Background
Radiotherapy is one of the most important treatments of metastatic and primary brain tumors of which 60 % are high grade glioblastomas. With the recent development of modern irradiation techniques, survival of patients has increased and mid- to long-term side effects became more visible, such as neurologic complications [
1]. Among these complications, leukoencephalopathy seems to be the most frequent. It is characterized by a progressive and diffuse demyelination, an axonal loss and vascular lesions [
2]. Consequences of leukoencephalopathy involve cognitive deficits which dramatically reduce the patient’s quality-of-life [
3‐
5]. Thus, since the last few years, the neuropsychological status represents an important issue in clinical trials as well as in individual outcomes [
6]. Long-term memory, information speed processing, attention and executive functions are recognized to be the most sensitive functions to be affected by radiations [
2,
7‐
10]. However, there is no consensus to describe the main evolution of cognitive decrement following radiotherapy because of important differences in studies’ protocols (assessment time, decrement definitions, material). The radiation-induced leukoencephalopathy incidence is thus difficult to estimate precisely and varies from 30 to 50 % [
10,
11] according to the length of follow-up. Moreover, available studies are often retrospective which may induce bias and based on small samples which limits statistical robustness of results.
Although several risk factors of neurotoxic complication have been identified such as patient’s age, tumor location, total dose of radiation, fractionation, field size [
2,
9,
12], the pathophysiology of radiation-induced neurotoxicity is still poorly understood. It could involve inflammation, blood barrier disruption, vascular lesion, demyelination, radio-necrosis and edema [
2,
9]. Until now, it is impossible to precisely estimate at individual level the risk for a patient to develop this neurotoxic complication [
13,
14]. Some individual risk factor such as cardio-vascular diseases (hypertension, diabetes), smoking, old age [
15,
16] seem implicated in leukoencephalopathy. Assessment of the impact of both individual risk factors and treatment toxicity requires to study a large group of patient with prospective collection of accurate data and follow-up.
From a biological point of view, biological mechanisms of the initiation and progression of cognitive impairements is not well known. However, specific biomarkers predictive of the cognitive impairments in this population would help in screening patients at risk of neurotoxicity. Currently, biomarkers of neurotoxicity have been poorly studied. Thus, several markers deserve to be explored such as the S-100B protein known to be a marker of traumatic cerebral lesion, neurodegenerative diseases and aggressive gliomas [
17], specific isoprostanes (as 8,12-
iso-iPF
2α-VI) implicated in the oxidative/nitrate stress in neurodegenerative diseases [
18] and homocystein which plasma concentration has been associated with poor memory performances in old individuals [
19]. Furthermore, new biomarkers seems to be potentially very interesting. Indeed, micro RNA and microparticules have been identified as potential biomarkers of neurological defects [
20,
21]. Then the strategy proposed is to test classical and new biomarkers in order to individualize those, which could be accurate for the screening of patients at risk of cognitive impairments.
At last, assessment of cognitive impairment is difficult because the exploration of cognitive side effects is not systematic and often depends on patients’ complaints and clinicians’ sensibility to this aspect. A formal neuropsychological assessment can’t be performed in routine, as often as it should be for an adapted follow-up of brain tumor patients. Indeed, it is time consuming, needs expert professionals and validated material, and consequently it is not easily implemented in most medical center. A new tool for exploration of cognitive deficits is the
Computerized Speed Cognitive Test (Legal deposit: IDDN.FR.001.180018.000.S.P.2014.000.31230) (CSCT) [
22]. The CSCT was first developed to assess information speed processing in multiple sclerosis. Because it presents a low learning-effect and focuses on a cognitive characteristic often impaired in neuro-oncologic population, it could be used to detect a cognitive deterioration during repeated medical visits, and thus be used as an alarm to start a more extensive formal assessment. Then, it is suitable for the follow-up of a cohort of patients treated for brain tumor and allows to give quick and reliable information on cognitive impairment, compatible with the usual clinical follow-up of the patients.
Objectives
The purpose of the EpiBrainRad study is to establish a cohort of patients treated with radiotherapy for a high grade glioma.
The main objective is to estimate the cognitive impairment incidence related to radio-induced leukoencephalopathy in this population.
Secondary objectives are:
-
To study the impact of associated risk factors on leukoencephalopathy development, including individual factors and treatment.
-
Biologic markers of neurologic degradation will be studied to evaluate the correlations between cognitive impairments and biological abnormalities.
-
Specific organs dosimetry (such as hippocampus, temporal lobes, corpus callosum, peri-ventricular white matter, posterior fossa) correlated with radiologic abnormalities on magnetic resonance imagery (MRI) and clinical symptoms will be analyzed to better understand the evolution of radio-induced leukoencephalopathy.
-
Finally, the assessment of the sensibility and specificity of a quick cognitive test,
the Computerised Speed Cognitive Test [
22], to detect a cognitive decrement during the follow up of the patients.
Discussion
This study should improve our knowledge on neurologic complications of radiotherapy through an original multidisciplinar approach combining cognitive, biologic, imagery and dosimetric investigations. Our primary objective is to precisely explore cognitive impairments present before radiotherapy and to follow their worsening, or the onset of new impairments not present at baseline, during the first years after the treatment. The collection of data from different nature could be very useful to understand the leukoencephalopathy process and risk factors associated. Indeed, the assessment of cognitive defect linked to leukoencephalopathy could be obscured by the progression of the disease. Then, precise assessment of the type of cognitive defect associated with information on dose received by organs of interest and MRI results will be a major issue to study the dose response relationship between leukoencephalopathy development and radiation exposure to the brain.
Chemotherapy is known to induce cognitive impairments as well and produce a synergistic effect when administrated in combination with RT [
2,
12]. Unfortunately, the treatment protocol received by our patient population doesn’t allow to specifically study the participation of chemotherapy in cognitive decrement. Nevertheless, chemotherapy related impairment are assumed to be transient [
33] and not as strong as radiation-related impairments. Moreover, neurotoxicity of chemotherapy is not always proved in studies investigating this problem [
34], and subjective complaints of patient seems to be more related to emotional distress and fatigue than to formal dysfunctions [
35].
One other important goal of our project is to improve the detection of cognitive defects at early stage. Current formal assessment of cognitive status lasts between 1 and 2 h or more, and cannot be performed as often as needed in this population because of an important learning-effect. The
Compurterised Speed Cognitive Test (CSCT) is a quick cognitive assessment tool validated in a population of patients presenting multiple sclerosis. The CSCT just need few minutes to be performed and appears to be a potential useful tool in the patient follow-up [
36]. This test use in the neuro-oncologic context could importantly improve the detection of cognitive impairments and decrement. Our study will help to validate its use in our population by comparing the CSCT to a more complete battery at baseline time before radiotherapy and during the follow-up after treatment. Several biomarkers of neurotoxicity will be also tested in our population in order to try to individualize prognostic biomarkers of leukoencephalopathy.
Prospective methodology of data collection and the choice of a homogenous population will allow us to analyze precisely the selected outcomes, avoiding potential bias linked to retrospective studies. However, one limit of our study is to focus only on patients with high grade of glioblastoma, who are known to have a very short life expectancy, with a median expected survival being less than 18 months [
37]. Nevertheless, it seems that leukoencephalopathy could appear as soon as within the 6 first months after radiotherapy. Furthermore, the rather large number of included patients will allow us to characterize cognitive defects at short and medium term.
With a better screening and understanding of neurotoxicity, the treatment regiments could be adapted to risk factors present for each patient in order to reduce complication. More, preventive actions and cares could be developed to reduce the burden of cognitive deficits and preserve the quality-of-life and autonomy for patient at risk.
Competing interests
The authors declare that they have no competing interest.
Authors’ contributions
Conception and design of the study: TD, PL, DP, DL, GN, NV, RT, FM, MB, DR, MOB. Data acquisition: TD, LL, AR, DP, LF, GN. Data interpretation: TD, SJ, PL, DP, LF, DL, GN, DR, MOB. Study supervision: TD, DP, GN, DR, MOB. Manuscript drafting: TD. Critical revision of the manuscript: all authors. All authors read and approved the final manuscript.