Radiation therapy for brain stem tumor in children

Background. Tumors of the central nervous system occupy the first place in the structure of causes of death from malignant tumors among children. The tumors of brain stem structures account for 10 to 15% of all intracranial neoplasms in this age group. The etiology of these tumors is not completely known. Diagnosis of pathology is based on clinical manifestations and magnetic resonance imaging. Obtaining material for histological examination at this location is associated with the risk of severe neurological disorders. Despite clinical trials in search of targeted therapy, the treatment of this pathology is based on chemoradiation therapy. Purpose – to analyze the effectiveness of radiation therapy in mono-mode and in patients with the tumors of brain stem structures without intake of Temozolomide, a ccording to the results of clinical studies conducted on the basis of National Children’s Specialized Hospital «OKHMATDYT»

Робота не є частиною наукових програм, планів та тем. Виконана загальна аналітична робота у спеціалізованому дитячому відділенні променевої The work is not a part of scientific programs, plans and topics. The general analytical work in the specialized children's department of radiotherapy was performed Background. Tumors of the central nervous system occupy the first place in the structure of causes of death from malignant tumors among children. The tumors of brain stem structures account for 10 to 15% of all intracranial neoplasms in this age group. The etiology of these tumors is not completely known. Diagnosis of pathology is based on clinical manifestations and magnetic resonance imaging. Obtaining material for histological examination at this location is associated with the risk of severe neurological disorders. Despite clinical trials in search of targeted therapy, the treatment of this pathology is based on chemoradiation therapy. Purpose -to analyze the effectiveness of radiation therapy in mono-mode and in patients with the tumors of brain stem structures without intake of Temozolomide, a ccording to the results of clinical studies conducted on the basis of National Children's Specialized Hospital «OKHMATDYT» of the Ministry of Health of Ukraine. Materials and Methods. On the basis of the National Children's Specialized Hospital «OKHMATDYT» of the Ministry of Health of Ukraine, in the Department of Radiation Therapy of the Radiology Center during the 3-year existence, 22 people with brain stem tumor were treated on a linear electron accelerator Elekta Sinergy S. By gender: 12 boys aged 3-10 (54%), 10 girls aged 3-11 (46%). The average life expectancy of girls was longer and exceeded one year, compared with boys. The average age was 6 ± 4 years. The diagnosis in most cases was made radiologically, but 4 patients (18%) had histological confirmation. Radiation therapy was performed according to the High grade glioma protocol with total basic dose (TBD) of up to 54 Gy for 30 fractions. 2 patients received repeated radiation therapy due to the deterioration of neurological symptoms and negative dynamics on MRI. Planning of 3D-CRT, IMRT, VMAT irradiation techniques was performed on a Monaco planning system using the Monte Carlo calculation algorithm. Results. The use of radiation therapy with appropriate anti-edematous drug support, provided significant improvement in the neurological status of the child in 5-14 days from the beginning. After 4-6 weeks of control in 21 patients there was a decrease in the pathological focus compared to the original size by 17-70%. In 5 patients the tumor spread to the large hemispheres and/ or spinal cord after radiation therapy. 2 patients received repeated radiation therapy in 1 year and 1 year and 1 month after the previous one, based on the deterioration of neurological symptoms and negative dynamics on MRI. The average life expectancy was 13 months ± 7 months. It was longer for girls -more than a year, compared to boys. Conclusions. Diffuse intrinsic pontine gliomas are the leading cause of child mortality among patients with CNS tumors. Less than 10% of children live more than 2 years after diagnosis. At present, there is no method of radical treatment of patients with diffuse intrinsic point glioma. Radiation therapy still remains the main standard of treatment for DIPG, which improves the quality and duration of a child's life. пухлини у великі півкулі чи/або спинний мозок після променевого лікування. Двоє пацієнтів отримали повторну променеву терапію через 1 рік та 1 рік і 1 місяць після попередньої, на підставі погіршення неврологічної симтоматики та негативної динаміки за МРТ дослідженням. Середня тривалість життя складала 13 ± 7 міс., у дівчаток була довшою та перевищувала рік в порівнянні з хлопчиками. Висновки. Пухлини стовбурових відділів головного мозку/дифузні гліоми стовбуру мозку -основна причина дитячої смертності серед пацієнтів із пухлинами центральної нервової системи. Натепер не існує методу радикального лікування хворих із таким діагнозом. Променева терапія є основним стандартом лікування пухлин стовбурових відділів головного мозку, що покращує якість та тривалість життя дитини. INTRODUCTION терапії осіб до 18 років з діагнозом: пухлина стовбурових відділів головного мозку, для аналізу проведення діяльності на підставі сучасних світових рекомендацій та розробок перспективних напрямків у подальшому.
on patients under the age of 18 diagnosed with brain stem tumor for the analysis of the conducted activity on the basis of modern world recommendations and developments of perspective directions in prospect.
According to the National Cancer Registry of Ukraine for 2019, tumors of the central nervous system occupy the second place in the structure of the first detected cancer in children and adolescents and the first -in the structure of causes of death from malignant tumors [4].
Over the past 20 years, significant progress has been made in the treatment of CNS malignancies such as germinomas and medulloblastomas. But regarding the treatment of diffuse intrinsic pontine gliomas (DIPG), which account for 10 to 15% of all intracranial neoplasms in this age group, the progress is much slower [3,5].
Nearly 90% of children die within 18 months after the diagnosis and an average median survival is around 9 months [6].
The etiology of these tumors is not completely known, but much attention is paid to genetic changes in certain genes, although it is unclear whether these changes are primary, or they occur as a consequence of this pathology [1,[7][8][9].
Pathology diagnostics is based on clinical manifestations and magnetic resonance imaging (MRI). Clinical manifestations of DIPG, depending of the tumor location within the stem can develop in two directions: the path of damaging nerve centers and conductive pathways located in the stem, or the path of disruption of cerebrospinal fluid flow due to the compression of the aqueductus cerebri (Sylvii) by the growing tumor. Based on this, there may be symptoms of impaired cranial nerve function, impaired statics and coordination, increased intracranial pressure.
The main method of diagnosing DIPG, at present, is MRI with contrast enhancement [2,5]. Although the imaging criteria, which are used to define a classical or «typical» DIPG (tDIPG), vary to some extent, and there are inconsistencies in the interpretation of the images, the general consensual radiographic features of tDIPG include a T1-hypointense and T2-hyperintense tumor involving at least 50% of the pons by cross-sectional area. In some cases, the areas of necrosis or hemorrhage are also present. In many centers in the United States, biopsy is reserved for patients with clinical diagnosis of «atypical» DIPG (aDIPG), i.e., pontine tumors in which the imaging features mentioned above are absent or incomplete. These patients have traditionally been considered separate from patients with tDIPG for therapy or research purposes. Molecular profiling of tDIPG has resulted in a newly defined pathologic entity, H3 K27M-mutant diffuse midline glioma (DMG), which represents approximately 80% of radiographically recognized tDIPG. However, the clinical entity «aDIPG» has not been systematically studied, the attendant risks Ukrainian journal of radiology and oncology. 2022;30(1):78-90 ISSN 2708-7166 (Print) ISSN 2708-7174 (Online)
of biopsy in these patients have not been formally evaluated, and the extent to which pontine DMG manifesting as aDIPG is biologically and clinically distinct from tDIPG is poorly defined [2].
Obtaining material for histological examinations at this location is associated with the risk of severe neurological disorders, so most clinics prefer to make a diagnosis based on clinical and radiological data. But in accordance with the consensus of 2011 in Paris [10], a biopsy for DIPG is justified in order to conduct research and plan possible targeted therapy. According to the results of operations and autopsies, in most cases these are gliomas of varying degrees of malignancy [9][10][11].
According to the current data, the Classification of Central Nervous System Tumors is updated from time to time by the World Health Organization. The fifth edition of the WHO Classification of Tumors of the Central Nervous System (WHO CNS5) is the sixth version of the international standard for the classification of brain and spinal cord tumors, following the prior publications from 1979, 1993, 2000, 2007, and 2016.
Radiation therapy (RT) in children is usually performed according to the treatment protocol of High grade glioma (HGG) with TBD up to 54 Gy for 30 fractions (1.8 Gy per fraction) [10,11].
The objective was to analyze the effectiveness of radiation therapy in mono-mode and in patients with the tumors of brain stem structures without intake of Temozolomide, according to the results of clinical studies conducted on the basis of National Children's Specialized Hospital «OKHMATDYT» of the Ministry of Health of Ukraine.

МАТЕРІАЛИ ТА МЕТОДИ ДОСЛІДЖЕННЯ MATERIALS AND METHODS
22 children diagnosed with brain stem tumor were studied. They underwent radiation therapy on a linear electron accele-rator Elekta Sinergy S on the basis of the National Children's Specialized Hospital «Okhmatdyt» of the Ministry of Health of Ukraine, in the Department of Radiation Therapy during its 3-year existence. The treatment plan, observation and prognosis were formed on the basis of publications found in the databases Scopus, Web of Science Core Collection and PubMed for the period 2007-2020. Серед 22 пролікованих пацієнтів з ПСВГМ за гендерним розподілом було: 12 хлопчиків віком 3-10 років (54%), 10 дівчаток віком 3-11 років (46%). Середній вік склав 6 ± 4 роки.
The decision to perform RT was made according to the conclusion of the Neurooncological Concilium of National Children's Specialized Hospital «Okhmatdyt» of the Ministry of Health of Ukraine, which, in addition to radiation oncologist, includes: neurosurgeon, neurologist, pediatric oncologist and radiologist.
Topometric training was performed on a 16-slice Toshiba Aquilion computed tomograph, with proper fixation of the head with a thermoplastic mask in accordance with the scanning protocol prescribed for a certain age category. For the accuracy and quality of irradiation, the delineation of the target and critical structures was performed by fusing CT images obtained during topometric preparation and images of previously performed MRI (Fig. 1, Fig. 4). MRI images used for the fusion were taken no later than 10 days. Target delineation: GTV determined the area of brain stem with pathological signal, registered on MRI (T1/T2/FLAIR), CTV = GTV + 1 cm including anatomical borders of the brain stem (1.5 cm CTV in some cases), PTV = CTV + 3-5 mm [12][13][14] (Fig. 2).
The planning of 3D-CRT, IMRT, VMAT irradiation methods was performed by medical physicists on the Monaco planning system using the Monte Carlo calculation algorithm (Fig. 3), taking into account the tolerance of healthy sensory tissues according to QUANTEC criteria (Quantitative Analysis of Normal Tissue Effects in the Clinic) ( Table 1). Although the target of irradiation is relatively close to critical structures, modern planning techniques, features of equipment and professionalism of specialists allow the recommended doses to critical organs not to be exceeded.
The Neurooncological Concilium decided to repeat the course of RT.
Approximately 1/3 of DIPG patients had leptomeningeal spread of their tumor to supratentorial white matter tracts in the large hemispheres and/ or spinal cord [15,16].
In our department, this was recorded in 5 patients 3-6 months after RT. 2 of them had received repeated radiation therapy in 1 year and 1 year and 1 month after the previous one due to the deterioration of neurological symptoms and negative dynamics on MRI. Against the background of radiation therapy, the general condition of both patients improved by 3-4 months (Fig. 9).
The average life expectancy was 13 months ± 7 months. It was longer for girls -more than a year, compared to boys.
It should be noted that according to the protocol, concomitant administration of Temozolomide (TMZ) is recommended daily at the dose of 75 mg/m² per every fraction of RT based on proven efficacy in adults [6,17].
Treatment with TMZ results in the depletion of O6-methylguanine methyltransferase (MGMT), a DNA repair protein, which causes dominant cytotoxic effect, and also shortens time for its replenishment, which occurs between the doses of TMZ. Thus, an assumption was made that the same effect may be seen in tumor cells. A prolonged dosing regime has been shown to be feasible and safe in a pediatric population [6,[17][18][19].
TMZ is the standard treatment for adult patients with HGG, but there is no standard chemotherapy backbone that is universally acknowledged in the setting of pediatric HGG. For DIPG in particular, there is no established role for chemotherapy, and radiation therapy is the standard treatment. [17,18,20].
The results of clinical trials, such as the United Kingdom phase II trial (CNS 2007 04), did not confirm the efficacy of the long-term regimen of TMZ in MGMT depletion in DIPG due to possible high expression of this protein or other resistance mechanisms associated with insufficient drug concentration integrity of the blood-brain barrier in DIPG [6,18].
Similar studies have shown that the administration of TMZ does not improve the prolongation of median survival in children with diffuse brain glioma [6,9,[17][18][19]. In this study, 4 patients were observed who were receiving concomitant administration of TMZ at a daily dose of 75 mg/m² each RT session, but an overall prolongation of survival of more than 2 years was not observed.
Therefore, based on clinical trials, in National Children's Specialized Hospital «Okhmatdyt» of the Ministry of Health of Ukraine, patients are treated without background intake of Temozolomide to reduce the influence of toxicity on the child's condition.
As new treatment options continue to be explored, re-irradiation may also be considered. American-European studies have shown a median survival of 5 to 7 months after re-irradiation, although there are no prospective randomized phase 2 studies, as well as no standards. TBD of re-irradiation ranged from 18-36 Gy at 1.8-2 Gy by fraction, and there are no clear recommendations due to the small cohort of the patients [21].
In 2 patients from the studied cohort, improvement was observed for 3-4 months after repeated radiotherapy, followed by spreading to leptomeningeal membranes and spinal cord injury. In February 2022these patients were still alive, but under the supervision of related specialists.
According to our observations, in case of disease progression and before resolving the issue of re-irradiation, we recommend performing MRI control not only of the brain, but also of the vertebral canal. At timely detection of pathological changes in a spinal cord we will do craniospinal irradiation with a boost. В подібних дослідженнях доведено, що введення ТMZ не покращує пролонгації середньої виживаності у дітей з дифузною гліомою мозку [6,9,[17][18][19].
Diffuse intrinsic point gliomas are the leading cause of child mortality among patients with CNS tumors. At present, there is no method of radical treatment of patients with this diagnosis. RT is the main standard of treatment for DIPG, which improves the quality and life expectancy of the child. Given the unproven efficacy of Temozolamide [6,18,20], the risk of hematological toxicity and malaise (nausea, headache, ataxia) [6], does not exclude the progression of tumor growth against the background of radiation therapy. Children with localized DIPG in National Children's Specialized Hospital «Okhmatdyt» of the Ministry of Health of Ukraine are treated without Temozolomide. Instead, only radiation therapy with appropriate anti-edementous medication is used. For timely detection of metastatic spread to the spinal cord, we recommend doing an MRI of the vertebral canal.
Of course, 22 children make up a group too small to draw conclusions which are close to larger studies, but National Children's Specialized Hospital «Okhmatdyt» of the Ministry of Health of Ukraine has the largest number of such children from Ukraine.
However, with an increasing understanding of molecular genetics of this pathology, a growing number of promising preclinical models, and novel techniques to overcome the limitations of effective drug delivery across the blood-brain barrier, we hope that the future of DIPG therapy will change dramatically in a relatively short time, and it will benefit a lot of children with this devastating brain tumor described above [6,21,22].