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:
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.
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.
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.
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.
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.
