Every year, thousands of patients worldwide undergo radiotherapy (RT) for primary brain
tumors (BT) and brain metastases originating from extracranial tumors. Radiation injury
is multifactorial and is characterized by e.g. vascular abnormalities, inflammation,
gliosis, demyelination, and often at high doses, white matter necrosis. Standard
treatment of BT includes high dose megavoltage radiation to the cranial vault, but 50-90%
of overall survivors exhibit impaired cognition and functional dysfunction. The radiation
cognitive syndrome is still poorly understood, and there is no effective prevention or
long-term treatment. Therefore, the investigators will analyze specific molecular markers
which may have a relationship with morfological changes in the brain, its secretive and
imunological role as well as cognitive function and postulate that previously undetected
and comparatively subtle early manifestations of irradiation damage to CNS may synergize
over time to form macro- and microstructural abnormalities. The investigators plan to
corroborate a hypothesis that impairment of cognitive and motor functions in patients
undergoing RT can be limited. In study, the investigators will quantitatively and
objectively evaluate the effects of exercise on brain activity during cognitive and
physical training in BT patients treated with RT. Therefore, specific objectives include:
1. Analysis of the molecular mechanism in BBB disruption. 2. Multidimensional analysis of
specific neuroplasticity markers, onconeural-antibodies etc. 3. Assessment of the volume
of the brain structures and their morphology. 4. Analysis of the results of
neurocognitive and functional tests.
Significance of the project The Response Assessment in Neuro-Oncology working group
recommended that neurocognitive outcome should be considered one of the primary endpoints
in BT clinical trials. Despite the importance and clear concern about radiation-induced
cognitive decline, the pathophysiology driving the progression of this syndrome remains
poorly understood, and there are no effective preventative measures or long-term
treatments. To date, there has been no study comparing different techniques of
irradiation, namely intensity-modulated photon RT (IMRT), whole brain RT (WBRT), and
stereotactic radiosurgery (CyberKnife), in BT patients in the aspect of pathophysiology
of BBB or immunological aspects, as well as neurogenesis, neuroplasticity. These methods
will be rely on a detailed understanding of radiation dose-volume effects, which link the
incidence and severity of neurocognitive and functional impairment to specific volumes
and morphology of normal brain. Possible explanations for the preservation of cognition
and behavior include the resiliency of the cerebellum, frontal and tempo-parietal lobes,
the hippocampus-mammillary complex and other supratentorial regions. Radiation is now
known to suppress the proliferation of progenitor cells and their differentiation into
neurons. The relatively recent discovery of neural stem cells in discrete areas of the
brain is the impetus behind the most recent potential target for radiation. Early changes
below the gross anatomical level, including a decline in neurogenesis, microvascular
damage, subtle loss of white matter integrity, and disturbances of neuronal
morphophysiology, may interact and progressively alter neuronal stem cell niches to
impede neuronal function, viability, and progenitor cell differentiation. Therefore, the
investigators will thoroughly observe the mechanism of neurogenesis and the possible
improvement of neuroprotection and neuroregeneration in BT patients undergoing various
forms of RT. Previous research has shown that physical exercise in healthy people is
associated with increased structural and functional integrity in regions that overlap
with brain functions, including the frontal, motor cortex, and the cerebellum. The
precise neurobiological mechanism for cognitive effects of rehabilitation remains
unknown, however a vast rodent literature supports a central role of protective
neurotrophins, which have been shown to facilitate production of new neurons in the
hippocampus, promote synaptic plasticity in cerebral cortex, and enhance growth and
protection of neurovasculature and suggests exercise may promote formation and
strengthening of connections between the hippocampus and its widespread cortical
connections, which improve cognitive and behaviour functioning. However, the specific
brain structure and function regions activated during rehabilitation exercise in patients
with BT during oncological treatment still remain largely undefined. The study results
obtained in this project will provide new knowledge about metabolic and structural
pathways of the CNS in the context of RT and will also provide the basis for the
development of regenerative medicine in oncology.
Work plan The investigators will conduct study in the Greater Poland Cancer Centre. The
participants will be enrolled in this study according study criteria from the Department
of Radiotherapy after medical assessment by an oncologist (physician). Evaluation of the
all subjects will be carried out: at baseline (T0), one month after RT (T1), and control
(T2)
- - 3 months after RT and final (T3) - 6 months after RT (unless there is a
deterioration of health making the assessment impossible, or death).
The investigators
will monitor the patients by:
A. Analysis of the patient's blood serum: 1/ markers of BBB disruption: S-100β and
circulating tight junction-related proteins (occludin, claudin-5, zonula occludens-1); 2/
factors with potential effect on neuroplasticity
- - immune-cell production of
neurotrophins e.g. brain-derived neurotrophic factor, beta-nerve growth factor,
neurotrophin-3, neurotrophin-4/5; 3/ activity of carnosinase and its isoenzymes; 4/
onconeural antibodies (anti-Hu, anti-Ri, anti-Yo, anti-Ma/Ta, anti-Cv2, and
anti-amphiphysin as well as anti-myelin, anti-MAG, anti-GAD) and anti-surface neuronal
antigens (anti-NMDA, anti-AMPA, anti-GABA, anti-DPPX, anti-LGI1, anti-CASPR) to
investigate correlations with types of BT, RT, and possible paraneoplastic syndromes or
cognitive impairment.
B. Assessment of brain structures and volume testing of selected brain structures.
C. Cognitive and functional assessment using clinical tests. All participants groups
treated with different RT techniques (three groups) will by randomly divided to two
subgroups: exercise subgroup
- - EG (these are the patients who will have regular cognitive
and physical training) and second subgroup (control group - CG).
Analysis of risk in planned study will be connected with failure to reach targeted number
of patients (the investigators will enlarge the recruitment pool across additionally
cancer hospitals) or increase dropout rate (motivational information will be provided to
participants and clinicians). The Greater Poland Cancer Centre has very modern research
infrastructure allowing for execution of the proposed project.
Methods of research The study protocol was accepted by the Ethics Committee of Poznan
University of Medical Sciences (No. 703/18), and each recruited participant will be given
a written informed consent. The investigators will enroll patients with BT using the
updated 2016 edition of the World Health Organization Classification of Tumors of CNS
which uses molecular parameters and the histology to define the main tumor categories for
the first time. The investigators will analyze 150 patients together with three different
CNS groups of tumors: from III and IV brain tumor groups, and metastatic tumors. The
study will include patients with BT enrolled to RT, between 18-70 y o , in good general
health conditions (according to Eastern Cooperative Oncology Group 0-2), after obtaining
informed consent for participation in the study. The investigators are planning to
exclude patients with numerous tumors (> 2), with psychological or psychiatric illnesses
treated pharmacologically, or with other neurological disorders (e.g. sclerosis
multiplex, Parkinson's disease, meningitis, etc.), or significant clinical circulatory
failure (> III NYHA). Enrolled patients will be treated with the one of three RT
techniques in the Department of Radiotherapy: 1) CyberKnife, which relies on precise 3D
imaging and localization to deliver ablative doses of radiation to the tumor, and can
significantly reduce exposure of healthy brain tissue (18 Gy per dose to total 66 Gy) or
2) IMRT using conventional fractionation of 1.8 Gy per day to total dose 54 Gy or 2 Gy
per dose to the total dose 60 Gy) or 3) WBRT as the treatment choice for metastatic
tumors
- - the fractionation schedule used is 30 Gy delivered in 10 fractions or 20 Gy in 5
days.
Participants randomly selected to EG will perform cognitive and physical training
(120 min./5 times per week during study observation) conducted by rehabilitation staff
who will be employed for this project: physiotherapist and neuropsychologist. For
neuropsychological rehabilitation, the investigators will use the RehaCom system
- - a
special neurocognitive programs and software.
During RT, EG will do physical training
(such as cycling, running on properly calibrated equipment as well as neuromuscular
reeducation exercises using advanced technical tool
- - Neuroforma computer software) with
maximum heart rate to 70%HRmax.
After RT, participants in EG will do special exercise
training at home under supervision of the hospital staff. Participants from CG will be
provided with normal hospital care during RT and next will conduct a normal daily
activity at home. According to the study evaluation plan, all participants will be
observed before and after end of RT, and during control visits (T2, T3) at cancer center.
Patients' blood samples will be collected in the Laboratory Ward in the morning, before
breakfast according to the study plan. The investigators will evaluate individual markers
in the Department of Radiobiology in collaboration from the Department of Neurochemistry
and Neuropathology at Poznan University of Medical Sciences, because the Radiobiology
Laboratory is fully equipped with all specialized, high-tech instruments required for the
execution of this project.. In the Department of Rehabilitation in cancer center, all
study participants will be evaluated in terms of cognitive and physical functioning. Raw
cognitive test scores will be compared with published normative values according to age
and to education. The investigators will include in the study evaluation with the use of
Mini-Mental State Examination (MMSE), Benton Visual Retention Test (BVRT), California
Verbal Learning Test (CVLT), Color trials test (CTT), Wisconsin Card Sorting Test (WCST),
Trail Making Test A and B (TMT A & B), Montreal Cognitive Assessment (MoCA) 7.2 scale,
and Addenbrooke's Cognitive Examination III (ACE III) test as well as the Psychology
Experiment Building Language (PEBL) software for objective evaluation of selected
cognitive and behavior functions. For general assessment of physical, psychological and
social function the investigators will use the Functional Independence Measures (FIM)
scale. This will be an unprecedented study yielding unique results on neuroscience in the
process of cancer treatment with modern techniques.
