**6. Treatment of brain tumors**

tumors (ganglioglioma—GG, desmoplastic infantile astrocytoma—DIA, ganglioglioma— DIGG, dysembryoplastic neuroepithelial tumor—DNET and papillary glioneuronal tumor), embryonal tumors (embryonal tumor with multilayered rosettes, *C19MC*-altered—ETMR, medulloepithelioma, CNS neuroblastoma, CNS ganglioneuroblastoma, CNS embryonal tumor and CNS embryonal tumor with rhabdoid features), AT/RT, ependymomas, meningiomas, choroid plexus tumors, pineal tumors (pineocytomas, pineal parenchymal tumor of intermediate differentiation and papillary tumors of the pineal region) and rarely metastases

Tumors occurring in **parasellar** region usually are: craniopharyngiomas, adenomas, LGG astrocytomas (tumors of central regions, chiasma, hypothalamus, thalamus, PA or diffuse

Symptoms of brain tumors can develop gradually and worsen over time, or they may manifest suddenly and dramatically. Symptoms may be general or specific, resulting from tumor localization. **General symptoms** are manifestation of intracranial hypertension that is caused either by tumor growth, brain swelling or onset of hydrocephalus or a combination of these factors. Symptoms of intracranial hypertension include: headache (especially in the morning after awakening), nausea or vomiting, diplopia and strabismus, disturbances of balance, personality changes, epileptic seizures or loss of consciousness. Infants may experience irritability, loss of appetite, delay or regression of psychomotor development. There is also bulging of the fontanelle and the disproportionate enlargement of the head circumference. Children of school age may suffer from increased fatigue, psychological changes, impairment of school performance, disturbances of memory and impaired concentration. Regarding the localization of the tumor, other locally **specific neurological symptoms** may also occur: visual disturbances, narrowing and outages of visual field, abnormal bulb movements, nystagmus, hearing or speech disorders, paresis or hemiparesis, muscle weakness, loss of sensitivity or coordination, ataxia, posture disorder, walking instability, tingling of body parts, cranial

Diagnosis of brain tumor is based on a patient history and complete neurological examination. Imaging examination is performed when a brain tumor is suspected. Basic imaging examination is **magnetic resonance imaging (MRI).** It is the most spectacular imaging for intracranial structures that is currently available in medicine. In brain tumor diagnostics the use of contrast media—gadolinium—is essential. **MR-angiography** displays brain vessels alongside with pathological tumor vasculature, what is important for planning of the surgical treatment. **MR-spectroscopy** is a metabolic examination of the brain. The **perfusion MRI** monitors blood flow in the investigated area. Tumors are metabolically active and require greater blood supply. **Functional MRI** and **MR-tractography** are used for planning of surgical approach.

of extra-neural malignant tumors.

110 Brain Tumors - An Update

astrocytomas) as well as germ cell tumors.

**4. Brain tumors symptoms in children**

nerves palsy as well as hormonal disorders.

**5. Brain tumors diagnostics**

Treatment consists of surgical intervention, followed by oncological and symptomatic treatment and requires multidisciplinary approach.

**Surgical treatment** is the basis of treatment and, in some tumors, it is the only sufficient form of therapy. Also histologically, benign tumors can be a surgical challenge by their localization. An essential part of brain tumor surgery is the use of microscope and micro instruments. Nowadays, it belongs to the usual equipment of surgical department, as well as ultrasonic aspirator, **navigation systems,** intraoperative sonography and possibility of realization of electrophysiological monitoring. **Electrophysiological monitoring** requires appropriate instrumentation and personnel equipment that enhances the safety of the operation to the full possible extent in the eloquent areas of the CNS. Use of 5-aminolevulic acid is very helpful in operations of HGG. Patient ingests this acid prior to surgery, and then during surgery, with use of fluorescence on the microscope, high-grade glial cells begin to gleam, which also contributes to performance of accurate resection and representative tumor sampling for histological examination. **Awake operations** with the possibility of intraoperative stimulation, in which the patient is conscious either during the entire procedure or in a certain part of it, are used in adult patients, especially in tumors in motor, sensory and speech areas. In children, it is significantly limited by age and ability to cooperate. They are mainly performed in older age groups of children [15].

take various forms, using external radiotherapy as well as local forms. **External radiotherapy** is mostly accomplished with a linear accelerator by various techniques, such as conventional radiotherapy, 3D conformal radiotherapy, modulated beam intensities, stereotactic radiotherapy using stereotactic frames or radio-surgical methods (single irradiation) that use a linear accelerator, gamma knife or cyber knife as the source of radiation. **Local forms** of radiotherapy require an invasive approach. This group includes intraoperative radiotherapy, which is applied during surgery and interstitial brachytherapy requiring surgical delivery of emitters close to the tumor. Subsequently, radiotherapy is applied in the postoperative period. Local forms have, of course, a minor incidence of undesirable radiotherapy effects, of which the most common are: fatigue, hair loss, radiation dermatitis, brain edema and presence of post radiation necrosis and encephalopathy. Proton therapy is becoming increasingly popular.

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The novelty in the treatment of HGG is the use of an **alternating electric field.** It appears to be the most effective in connection to concomitant chemoradiotherapy. It is recommended for

Very necessary is also **supportive medical treatment**, in particular corticosteroids which suppress perifocal and postoperative edema, anticonvulsants (in the presence of epileptic seizures), analgesics, antiemetic drugs, nutritional support and oncological rehabilitation [21].

The most common CNS tumors in children are: gliomas, ependymomas, neuroglial tumors, embryonal tumors, choroid plexus tumors, craniopharyngiomas and germ cell tumors.

Glial tumors account for 55% of pediatric CNS tumors [3]. It is a heterogeneous group of tumors that varies from a well-defined, potentially curable low-grade pilocytic astrocytoma and diffusely growing astrocytomas (grade II) to high-grade, aggressive and incurable tumors, such as diffuse glioma of midline structures. They arise from CNS glial precursor cells: astrocytomas originate in astrocytes, oligodendrogliomas in oligodendrocytes, mixed gliomas are derived from astrocytes, oligodendrocytes and ependymal cells. The histologi-

The most common LGG in children are: pilocytic astrocytoma—PA (grade I), diffuse astrocytoma (grade II), oligodendroglioma (grade II), subependemal giant astrocytoma (SEGA) and pleomorphic xanthastrocytoma (PXA). The prognosis of LGG in children is relatively good, especially in well-defined grade I lesions with the possibility of total resection. Dissemination within the CNS is rare, but may be multifocal, especially in patients with neurofibromatosis type 1 syndrome [22]. Unfavorable prognostic factors include: low age, impossibility of total resection, diffuse growth (especially *IDH* mutated), diencephalic syndrome, presence of

**7. Most common brain tumor types occurring in childhood**

cally most common glioma in children is astrocytoma.

symptoms of intracranial hypertension and metastasis [23].

*7.1.1. Low-grade gliomas in children*

treatment of recurrent tumors [20].

**7.1. Gliomas**

According to extent of resection, we divide surgical treatment into: **total resection, near-total resection**, **partial resection** and **biopsy.** In most tumors (except well-defined benign tumors or well-defined metastases), total resection is only a radiological rather than a biological term. The surgical approach can serve (though not as a standard treatment method) for the targeted administration of radiotherapy in the form of **intraoperative radiotherapy** with a single irradiation of the tumor bed directly after resection of the tumor [16] **or chemotherapy**—for example, intraoperative administration of biodegradable carmustine [17]. In addition to **craniotomy**, other techniques—for example, **endonasal trans-sphenoidal approach**—can also be used, including endoscopy for pituitary tumor tumors. Another option for biopsy or tumor removal (often when located in brain ventricles) is **endoscopic surgery**. From other surgical methods, shunts in hydrocephalus can be used, most commonly **ventriculoperitoneal shunt**. Another option is implantation of Ommaya reservoir, which is useful for repeated sampling of CSF for laboratory examinations, for therapeutic evacuation puncture of CSF, as well as for the local administration of chemotherapy.

**Chemotherapy** is part of adjuvant oncological treatment after surgical resection alone or along with radiotherapy. It can be administered **systemically** (intravenously or orally), **locally** during surgery, or postoperatively into an implanted reservoir. Most serious side effects of chemotherapy are: bone marrow depression, nausea, vomiting, diarrhea and temporary hair loss. Generally, children better tolerate high doses of chemotherapy compared to adults, which may increase the aggressiveness of treatment if necessary.

**Targeted biological therapy** is directed against the specific protein and gene targets of the tumor, or against the environment that affects its growth and survival. But even all tumors of the same histological type do not have the same alterations and the treatment goals. Therefore, it is essential to examine each tumor sample for the presence of altered genes and proteins in order to determine targeted individualized treatment. One of the best known drugs is bevacizumab with an antiangiogenic effect, which stops the nutrient intake into the tumor by blocking of angiogenesis. This treatment is used for HGG. However, the effect of this treatment is lower than expected. Therefore, it is reserved as supportive treatment in relapsing non-responding tumors. Also used is everolimus, the *mTOR* pathway blocker in the treatment of subependemal giant astrocytoma, or tyrosine kinase inhibitors, in particular *EGFR* (erlotinib and gefitinib) in the treatment of ependymomas [18]. Patients with HGG with a proven *BRAF V600E* mutation also receive *BRAF* inhibitors (vemurafenib and dabrafenib) with partial effects [19].

**Radiotherapy** is also often used in treatment of pediatric brain tumors, either alone or as part of concomitant therapy. It uses high energy RTG beams to damage tumor cell DNA. It can take various forms, using external radiotherapy as well as local forms. **External radiotherapy** is mostly accomplished with a linear accelerator by various techniques, such as conventional radiotherapy, 3D conformal radiotherapy, modulated beam intensities, stereotactic radiotherapy using stereotactic frames or radio-surgical methods (single irradiation) that use a linear accelerator, gamma knife or cyber knife as the source of radiation. **Local forms** of radiotherapy require an invasive approach. This group includes intraoperative radiotherapy, which is applied during surgery and interstitial brachytherapy requiring surgical delivery of emitters close to the tumor. Subsequently, radiotherapy is applied in the postoperative period. Local forms have, of course, a minor incidence of undesirable radiotherapy effects, of which the most common are: fatigue, hair loss, radiation dermatitis, brain edema and presence of post radiation necrosis and encephalopathy. Proton therapy is becoming increasingly popular.

The novelty in the treatment of HGG is the use of an **alternating electric field.** It appears to be the most effective in connection to concomitant chemoradiotherapy. It is recommended for treatment of recurrent tumors [20].

Very necessary is also **supportive medical treatment**, in particular corticosteroids which suppress perifocal and postoperative edema, anticonvulsants (in the presence of epileptic seizures), analgesics, antiemetic drugs, nutritional support and oncological rehabilitation [21].
