Clinical trial NCT02300766: Cerebellar Mutism Syndrome Study
Official title: Nordic Study of the Cerebellar Mutism Syndrome in Children With Brain Tumours of the Posterior Fossa
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Infratentorial Neoplasms
Mutism
Keywords: Cerebellar Mutism Syndrome
Posterior Fossa Tumor
Pediatric cancer
Neurosurgical techniques
Lead sponsor: Rigshospitalet, Denmark
Sponsor class: OTHER
Collaborators: name: Odense University Hospital
name: Aarhus University Hospital
name: Aalborg University Hospital
name: Technical University of Denmark
name: Karolinska University Hospital
name: Skane University Hospital
name: University Hospital, Linkoeping
name: Uppsala University Hospital
name: Sahlgrenska University Hospital
name: University Hospital, Umeå
name: Oslo University Hospital
name: Trondheim University Hospital
name: Haukeland University Hospital
name: University Hospital of North Norway
name: Helsinki University Central Hospital
name: Tampere University Hospital
name: Kuopio University Hospital
name: Turku University Hospital
name: Oulu University Hospital
name: Radboud University Medical Center
name: Liverpool University Hospitals NHS Foundation Trust
name: Great Ormond Street Hospital for Children NHS Foundation Trust
name: Nottingham University Hospitals NHS Trust
name: University Hospital Birmingham
name: University Hospitals Bristol and Weston NHS Foundation Trust
name: Royal Infirmary of Edinburgh
name: South Glasgow University Hospitals NHS Trust
name: University Hospital Tuebingen
name: Medical University of Vienna
name: Ospedale Pediatrico Bambin Gesù
name: Motol University Hospital
name: University of Leipzig Medical Center
name: Universitaire Ziekenhuizen KU Leuven
name: Queen Fabiola Children's University Hospital
name: Cliniques universitaires Saint-Luc- Université Catholique de Louvain
name: University Hospital, Ghent
name: Hospital De La Citadelle
name: CHC MontLégia
name: University Hospital, Antwerp
First posted: 2014-11-25
Enrollment: 1000
Sex: ALL
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: All children (0-18 years) with a tumour in the posterior fossa (cerebellum/4th ventricle/brainstem ) requiring surgery or open biopsy at one of the participating centres.

Brief summary: The purpose of this study is to determine why up to 25% of the pediatric patients who have surgery for a tumor in the posterior fossa develops the Cerebellar Mutism Syndrome (CMS). Furthermore the purpose is to explore the clinical course and the best treatment of the syndrome.

Detailed description: Background:

Cancer accounts for 22 % of all deaths among children in Europe and is thus the leading non-traumatic pediatric cause of death. Central nervous system (CNS) tumours constitute 25% of all childhood cancers, and the majority of these are located in the posterior fossa. One of the most troublesome late effects after neurosurgery for such a tumour is the cerebellar mutism syndrome which is seen in up to 25% of the patients. It is characterized by mutism, hypotonia, ataxia and irritability. The exact aetiology, risk factors, clinical course and treatment have yet to be identified. The aim of this study is to accomplish that.

Method:

This is an observational prospective multicentre study that will include a minimum of 500 paediatric patients with posterior fossa CNS tumours from the Nordic countries. Additional countries might be added later once the study is running. The study has started in fall 2014 in 20 centres from 5 Nordic countries. Prior to this a pilot study was performed on 43 Danish adult patients to validate and fine-tune registration procedure. All patients will be treated according to local standards, but clinical data will be collected and imaging will be reviewed centrally.

To calculate the participation rate the annual number of included patients from each country will be compared to the number of registered patients in the cancer registers of the respective country and year.

A blood sample for genetic analysis will be collected from all patients. The patients' neurology and speech functions will be examined both pre-operatively and repeatedly post-operatively, including recording of standardised speech samples. All data will be collected trough a, for the purpose developed, online database.

Registration of data

The following data will be registered at the following 5 time points:

1. Preoperatively Hospital and country, and patient related variables (date of birth, handedness, bilingualism, sex and date of diagnosis). Medical history (Previous neurological/neuropsychological/ psychiatric problems, comorbidities, previous operations or other treatment for the tumour, previous regular use of any kind of medication). Preoperative neurological status will be examined and a language and speech test will be performed and recorded. If the patient is younger than 2 years a bedside assessment of the speech will be performed instead of a test. A blood sample for genetic analysis will be drawn together with the standard blood samples. Alternatively this can be done at any time during follow-up.
2. Postoperatively within 72 hours of surgery Operation related variables (date, duration and course of operation, surgical position, surgical approach, and tumour removal method), complications, technology employed, preoperative hydrocephalus and estimated completeness of tumour resection.
3. Postoperatively within 1-4 weeks from surgery Approximately 1-2 weeks post-op: Postoperative language and speech status and for those older than 2 years, a recording of a speech sample. Neurological examination. Glucocorticoid administration pre-, intra- or postoperatively plus other medications used to treat the CMS postoperatively and their effects. Kind(s) of imaging performed on the tumour pre- and postoperatively. Approximately 4 weeks post-op: Development and treatment of postoperative intracranial haematoma and hydrocephalus, leakage of cerebrospinal fluid and need for ventilator.
4. Postoperatively at about 2 months from surgery Postoperative development of CMS, detailed survey of the status of CMS in those affected including recording of speech sample and neurological examination. Medications used to treat the CMS since last registration and their effects.
5. Postoperatively at about 12 months from surgery Language and neurological status including a speech sample for those older than 2 years. Medications used to treat the CMS since last registration and their effects. Other anti-cancer treatment given (chemotherapy and/or radiotherapy). Results from the pathology department regarding the kind of tumour histology and genetics. Registration of whether neuropsychological assessment(s) have been performed. Kind(s) of imaging performed on the tumour since 1st follow-up. Copies of the MRIs and descriptions performed pre-op, right after the operation and approximately. 12 months post-op are obtained.

All registered data will be examined by a third party who will check for missing data or misentries in order to ensure a high quality of the data. In case of missing data or misentries the third party will contact the person who made the registration.

The database is administered by the children's cancer epidemiology group (CCEG) at Karolinska Hospital in Stockholm, which is also responsible for the Swedish children's brain tumour registry and the leukaemia database for the Nordic Society of Pediatric Hematology and Oncology (NOPHO)

Other courses:

In case of acute surgery, coma etc. information about the study and the offer to participate can be given within 7 days from the operation. In these cases preoperative data about the patient can be obtained from the patient's medical record and/or from the parents, but a preoperative speech sample cannot be performed. These patients will not be included in the analysis of whether and how preoperative speech and language status affects the risk of developing CMS, but will be included in all the other study analyses. Speech samples will be performed postoperatively in exactly the same manner as in patients that were included before operation to able to monitor the patient's speech postoperatively and register signs of the CMS.

Should the patient have posterior fossa tumour surgery performed again during the 12 months follow-up period, the patient will re-start the follow-up programme from that date. A separate pre-op and all the post-op registrations will be performed again, and used in the analysis of risk of first versus second or further surgery. New genetic blood samples will not be necessary in these cases. Should the patient have posterior fossa tumour surgery performed after the last 12 months follow-up, the patient will be offered to participate in the study again and a new consent will have to be obtained. New genetic blood samples will not be necessary in these cases.

If the patient leaves the study for any reason before the follow-up 12 months post-op, a separate form will be filled out explaining why the patient left.

If the patient turns 18 while included in the study, a new consent to participate will have to be given by the patient him- /herself.

Blood samples and analyses:

As soon as a patient has been registered, the study centre will request a 2 ml anticoagulated blood sample for genetic profiling (Single-Nucleotide Polymorphism (SNP) analysis).

The investigators will use a newly developed single nucleotide polymorphism (SNP) sequencing strategy that allows cost-effective mapping of 25-30.000 genetic polymorphisms within biological domains that could potentially be linked to the development of CMS (e.g. inflammation, vascularization, blood-brain-barrier markers, and apolipoprotein E and other lipoprotein pathway genes). The genetic data will be linked to the clinical data to identify genetic variants associated with the risk of CMS or the course of CMS. Specifically the investigators will map all SNPs in all genes that are known or are likely to be linked to these pathways, including mRNA binding sites and first order protein-protein interactions. Rather than expecting large effects of single SNPs, the strategy of this approach is to use front-line bioinformatics and pathway analyses to explore the additive effect of numerous SNPs involved in the same biological pathway. This will identify high-impact pathways, although with individual low-impact SNPs. The results obtained could guide future therapeutic approaches to CMS.

If the custodial parents do not consent to their child contributing a blood sample to the study, the child may still participate in the study, albeit not in the part involving genetic analysis. The samples as well as the rest of the study data will be protected under the Act on Processing of Personal Data and the Act on the Health Act.

All MRIs are analyzed by neuroradiologists with respect to tumour resection and neuroradiographic signs associated with CMS.

All speech recording are analyzed by speech therapists with respect to signs associated with CMS. The results of neuropsychological tests that may have been performed routinely will be separately obtained and analyzed.

Power calculations:

For the surgical hypothesis, assuming that 35% of patients are operated with an approach that has a lower risk of CMS (assumed to be 10%) and the remaining 65% of patients are operated using other approaches that carries a 20% risk of CMS, the investigators will with 80% power be able to identify a difference at a 5% significance level if the investigators include a total of 450 patients.

For the genetic analysis, several pathways and SNP-profiles will be explored with appropriate adjustments for multiple comparisons. Multiple SNPs will due to randomness be found to be related with the risk of CMS. Their true biological significance will subsequently be validated through internal validation, as the investigators will explore if other SNPs in the same biological pathway, e.g. SNPs in the same genes but not the same haplotype or SNPs that affect coding or regulatory regions in the identified risk-related genes are more significantly associated with risk of CMS than randomly selected SNPs. Furthermore, the genes/SNPs will be explored by bioinformatic predictions of the impact of the SNPs on protein-folding, binding affinity etc. Once such high-risk SNPs/genes/pathways have been identified and published, the investigators will attempt to have them confirmed in independent patient cohorts from Europe or the US. Based on a projected overall risk of CMS of 20%, a frequency of a specific SNP (or SNP-profile) of 30%, and a projected doubled risk of CMS in the group that harbour the SNP (or SNP-profile), the investigators will with 90% power be able to identify such a genetic predisposition at a 5% significance level, if a total of 343 patients are included in the study. Thus, the study has sufficient power.

To analyze the effect of the above mentioned variables (surgical method, administration of corticosteroid, handedness etc.) on the risk of developing CMS the investigators will perform univariate and multivariate regression analyses as well as standard descriptive analyses. These analyses will be performed using R.

Discussion:

The study will be the largest prospective multicenter study on cerebellar mutism syndrome to date, and the first one of its kind to systematically gather detailed information about 1) the surgical approaches least likely to cause the syndrome, 2) how the syndrome is best treated, 3) the role of genetics and 4) differences in incidence and clinical course of the syndrome for different patients.

The ultimate aim of the study is to reduce the incidence and improve the treatment of cerebellar mutism syndrome and lead to harmonization of the treatment of CNS tumour patients across the Nordic countries.

Eligibility criteria: Inclusion Criteria:

* Age \< 18 years at the date of first imaging showing this tumour
* Tumour in the cerebellum/4th ventricle/brainstem with intention to treat with surgical resection or open biopsy. Second and further surgeries are also included.
* Informed consent from custodial parent(s)

Exclusion Criteria:

* None

Primary outcomes:
measure: Development and progress of Cerebellar Mutism Syndrome
timeFrame: 1 year after surgery
Secondary outcomes:
measure: Development and progress of reduced speech output
timeFrame: 1 year after surgery
Other outcomes:
Locations:
city: Vienna
country: Austria
facility: Medical University of Vienna
city: Leuven
country: Belgium
facility: University Hospital Leuven
city: Praha
country: Czechia
facility: Motol University Hospital
city: Aalborg
country: Denmark
facility: Aalborg University Hospital
city: Aarhus
country: Denmark
facility: Aarhus University Hospital
city: Copenhagen
country: Denmark
facility: Rigshospitalet
city: Odense
country: Denmark
facility: Odense University Hospital
city: Helsinki
country: Finland
facility: Helsinki University Central Hospital
city: Kuopio
country: Finland
facility: Kuopio University Hospital
city: Oulu
country: Finland
facility: Oulu University Hospital
city: Tampere
country: Finland
facility: Tampere University Hospital
city: Turku
country: Finland
facility: Turku University Hospital
city: Leipzig
country: Germany
facility: University of Leipzig Medical Center
city: Budapest
country: Hungary
facility: Semmelweis University, 2nd Dept of Pediatrics
city: Rome
country: Italy
facility: Ospedale Pediatrico Bambino Gesù
city: Kaunas
country: Lithuania
facility: Hospital of Lithuanian University of Health Sciences Kauno klinikos
city: Nijmegen
country: Netherlands
facility: Radboud University Nijmegen Medical Centre
state: Gelderland
city: Groningen
country: Netherlands
facility: UMC Groningen
city: Utrecht
country: Netherlands
facility: UMC Utrecht
city: Bergen
country: Norway
facility: Haukeland University Hospital
city: Oslo
country: Norway
facility: Oslo University Hospital
city: Tromsø
country: Norway
facility: University Hospital of North Norway
city: Trondheim
country: Norway
facility: St. Olav's Hospital
city: Gothenburg
country: Sweden
facility: Sahlgrenska University Hospital
city: Linköping
country: Sweden
facility: Linköping University Hospital
city: Skåne
country: Sweden
facility: Skåne University Hospital
city: Stockholm
country: Sweden
facility: Karolinska University Hospital
city: Umeå
country: Sweden
facility: University Hospital of Umeå
city: Uppsala
country: Sweden
facility: Uppsala University Hospital
city: Liverpool
country: United Kingdom
facility: Alder Hey Childrens NHS Foundation Trust
Study officials:
affiliation: Rigshospitalet, Denmark
name: Kjeld Schmiegelow, MD, Dr. med
role: STUDY_CHAIR
affiliation: Rigshospitalet, Denmark
name: Marianne Juhler, MD, Dr. med
role: PRINCIPAL_INVESTIGATOR
affiliation: Rigshospitalet, Denmark
name: Karsten Nysom, MD
role: STUDY_CHAIR
References:
citation: Wibroe M, Cappelen J, Castor C, Clausen N, Grillner P, Gudrunardottir T, Gupta R, Gustavsson B, Heyman M, Holm S, Karppinen A, Klausen C, Lonnqvist T, Mathiasen R, Nilsson P, Nysom K, Persson K, Rask O, Schmiegelow K, Sehested A, Thomassen H, Tonning-Olsson I, Zetterqvist B, Juhler M. Cerebellar mutism syndrome in children with brain tumours of the posterior fossa. BMC Cancer. 2017 Jun 21;17(1):439. doi: 10.1186/s12885-017-3416-0.