.6 The Plan: Generating evidence-based information &
5
distributing harmonised guidelines for holistic long-term care
6
concepts.
7
Quality-assured LTFU care of CCS is one of SIOP's major missions [35]. Several
8
national guidelines already exist [202,203]. However, due to a rather non-integrated
9
approach, they may require harmonisation.
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New initiatives (PanCareSurFup, PanCareLife, VIVE [204]) use a pan-European or
11
pan-German, respectively, approach in collaboration with partners, such as the Late-
12
Effects-Study-Group/Late-Effects-Surveillance-System (LESS) and the Cardiac and
13
Vascular Late Sequelae in long-term survivors of childhood cancer (CVSS)-Study
14
Group, to develop better harmonised LFTU guidelines. Additionally, they collaborate to
15
evaluate the risks of SMN, late mortality, cardiovascular damage, infertility, ototoxicity,
16
and compromised HRQoL. However, these initiatives deal with CCS in general, not
17
with CBTS' unique needs in particular.
18
1.7 The Conclusion: A new science has emerged.
19
An important step for research towards better understanding and improving the current
20
situation of CBTS is to collaborate on national levels and in larger-scale studies, that
21
provide sufficient statistical power for a) analysing the relative contributions of host-,
22
tumour- and treatment-related variables, b) identifying risk factors, c) characterising the
23
mechanisms underlying each of the LE and d) how these may impact a CBTS's QoS.
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The HIT-network provides favourable preconditions to conduct these studies.
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ACKNOWLEDGEMENTS
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We would like to thank the German Childhood Cancer Foundation for supporting the
3
HIT-Network, including all study- and reference centres since 2000. We also thank the
4
Fördergemeinschaft
5
neuropsychological evaluations by A.R. within the HIT-MED trials. Our thanks also go
6
to PD Dr. Claudia Spix, deputy head of the German Childhood Cancer Registry
7
(GCCR), University Medical Centre, University of Mainz, Germany, for providing
8
Figure 2A and B.
9
CONFLICT OF INTEREST STATEMENT
Hamburg
e.V.
for
support
of
RI PT
Kinderkrebs-Zentrum
None.
11 12
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DEFINITIONS
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The following terms (listed in alphabetical order) will be used more than once in this
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review in the context of childhood brain tumour survival. They are based on the
31
following definitions of the World Health Organization (WHO) Quality of Life
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Assessment Group, the International Classification of functioning, disability and health
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ACCEPTED MANUSCRIPT according to the WHO [33,34] and the International Society of Paediatric Oncology
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(Europe) (SIOP-E) [205]:
3
Activity
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Relating to the execution of a task or action by a childhood brain tumour survivor
5
(CBTS). Activity limitations comprise problems a CBTS may have in executing
6
activities.
7
Functional outcome (FO)
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Summarizes all aspects of a CBTS's physiological functions of body systems, including
9
neurocognitive function as well as neuropsychological and psychooncological outcomes
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(see below).
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Environmental factors
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Relating to the physical, social and attitudinal environment in which the survivor lives
13
and conducts her/his life as well as to the survivor's individual internal influences, such
14
as socio-economic status (SES), ethnic and cultural heritage, religion and spirituality. In
15
this review also referred to as "host-related factors".
16
Impairment
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Relating to a CBTS's problems in body function or structure such as a significant
18
deviation or loss.
19
Neurocognitive functioning (NCF)
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Relating to a CBTS's central nervous system (CNS) function and structure as it relates
21
to her/his cognitive (i.e. relating to, or being conscious intellectual activity such as
22
thinking, reasoning, remembering, imagining, or learning words) functions associated
23
with particular areas, neural pathways and cortical networks of the CNS.
24
Neuropsychological outcome
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A CBTS's CNS function and structure as it relates to her/his neurologic, emotional,
26
behavioural and neurocognitive functioning (see above) and related physical abilities.
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ACCEPTED MANUSCRIPT Participation
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Relating to the CBTS's involvement in a life situation. Participation restrictions are
3
difficulties a CBTS may have in involvement in life situations.
4
Psychooncological outcome (PO)
5
Referring to the survivors' psychological health and the social and behavioural factors
6
that may affect the disease process as well as the development in, and interaction with a
7
social environment.
8
Quality of Life (QoL), Health-related QOL (HRQoL)
9
QoL is a broad multidimensional concept that mainly addresses the subjective indicators
10
of the wellbeing of an individual, i.e. everyday emotional experiences as well as life in
11
general. In contrast, HRQoL is a concept (including physical, social, emotional,
12
cognitive, work-/role-related, spiritual aspects) that focuses on this wellbeing with
13
respect to a disability, disorder or underlying disease like a primary childhood brain
14
tumour (CBT). Using self-reporting questionnaires, subjects describe their individual
15
situation in the context of their personal expectations and goals.
16
Quality of Survival (QoS)
17
In this review: includes long-term neurocognitive, endocrine and other medical,
18
behavioural, emotional and adaptive functional sequelae of CBT and environmental
19
(host-related) factors (see above).
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ACCEPTED MANUSCRIPT
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Table 1. Trials/registries of the German Paediatric Brain Tumour Consortium (HIT-Network) for treatment/registration of children and adolescents with primary central nervous system (CNS) tumours.
intracerebral and spinal Ependymoma (WHO°II, III)
HIT-2000 (01/2012-12/14: HIT-2000-Interim-Registry) (ClinicalTrials.gov Identifier: NCT02238899) SIOP-PNET5 MB (ClinicalTrials.gov Identifier: NCT02066220) low and standard risk MB I-HIT-MED registry (since 1/2015)
Major Objectives
interventional & registry multicentre, prospective, randomised, therapy optimisation clinical phase III & II/III (SIOP-PNET5 MB)
Recurrent/refractory: MB Supratentorial CNSPNET Ependymoma (WHO°II, III)
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Pineoblastoma
Study Type Design
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MB Medulloepithelioma CNS-PNET
Acronym of trial/registry (ClinicalTrials.gov Identifier, EudraCT)
HIT-REZ 2005 (ClinicalTrials.gov Identifier: NCT00749723)
1) increasing the probability of survival rates using intensified CT and/or RT, risk-stratification and improved quality controls of surgery, CT and RT
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CNS tumour
interventional multicentre, prospective non-randomised, therapy optimisation clinical phase II
Activity/Recruitment
HIT 2000: 01/2001 - 12/11 HIT 2000-Interim-Reg.: 01/2012-12/2014 I-HIT-MED Registry: 01/15ongoing SIOP-PNET5 MB: 06/2014ongoing
2) reducing late effects by using less craniospinal and or no cranial RT-doses in children < 4y 3) acquiring epidemiological data, reference results, tumour-, CSF- and blood samples for current and future clinical and biological studies patients: 0 - 21 y 1) increasing probability of survival with adequate QoL
2) studying safety and efficacy of new agents: a) P-HIT-REZ 2005: oral temozolomide vs carboplatin/VP16 P-HIT)
02/2006-02/2013 (end of recruitment) 02/2016 (end of P- and EHIT-REZ 2005) 04/2014 (end of phase II intraventricular VP16)
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Brain stem gliomas WHO°°III/IV
without NF1 or other phacomatosis)
Astrocytoma Ganglioglioma Oligodendroglioma
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Gliomatosis cerebri
LGG WHO°°I/II (with or
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HIT-HGG 2007: interventional multicentre prospective, therapy optimisation clinical phase II HIT-HGG-CilMetro: interventional safety/efficacy, treatment clinical phase II
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DIPG
HIT-HGG 2007 (primary) (EudraCT: 2007-000128-42) HIT-HGG-CilMetro (recurrent) (ClinicalTrials.gov Identifier: NCT01517776)
HIT-HGG 2007: 07/2009 ongoing HIT-HGG-CilMetro: 01/2012 - ongoing
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Primary/recurrent malignant glioma WHO°°III/IV
b) E-HIT-REZ 2005: neuro(radio)logical and CSF-response to temozolamide on d 60 c) intraventricular VP16 patients: >3m - <30y 1) HIT-HGG 2007: assessing treatment efficacy (defined as 6m EFS after diagnosis) of oral temozolomide and RT for induction and oral temozolomide for consolidation in order to justify subsequent phase III trial with oral temozolomide for the same cohort (patients >3y-<18y)
SIOP-LGG 2004 (ClinicalTrials.gov Identifier: NCT00276640) SIOP-LGG 2004 Interim Registry
SIOP-LGG 2004: interventional, multicentre randomised, safety/efficacy, therapy optimisation SIOP-LGG 2004 Interim Registry:
2) HIT-HGG-CilMetro: evaluating the efficacy of a combined treatment with cilengitide and metronomic oral temozolomide as measured by 6m OS after diagnosis of relapse or tumour progression patients with relapsed or refractory HGG and DIPG (patients >3y-<18y) 1) comparing efficacy (defined as PFS) of/response to standard induction with carboplatin and VCR vs intensified induction with additional
SIOP-LGG 2004: 04/2004 04/2012 SIOP-LGG 2004-InterimReg.: 04/2012-04/2014
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2) acquiring epidemiological data, reference results, tumour-, CSF- and blood samples for current and future clinical and biological studies (patients 0-<18 y) 1) maintaining current EFS a) by applying risk-adapted treatment strategies/CSI (localized germinoma) b) by treatment as of localized germinoma and by replacement of CSI by combined CT and ventricular RT (bifocal germinoma) c) by replacement of CSI by combined CT and ventricular RT (metastasized germinoma) d) by dose-escalating CT (HR-non-germinoma) e) by standardizing surgical approach (residual malignant non-germinoma)
interventional multicentre, prospective non-randomised, therapy optimisation efficacy
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SIOP CNS GCT II (ClinicalTrials.gov Identifier: NCT01424839)
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Intracranial germ cell tumours
VP16
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registry multicentre, prospective non-randomised, safety/efficacy
Oligoastrocytoma Dysembryoblastic neuroepithelial tumour
2) patient registration and data acquisition on diagnosis, treatment strategies and -efficacy for development of future protocols (teratoma)
10/2011 - 10/2016
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Pituitary adenoma
KRANIOPHARYNGEOM 2007 (ClinicalTrials.gov Identifier: NCT01272622)
interventional & registry/observatory multicentre, prospective, randomised, therapy optimisation, efficacy
Meningioma
2) assessment of different treatment strategies and evaluation of remission status (craniopharygioma) 3) assessment of QoL (> 3y after randomisation; incompletely resected craniopharyngioma) 4) assessment of PFS and OS depending on timepoint of postoperative RT (incompletely resected craniopharyngioma) patients 0 - 18y 1) evaluation of epidemiological and clinical data of patients with CPT 2) developing infrastructure for reference centers (pathology, genetics, radiology, RT) 3) improving understanding of tumour biology and genetics 4) supporting tumourbanking 5) conducting biological studies 6) comparing safety/efficacy of 4 chemotherapy regimens
interventional & registry multicentre, prospective, randomised, therapy optimisation safety/efficacy clinical phase III
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CPT-SIOP-2000 CPT-SIOP-2009 (ClinicalTrials.gov Identifier: NCT01014767)
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Cysts of Rathke Pouch
Choroid plexus tumours (APP, CPP, CPC)
10/2007-ongoing
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Xanthogranuloma
1) acquisition of epidemiological, diagnostic, treatment and response data (all tumour types)
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Craniopharyngioma
11/2009-11/2017 temporarily closed
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RB-Registry
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Retinoblastoma
registry
start: 07/2010
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European Rhabdoid Registry (EUR-RHAB)
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Atypical teratoid/rhabdoid tumours of the brain (AR/RT)
7) development of future treatment strategies/clinical phase I/II studies 8) establishing panEuropean and other international collaborations 1) evaluation of all patients with AT/RT (EFS, PFS after different treatment approaches, efficacy of surgery, RT) 2) developing infrastructure for reference centres (pathology, genetics, radiology, RT) 3) improving understanding of tumour biology and genetics 4) supporting tumourbanking - conducting biological studies 5) development of future treatment strategies/clinical phase I/II studies 6) establishing panEuropean and other international collaborations 1) evaluation of epidemiological and clinical data of patients (0 - < 18y) with RB 2) establishing reference centres (pathology,
registry
start: 11/2013
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neuroradiology) Abbreviations: APP-atypical plexus papilloma, AT/RT-atypical teratoid/rhabdoid tumour, CNS-central nervous system, CNS-PNET-primitive neuroectodermal tumour of the CNS, CPC-choroid plexus carcinoma, CPP-choroid plexus papilloma, CPT-choroid plexus tumour, CSF-craniospinal fluid, CSI-craniospinal irradiation, CT-chemotherapy, d-day, DIPG-diffuse intrinsic pons glioma, EFS-event free survival, GCT-germ cell tumour, HGG-high grade glioma, HIT-Hirntumor (German for "brain tumour"), HR - high-risk, LGG-low grade glioma, m-months, MB-medulloblastoma, NF1Neurofibromatosis Type 1, PFS-progression free survival, (p)OS-(probability of) overall survival, QoL-quality of life, RB-retinoblastoma, RTradiotherapy, SIOP-International Society of Paediatric Oncology, VCR-vincristine, VP16-Etoposide, WHO-World Health Organization, y-years.
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Table 2: Multifactorial radiotherapy-related late effects (LE) and reported synergistic covariates in survivors of childhood primary central nervous system tumours: A) by pathogenesis and B) by impairment. A) ONSET
SYNERGISTIC COVARIATES
[mean y post RT]
Tx-related
Stroke/TIA
100-fold ↑
headaches, focal deficits, seizures
(all CBTS compared to healthy paediatric population)
cognitive NCF*↓
endocrine (s. table 2B)
4.7-4.9
field CRT (COW)/cervical CSI dose: >30 Gy
40-fold ↑
CRT)
NCF*↓
CCM ICA HM-AP FHD
headaches, focal deficits, seizures
cognitive
NCF*↓ (HM-AP)
neurologic recurrent complex migraine attacks (SMART)
nr
nr
(NF1patients)
cognitive
neurologic
field WBRT/ CRT (COW) cervical CSI dose: >45 Gy
4.6 3.2
3.4% (CCM, post CRT) 20% (HM-AP, post CRT) 80% (FHD post CRT)
3.1-19.5
field
(CCM)
CRT/WBRT/CSI
random MRI findings
AP: nr SMART: rare
NS
nr
(systemic)
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3.5% (post
headaches, focal deficits, seizures
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+
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neurologic
nr
TMrelated
site ST type ni
Host-related coexisting health conditions NF1, MMS, metabolic (DM, endocrine LE: s. table 2B), macro-/micro-AP, HTN gender male age at dx ni other: sedentary lifestyle
site PS, SS
coexisting health conditions NF1
gender male age at RT <5y nr
dose
site ST (HMAP/FHD)
>30 Gy (CCM; HM-AP/FHD: ni)
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MMS
(post CRT)
Mineralising MicroAP/SMART
NEUROVASCULAR DAMAGE
RT neurologic
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PATHOGENESIS
INCIDENCE
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CHARACTERISTICS OF LATE EFFECT CHRONIC HEALTH CONDITION
coexisting health conditions
PROGNOSIS/ COMPLICA-TIONS
recurrent events
(↑ with time after 1st RT), ICH,
irreversible chronic health conditions progessive NCF*decline stroke/TIA, ICH irreversible chronic health conditions progessive NCF*decline ICB, symptomatic epilepsy (CCM, ICA)
genetic predisposition age at RT <10y (CCM), >7y (HM-AP/FHD)
REF.
87-92
93-98
99105
(other)
2-10
field
CRT (SMART: PF, ST/TL) WBRT(AP) dose: >15 Gy (AP; SMART: nr)
nr
+
nr
gender male age at dx: young
self-limiting (within days to weeks)
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anosmia, sensorineural hearing loss, optic neuropathy, nystagmus, cerebellar ataxia, dysarthria, myelopathic syndrome
rare (post CRT & NS)
8-22
nr
nr
IT (PF) IS
cognitive NCF*↓
CRT)
cognitive
3m-5y
field WBRT > localized CRT (when including BS, CC: risk↑), CSI dose/fs
endocrine
72 Gy/<2.5 Gy: incidence=5% 90 Gy/<2.5 Gy: incidence=10% fs >2.5 Gy: nr other low conformality index
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(s. table 2B)
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NCF*↓
+ (HD-CT, MTX)
nr
nr
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5%-10% (post
headaches, focal deficits, symptoms of increased ICP
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neurologic
site
+
coexisting health conditions
progressive symptoms
110
CCM, ICA
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neurologic
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Necrosis/WML/WMV/Leuken cephalopathy
WHITE MATTER LOSS
Superficial Siderosis
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coexisting health conditions DM
gender male age at dx conflicting data (younger vs older children) other shorter overall Tx-time
nr
111114
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B)
CHARACTERISTICS OF LATE EFFECT INCIDENCE
ONSET
SYNERGISTIC COVARIATES
[mean y post RT]
Tx-related RT
up to 80%
1-5
(increases with time post CRT) GHD: 50-80% GnD: 20-50% TSHD: 3-6% primary ovarian insufficiency: 83% precocious puberty: 11.1% delayed puberty: 11.8%
(biphasic , GHD earliest)
hypothyroidism, hypogonadism (delayed puberty, permanent amenorrhoe, azoospermia), primary ovarian insufficiency, infertility, precocious puberty, hyperprolactinemia low HDL, insulin resistance, adrenal insufficiency
timepoi nt
busulfan, cis/carboplatin, cyclophosphamide, ifosfamide, etoposide, procarbacine, melphalan (dose dependent)
NS prior to CRT
coexisting health conditions pre-CRT endocrinopathy gender male (RE: growth failure) age at dx prepubertal stage at CRT (RE: infertility)
progressive and irreversible impairments*, dysproportional growth (after CSI), osteoporosis, osteopenia, obesity
30,41, 43, 47,57, 59, 70,115 -121
(controversial reports), stroke
risk↑
TSHD, ACTHD: nr
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social withdrawal, depression
nr
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psychooncological*
Dysproportional Growth
site PS, SS, P, HT
combined PB+conventional CRT >PB alone (earlier onset of impairments*)
NCF*↓
SPINE GROWTH
GnD:
site PS, SS, P, HT
Host-related
REF.
technique
cognitive
reduced sitting heigth (damaged vertebral growth plates)
dose GHD: >18 Gy: risk ↑, 30-50 Gy: 50100% risk ACTHD, GnD: > 30 Gy TSHD: >50 Gy (no TSHD post low-dose CRT or TBI) precautious puberty: 18-24 Gy (females), 2550 Gy (both genders)
metabolic
musculoskeletal
GHD: data controversial
TMrelated
PROGNOSIS/ COMPLICA-TIONS
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GH-/TSH-/ ACTH-/ GnD
ENDOCRINOPATHY
endocrine
field CRT (including hpaxis)/CSI
NS
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musculoskeletal growth failure, reduced bone mineral density, lean muscle mass
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IMPAIRMENT*
CHRONIC HEALTH CONDITION
nr
field CSI>CRT dose >18 Gy CSI
+
nr
nr
gender male age at RT young (<6y) at CSI
short adult height
116,12 2, 123
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36 Gy >24 Gy>18Gy (CRT)
14% (post CRT including cochlea, not treated with platinum-based CT) 28-68% (in combination with CT)
3-5
field CRT (including cochlea/PF) dose
low incidence after mean cochlear dose <30 Gy, risk↑: 4045 Gy & >50 Gy to PF
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Sensorineural Hearing Loss
hearing loss (high (68 kHz) > low frequencies) cognitive NCF*↓
dose
technique extent of resection
other hydrocephalus, shuntsurgery
site ST, PF riskstratification HR
coexisting health conditions
progressive NCF* decline
43,70, 86, 112,12 4-129
progressive hearing loss, permanent need for hearing aids
43,57, 70, 130133
exposure to glucocorticoids, and/or antiepileptic agents and/or opioids, homozygous GSTM1 deletion (MB-patients), perioperative morbidity (e.g.PFS), NF1, reduced WMV, WML, cerebrovascular disease (stroke, MMS) (s. table 2A), serious hearing loss (s. below) age at dx young other low baseline performance level at dx
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+ (MTX)
(MBpatients)
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attention deficits, impaired psychological development in, and interaction with social environment, inactive lifestyle/reduced participation in physical activities
field
RE NCF*↓: CRT (TL), conformal CRT (3D)>intensitymodulated CRT (HC-sparing) >proton-Tx (spot scanned), WBRT >local CRT, CSI >ventricular CRT, conven-tional > fractio-nated CRT; RE motor skills↓: CRT (including frontal regions)
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nr
psychosocial/ behavioural
neurosensory
AUDIOLOGICAL
40-100% (↑ post CRT)
+
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NEUROPSYCHOLOGICAL*
compromised physical performance, reduced everyday life activity cognitive NCF*↓ (RE: memory, attention, executive function, IQscores/academic achievements, everyday life participation)
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motor skills
(platinumagents)
nr
site PF, BS
coexisting health conditions genetic predisposition age at dx young other ethnic background
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legal blindness: CI = 1.8% (20 y post dx) cataract: CI = 2.1% (20 y post dx)
taste/smell disturbances
smell ca. 90% taste ca. 70%
during CRT or ca. 36w post start of CRT
nr
site HT, CO, DE
dry eyes: >2 Gy CRT to eye, >30 Gy to TL; double vision: >5 Gy to eye, >30 Gy to TL or PF; legal blindness (1 or both eyes): all doses to PF, >5 Gy CRT to eye, >30 Gy to TL; cataract: all doses to PF, TL, >2 Gy to eye, CI↑ with >5 Gy to eye retinal condition: >20 Gy to eye
field CRT/WBRT/RT (including nasopharyngeal region)
dose
60 Gy (median dose to tumor volume)
coexisting health conditions exposure to dexamethasone (RE dry eyes)/prednisone (RE cataract) other risk of double vision and legal blindness↓ after exposure to prednisone
dose
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neurosensory
nr
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5.7% (20y post dx)
(dry eyes/ double vision/ legal blindness/ cataract, post dx)
field CRT (including orbita/eye, TL, PF)
persistent need of eye medication/servic es for the visual impaired
133,13 4
altered dietary habits/malnutritio n
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double vision: CI =
7.2/2.2 / 1/4.7
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dry eyes: CI = 5.3% (20 y post dx)
nr
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amblyopia, legal blindness, double vision, cataract, kerato-conjunctivitis sicca (dry eyes)
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OLFACTORY
OCULAR / VISUAL
neurosensory
nr
site TL
nr
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ORN
dose/ volume developmental: >10 Gy to teeth >24 Gy CRT; xerostomia, caries: single dose and fractionated CRT >24 Gy; craniofacial deformities: >30 Gy with increased volumes; trismus: >40 Gy to pterygoid muscle
+ (high cumulative doses of alkylating agents/cyclophosphamide, HSCTconditioning regimens including cyclophosphamide/ busulfan)
nr
nr
coexisting health conditions invasive dental therapy in the former RT field (RE ORN risk), poor pre-RT dental/peridontal status age < 5y at cancer-Tx (RE developmental) gender female other low SES
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(ORN)
TBI/CRT (including oral cavity)/cervical CSI
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1-5
field
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peridontal disease, impaired salivary gland function/xerostomia/ caries, oral infections, impaired temporomandibular joint function, trismus/ speech difficulties
2 (xerostomia)
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ORAL / DENTAL
compromised oral/dental health
microdontia: 9.2% vs 3.3% hypodontia: 8.2 vs 5.3% root malformation : 5.4% vs 1.9% enamel hypoplasia: 11.7% vs 5.3% severe gingivitis: 6.7% vs 5.7% loss of > 6 teeth due to decay or gum disease: 4.8% vs 1.8% xerostomia: 2.8 % vs 0.3% craniofacial deformities: 35-90% (CBTS vs healthy controls)
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micro-/hypodontia, craniofacial abnormalities, root stunting, enamel defects
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developmental
increased need for dental care (including dentures), for reconstructive surgery, facial/dental cosmetic concerns, speech delay, increased cardiac late morbidity (due recurrent oral infections)
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field CRT/WBRT/TBI CSI
dose meningioma, glioma: mean of 1.5 Gy CRT (range 1-6 Gy)
other lower risk of breast cancer post PB-CSI
+ alkylating agents, platinum agents, topoisomerase II inhibitors (risk↑ compared to RT alone)
nr
nr
coexisting health conditions
nr
cancer predisposition syndromes (e.g. Li-Fraumeni-, Turcot-, Gorlin-Syndrome, NF1, NF2, von Hippel-Lindau disease, MES), alcohol and/or tobacco abuse (RE oral SMN) age young (< 5y) at tx (except for MB as primary dx: ni)
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CNS lymphoma, intracranial fibrosarcoma, oral carcinoma, osteosarcoma (skull), thyroid carcinoma, MDS, breast cancer
5-10y post CRT (median for MBpatients: 5.8y, range 31.-16.8y post dx)
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secondary nonprimary intracranial tumours and other SMN
(meningioma > HGG>LGG> CNS-PNET) 4.2% (MB, CI at 10y)
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Abbreviations and symbols: ACTHD-adrenocorticotropic hormone deficiency, AP-angiopathy, BS-brain stem, CBTS-childhood brain tumour survivor, CC-corpus callosum, CCM-cerebral cavernous malformation, CI-cumulative incidence, CNS-central nervous system, CNS-PNET-primitive neuroectodermal tumour of the CNS, CO-chiasma opticum, COW-circle of Willis, CT-chemotherapy, CRT-cranial RT, CSI-craniospinal irradiation, DEdiencephalon, DM-diabetes mellitus, dx-diagnosis, FHD-focal haemosiderin deposition, fs-fraction size, GHD-growth hormone deficiency, GnDgonadotropin deficiency, Gy-Gray, HC-hippocampus, HD-high dose, HDL-high density lipoprotein, HGG-high-grade glioma, HM-AP-haemorrhagic microangiopathy, hp-axis-hypothalamic-pituitary axis, HR-high risk, HSCT-haematopoietic stem cell transplantation, HT-hypothalamic, HTNhypertension, ICA-intracranial aneurysm, ICH-intracerebral haemorrhage, ICP-intracranial pressure, IQ-intelligence quotient, IT-infratentorial, ISintraspinal, LE-late effect, LGG-low grade glioma, m-month(s), MB-medulloblastoma, MDS-myelodysplastic syndrome, MES-multiple endocrine neoplasia, MMS-Moyamoya Syndrome, MRI-magnetic resonance imaging, MTX-methotrexate, NCF-neurocognitive functioning*, NF1(2)neurofibromatosis type I (II), ni-no impact on LE/pathology/impairment, nr-not reported for CBTS, NS-neurosurgery, ORN-osteoradionecrosis of facial bones, P-pineal, PB-proton beam, PF-posterior fossa, PFS-posterior fossa syndrome, PS-parasellar, QoL-quality of life*, RE-regarding, RT-radiotherapy, SES-socioeconomic status, SMART-stroke-like migraine attacks after CRT, S(M)N-secondary (malignant) neoplasm, SS-suprasellar, ST-supratentorial, TBI-total body irradiation, TIA-transient ischaemic attack, TL-temporal lobe, TM-tumour, TSHD-thyroid stimulating hormone deficiency, Tx-treatment, vs-versus, w-week(s), WBRT-whole brain RT, WML - white matter lesions, WMV - white matter volume, y-year(s); *: see definitions in main text, ↑: increased, ↓ : reduced/impaired, + : "yes".
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S(M)N
meningioma, glioma, CNS-- PNET, MB
1.3%
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secondary primary CNS tumours
116,12 7, 139,14 1-145
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LEGENDS TO FIGURES Figure 1. Organisation of multicentre, standardised therapy optimising studies and
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associated registries of the HIT-Network and SIOP-E. Abbreviations: CSF-craniospinal fluid, HIT-"HirnTumor" (German for "brain tumour"), SAE-severe adverse event, SIOP-E - International Society of Paediatric Oncology, European branch; for details regarding late effect- and biological studies: see main text.
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Figure 2. Increase in A) 10-, B) 15-year overall survival rates by year of diagnosis in 3-year groups of children with primary CNS tumours and other malignancies in Germany between 1981 and 2010 (estimation according to Brenner and Spix [206].
Oncology/Haematology (KPOH);
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Sources: German Childhood Cancer Registry (GCCR), Competence Network Paediatric
Abbreviations: ALL-acute lymphoblastic leukemia, AML-acute myeloid leukemia, CNS-
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central nervous system, NHL-non-Hodgkin lymphoma.
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Tallen et al._EJC_03/2015_Highlights
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Highlights/Bullet Points
1) For many childhood brain tumour survivors, survival means chronic disease.
2) For CBTS, QoS assessment should include tumour-, treatment- and host-related
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factors.
3) Many CBTSs' dilemma: Treatment takes CNS tumour, but bates CNS function.
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4) Predictive markers of LE-risks are needed for individual treatment planning.
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5) Empowering survivors and stakeholders: a new mission in Paediatric Neurooncology.