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.
