Leukoencephalopathy Clinical Trial
Official title:
EPIBRAINRAD : Study of Neurological Complication After Radiotherapy for Glioblastoma High Grade
The survival time and the number of long time survivors after radiotherapy in brain cancer
patients have increased for the last decades. Therefore the topic of late-delayed neurotoxic
effects of this therapy gains more and more importance. Among these side effects, the main
and most frequent one is the leukoencephalopathy, a diffused and progressive damage of the
white matter characterized by myelin loss, loss of axons and vascular lesions. The incidence
rate assessment, as well as the occurrence time, is based on retrospective studies with low
numbers of patients, but seems to reach 30 to 50 % of the patients according to the
follow-up. The risk seems to be increased during the first two years after the radiotherapy,
but persists for decades.
To gain further insight in the radiation-induced leukoencephalopathy, the objective of this
project is to study the onset and evolution of leukoencephalopathy in a 3-year prospective
cohort of patients having undergone cerebral radiotherapy for glioma (stage 3-4), using
specific cognitive tests, Magnetic Resonance Imagery (MRI) scans of the brain and predictive
bio-markers of cognitive impairments.
Context The survival time and the number of long time survivors after radiotherapy in brain
cancer patients have increased for the last decades. Therefore the topic of late-delayed
neurotoxic effects of this therapy gains more and more importance. Among these side effects,
the main and most frequent one is the leukoencephalopathy, a diffused and progressive damage
of the white matter characterized by myelin loss, loss of axons and vascular lesions. The
incidence rate assessment, as well as the occurrence time, is based on retrospective studies
with low numbers of patients, but seems to reach 30 to 50 % of the patients according to the
follow-up. The risk seems to be increased during the first two years after the radiotherapy,
but persists for decades.
No complete characterization of this cognitive impairment has been done yet due to crucial
discrepancies in the neuropsychological assessments that were used (namely missing of
pre-treatment assessment), in the follow-up of patients and in the applied treatment.
However, based on previous studies, it can be said that the short term memory and the
frontal functions are mainly affected and the quality of life is exceedingly impaired.
Irradiation schemes, in particular high doses and large irradiated volume, have been
identified as risk factors of leukoencephalopathy. However, in spite of modified protocols
that tended to limit the risk, the remaining occurrence of the disease suggests a high
dependency on individual risk factors, that are still poorly known and make the individual
sensitivity to develop these secondary effects unpredictable. Other factors such as
cardio-vascular factors, smoking, old age and combined radio-chemotherapy are linked to
leukoencephalopathy as well, although only few of these associations were proved in large
studies. Moreover, some specific bio-markers could complete clinical examinations to predict
risk of cognitive impairment in these patients. Several biomarkers could be of interest:
The protein S-100B is a protein synthesized mainly by glial cells and cells of Schwann. It
is an intracellular protein regulating the cytosolic availability of calcium. Its
concentration is 30-100 times brought up in the cerebral tissue that in the other tissues.
Its plasmatic half-life is a 1 hour, its elimination is renal. So, the protein S-100B is a
marker of traumatic brain injury, certain neurodegenerative disorders and malignant gliomas.
The dosage maybe so realized in serum and urines.
- Growing evidence implicates oxidative/nitrative damage in the pathogenesis of
neurodegenerative disorders. Subsequent studies were undertaken showing that specific
isoprostanes (iPs) levels are elevated in urine and blood of Alzheimer Disease patients
and that these values correlate with memory impairments. This suggests that iPs are
useful biomarkers in neurological diseases. Their levels could be measured in urine and
plasma of patients.
- Homocysteine is a sulfur-containing amino acid, derived from the metabolism of
methionine. Higher levels of homocysteine were associated with worse memory performance
in a large group of older subjects. While homocysteine is not a diagnostic test, it may
represent a modifiable risk factor for dementia.
Highlighting neuropsychological disorders including at an early stage requires a reliable
and reproducible assessment of the patient's cognitive state. However, a comprehensive
neuropsychological assessment takes several hours and a qualified staff, making it difficult
to implement in the conventional patient monitoring. The use of a simple and fast tool to
detect cognitive impairment would help to develop a systematic approach for screening these
disorders. A detection computerized neuropsychological standardized test (Computerized
Cognitive Speed Test - CSCT) assessing processing speed of information, attention and
working memory has been validated in multiple sclerosis patients compared to healthy
volunteers. CSCT quickly detects patients with cognitive impairment, who could be then
tested with more complete tests. It can be conducted by people with no neuropsychology
training and the testing time is less than 2 minutes.
This study will allow a better understanding of the impact of cognitive sequelae in patients
treated for glioma with current standard treatments, including radiation. The validation of
a new screening test, the CSCT, in this disease will eventually detect earlier these effects
and possibly initiate treatment before lesions are too advanced. Feasibility of the
implementation of the CSCT in "routine" practice for all patients treated with brain
radiotherapy will be tested.
• Objectives and methodology To gain further insight in the radiation-induced
leukoencephalopathy, the objective of this project is to study the onset and evolution of
leukoencephalopathy in a 3-year prospective cohort of patients having undergone cerebral
radiotherapy for glioma (stage 3-4), using specific cognitive tests, MRI scans of the brain
and predictive bio-markers of cognitive impairments.
Primary objective:
- To constitute a prospective cohort of patients treated for glioma (stage 3-4) with
radiotherapy in order to estimate the incidence rate and occurrence time of the
leukoencephalopathy at the end of the follow-up (3 years after first inclusion).
Secondary objectives:
- To validate the CSCT- Computerised Speed Cognitive Test to detect early cognitive
impairment in this patients population compared with complete cognitive tests
- Estimate precisely the dose received by the different anatomical parts of the brain
- To study the relation between the risk of leukoencephalopathy and the received dose to
the brain
- To analyze the prognostic risk factors of leukoencephalopathy (either linked to
radiation treatment or to patients' clinical conditions) among patients with glioma
(stage 3-4)
- To propose and test some bio-markers as predictive factors of cognitive impairment
- To study the radiological changes on MRI associated with neurological abnormalities
- To build a biological collection for patients treated in the Pitié Salpêtrière Hospital
Patients with a diagnostic of glioma (stage 3-4) treated with radiotherapy in 2 hospitals
(Hospital Pitié Salpêtrière, Paris and Institut Paul Strauss, Strasbourg) will be eligible
for the study.
Taking into account that about 100 patients with glioma are treated every year in the
Radiation Oncologic department of the Pitié Salpêtrière Hospital and 50 in the Paul Strauss
Institute, the inclusion of 200 patients will take about 2 years. Considering that the
survival of these patients is rather short, median of 2 years for glioma 3-4, complete
follow-up will be available for the majority of the highest glioma stages, those who are
most likely to develop leukoencephalopathy.
The study will be mainly observational with a follow-up of patients based on classical
monitoring. The only additional information collected will come from a CSCT test, a very
simple and quick test (90 seconds) to identify mild cognitive dysfunction. A detailed
neurological assessment by a neuro-psychologist will be performed before radiotherapy, at 12
and 36 months after radiotherapy and in case of abnormalities of the CSCT.
Methodology
- Study design: Observational prospective cohort of 200 patients, who will be followed
every 2-3 months for a period of 3 years after enrolment.
- Eligibility:
Study population: Patients undergoing brain radiotherapy for glioma (stage 3 to 4) between
April 2015 and April 2017 at the Mazarin Radiotherapy Department, Pitié-Salpêtrière
University Hospital and in the Paul Strauss Institute, Strasbourg .
Before the radiotherapy:
- Description of the cancer: histological type, date of diagnosis, treatment of the
cancer: type of surgery (total or partial resection), chemotherapy, etc…
- The radiotherapy planning record: type of radiotherapy (whole brain radiotherapy,
stereotactic radiotherapy), total and fractionary delivered doses,
- Results of the CSCT test and of the detailed neuro-psychological tests before treatment
Comorbidities will be collected from medical records: hypertension, diabetes, smoking
habits, cardiovascular diseases, etc…
After radiotherapy, every 2-3 months:
During routine consultations with neuro-oncologists, the following information will be
collected:
- Clinical examination: brain features: intracranial high pressure, progressive focal
neurological deficit, epilepsia… and toxicity features: alert symptoms (amnesia,
dysexecutive disorders, gait troubles, urinary dysfunction)
- MRI scan of brain: tumor features: progression, stability, response and toxicity
features
- Results of the CSCT test
Additional data will be collected:
- Neurocognitive tests results performed during a dedicated consultation with
neuropsychologist: before the radiotherapy and 12 and 36 months after the radiotherapy
- Blood samples : before the radiotherapy and 12 and 36 months after the radiotherapy In
case of abnormal results at 2 consecutive CSCT tests (-1.5 Standard deviation (SD) of
loss) with the exclusion of relapse at MRI, additional cognitive tests will be
performed during a dedicated consultation with neuropsychologist. At the end of the
follow-up, the vital status of the lost to follow-up patients will be assessed through
the National Register for Identification of Physical Persons (RNIPP).
- Outcomes:
Primary outcome Cognitive dysfunction due to leukoencephalopathy defined by both abnormal
results at the CSCT test (confirmed by a complete cognitive test) and a MRI scan of the
brain(exclusion of brain tumor relapse).
Secondary outcomes
- Overall death
- Death associated with leukoencephalopathy or cognitive dysfunction ● Data analysis: In
this longitudinal study, survival analysis methods will be applied. Occurrence time of
the leukoencephalopathy and incidence rates at different follow-up time points (month
6, 12, 18 and 36) will be considered. The Kaplan-Meier estimator will be used to
estimate the leukoencephalopathy free survival function. For potential risk factors,
hazard ratios associated with outcomes will be estimated using Cox models.
Specificity and sensitivity of the CSCT will be assessed in comparison with complete
cognitive test (gold standard)
This project will involve the Neurology department and in the Radiotherapy department in the
Pitié Salpétrière University Hospital and in the Paul Strauss Institute
;
Observational Model: Cohort, Time Perspective: Prospective
| Status | Clinical Trial | Phase | |
|---|---|---|---|
| Completed |
NCT00889174 -
The Nosology and Etiology of Leukodystrophies of Unknown Causes
|