**1. Introduction**

Pediatric central nervous system (CNS) tumors represent the second most common cancer in childhood after leukemias. Pediatric cancer is the leading cause of disease-related childhood mortality in high-income countries (HICs). Furthermore, it is becoming increasingly impor‐ tant in low-/middle-income countries (LMICs) because of the continuing success to decrease the infant and childhood mortality associated with malnutrition and communicable disease. Unfortunately, the 80% cure rate for HIC children suffering from cancer does not apply to many of pediatric patients in LMIC [1]. The barriers to optimize the management of children with cancer in LMICs to reach the same level as that in HICs were investigated in many situations; however, minimal advances have been made to improve the treatment and clinical end results of children especially those with brain tumors. Many factors were identified as responsible for this failure to achieve such an acceptable level of cure. These were underdiag‐ nosis, abandonment of therapy, incorrect assessment, lack of appropriate radiological, histopathologic, neurosurgical, radiotherapeutic, and pediatric oncologic services. More important is the deficiency of the real concept of multidisciplinary care and the team manage‐ ment that definitely contributes negatively to the results of treatment [2]. In many LMICs, a significant portion of pediatric brain tumors remains undiagnosed and the patients subse‐ quently die of their malignancy. Many others abandoned effective treatment due to different reasons: financial, social, long distance from the treating center, or being treated with herbal and unconventional therapy. The identification of these findings will help the development of targeted strategies, such as increased training and tools for neuropathology, improved access to neuroimaging and radiotherapy, improve early diagnosis, and optimal collaborate therapy. Interventions to implement and increase family support may positively contribute on improvement of outcome.

#### **1.1. Magnitude of the PROBLEM**

Underdiagnosis, treatment abandonment, improper assessment, lack of appropriate medical imaging, histopathologic, neurosurgical, radiotherapeutic pediatric oncologic services deficiencies, and the deficiency of the multidisciplinary care concept and the team manage‐ ment are well-known barriers that hinder successful neuro-oncologic management that leads to the obtainment of equivalent clinical end results already achieved in HICs. In addition, in many patients, treatment may be negatively affected because of poor general health, with the comorbidity of malnutrition and infections such as human immunodeficiency virus (HIV) and tuberculosis. Furthermore, the lack of adequate supportive drugs and supplements that ameliorate the oncologic treatment side effects and preserve a tolerable general condition may contribute not only in intolerance of therapy but also in lowering the survival rates and quality of life (QoL) of such patients. The applied treatment protocols have to take these factors and conditions into account. Protocols applied in HICs may not be optimum and may be even dangerous in LMICs especially whenever the supportive care is deficient [3]. The aggrega‐ tion of the necessary facilities and properly trained staff in one referral center serving an LMIC or a large sector of it may be the proper way to serve these children and to raise the stand‐

ard of care to reach the acceptable level of cure attained in HICs [4]. It is obvious that it is easier, more convenient, and cheaper to arrange for establishing a referral pediatric neuro-oncolog‐ ic center to be responsible for the welfare of such children. The tremendous improvements in imaging, surgical approaches, pathological diagnosis, radiotherapy techniques, and chemo‐ therapy drugs in the last three decades have improved survival rates in children with brain tumors and are attained in such referral centers. Innovations in radiation techniques, includ‐ ing the three-dimensional (3D) radiation therapy (RT) and different forms of intensitymodulated radiation therapy (IMRT) such as static IMRT, volumetric modulated arc therapy (VMAT), tomotherapy, cyberknife, and all forms of image-guided radiotherapy, have contributed to the precise and extremely accurate delivery of the radiation dose to the target while reducing the dose to the normal brain tissue. These techniques minimize RT-related toxicities through decreasing the dose to the surrounding functioning structures while increasing tumor control probability [5].

#### **1.2. Diagnosis delay in CNS tumors**

**1. Introduction**

448 Neurooncology - Newer Developments

improvement of outcome.

**1.1. Magnitude of the PROBLEM**

Pediatric central nervous system (CNS) tumors represent the second most common cancer in childhood after leukemias. Pediatric cancer is the leading cause of disease-related childhood mortality in high-income countries (HICs). Furthermore, it is becoming increasingly impor‐ tant in low-/middle-income countries (LMICs) because of the continuing success to decrease the infant and childhood mortality associated with malnutrition and communicable disease. Unfortunately, the 80% cure rate for HIC children suffering from cancer does not apply to many of pediatric patients in LMIC [1]. The barriers to optimize the management of children with cancer in LMICs to reach the same level as that in HICs were investigated in many situations; however, minimal advances have been made to improve the treatment and clinical end results of children especially those with brain tumors. Many factors were identified as responsible for this failure to achieve such an acceptable level of cure. These were underdiag‐ nosis, abandonment of therapy, incorrect assessment, lack of appropriate radiological, histopathologic, neurosurgical, radiotherapeutic, and pediatric oncologic services. More important is the deficiency of the real concept of multidisciplinary care and the team manage‐ ment that definitely contributes negatively to the results of treatment [2]. In many LMICs, a significant portion of pediatric brain tumors remains undiagnosed and the patients subse‐ quently die of their malignancy. Many others abandoned effective treatment due to different reasons: financial, social, long distance from the treating center, or being treated with herbal and unconventional therapy. The identification of these findings will help the development of targeted strategies, such as increased training and tools for neuropathology, improved access to neuroimaging and radiotherapy, improve early diagnosis, and optimal collaborate therapy. Interventions to implement and increase family support may positively contribute on

Underdiagnosis, treatment abandonment, improper assessment, lack of appropriate medical imaging, histopathologic, neurosurgical, radiotherapeutic pediatric oncologic services deficiencies, and the deficiency of the multidisciplinary care concept and the team manage‐ ment are well-known barriers that hinder successful neuro-oncologic management that leads to the obtainment of equivalent clinical end results already achieved in HICs. In addition, in many patients, treatment may be negatively affected because of poor general health, with the comorbidity of malnutrition and infections such as human immunodeficiency virus (HIV) and tuberculosis. Furthermore, the lack of adequate supportive drugs and supplements that ameliorate the oncologic treatment side effects and preserve a tolerable general condition may contribute not only in intolerance of therapy but also in lowering the survival rates and quality of life (QoL) of such patients. The applied treatment protocols have to take these factors and conditions into account. Protocols applied in HICs may not be optimum and may be even dangerous in LMICs especially whenever the supportive care is deficient [3]. The aggrega‐ tion of the necessary facilities and properly trained staff in one referral center serving an LMIC or a large sector of it may be the proper way to serve these children and to raise the stand‐

Despite advances in neuroimaging, timely diagnosis of CNS tumors remains a problem even in HICs. It is obvious that the issue of late diagnosis of CNS tumors is more obvious and more intense in LMICs. Beyond the usual challenges of nonspecific symptoms, the access to neuroimaging facilities is the main obstacle that patients and families face. The limited number of computerized tomography (CT) or magnetic resonance imaging (MRI) scans in LMICs; prolonged waiting lists, especially in children needing sedation; and high cost of these tests are among the reasons that delay the diagnosis of brain tumor. Furthermore, in many places, the imaging study is limited to the brain, regardless of the state-of-art recommendation. It is exceptional to have preoperative imaging of the spine when a malignant brain tumor such as medulloblastoma is suspected. Most developing countries lack specialized centers present‐ ing the complete multidisciplinary service equipped with the necessary diagnostic and treatment tools in hands of experienced staff [6].

The adoption of unified management protocols represents a major drawback. A single referral neuro-oncologic center in each LMIC that is fully equipped and adequately staffed could serve the patients in a more professional and efficient way that decrease the cost and improve the clinical outcome. Aggregation of the needed staff, equipment, and experience together with standardizing policies, treatment protocols, and managements may be the best way to overcome the difficulties facing LMIC challenges in pediatric neuro-oncology practice [4]. The obstacles of long distance and financial needs to access these specialized centers will remain as a problem that needs effort to be solved. The diagnosis of brain tumor in some LMIC cultures has a negative perception and stigmatization. Families may abundant treatment and even referred to cancer center, for the fear of marginalization associated with brain tumor. Stigma of the false belief that cancer means death or mental and physical disability may influence parental or family decisions including treatment abandonment. Some cultural preferences such as treating boys over girls have to be strongly faced.

Radiotherapy evolved tremendously in the last three to four decades, depending upon the advances in physics, atomic sciences, materials, engineering, computer science, and telecom‐ munication. Linear accelerator-based RT became the backbone technology. This phase represented a megavoltage (MV) power race, which would have skin-sparing properties, while delivering a high dose of radiation at depth. Linear accelerators initiated the new technolo‐ gies of 3D conformal RT, IMRT, and image-guided radiotherapy including the helical tomotherapy and others [7]. The technique of radiosurgery was developed through com‐ bined efforts of multiple specialties, where multiple cobalt-60 sources were fitted into a helmetlike configuration with precision beam collimation to produce remarkably tiny and accurate beams, resulting in the concept of using single-fraction radiation doses for the purposes of target ablation, which expanded the clinical utility beyond neoplasms into the field of benign and functional indications.

#### **1.3. Neuroimaging**

Neuroimaging is a key tool in the diagnosis and follow-up of neuro-oncologic patients. MRI and CT are the main imaging modalities involved in neuroimaging diagnosis of these patients. Nevertheless, in pediatric neuro-oncology MRI ranked superior not only due to lack of radiation exposure provided by CT but also due to the more significant details of the brain parenchyma offered by MRI. The standard MRI sequences (T1- and T2-weighted spin-echo in three planes; axial, coronal, and sagittal). Fluid attenuation inversion recovery (FLAIRE) sequences followed by post-contrast are usually adopted. These sequences are usually enough for an accurate differential diagnosis. However, newer sequences and techniques provide additional information for both the diagnosis and treatment management of difficult and/or atypical cases [8]. Although gadolinium-based contrast media is not nephrotoxic yet, it is not advisable for children younger than 2 years [8].

Ideally, post-surgery studies should be performed within the first 48 h after neurosurgical procedure in order to avoid misinterpretations of residual tumor enhancement with blood leakage across the blood-brain barrier. Diffusion study, describing the random thermal motion of the water molecule in tissues, detects the tissue cellularity. It gives a clue about the grade of the tumor and its cellularity. Diffusion tensor imaging (DTI) allows determination of fiber bundle directionality (tractography) study [9].

In neuro-oncology, 3D imaging is used for stereotaxy, a technique creating a coordinate system to guide lesion localization in a surgical procedure or radiotherapy treatment. In order to reduce morbidity in CNS tumor resection, this technique is usually supplemented by other maneuvers and techniques such as functional MRI and direct cortical stimulation [8].

MR spectroscopy (MRS) is a technique widely used to assess metabolites in the brain paren‐ chyma and lesions. The results of an MRS acquisition are typically displayed in a graphic of metabolite peaks. The assessed metabolites are choline, creatine, N-acetylaspartate (NAA), and lactate. Perfusion technique can be applied with both MRI and CT. Nevertheless, there is a new MRI sequence called arterial spin labeling (ASL) that can be used to study brain perfu‐ sion without the use of contrast media [10]. The perfusion images are frequently interpreted

in a color map. The red zones usually demonstrate increased perfusion and the blue zones decreased perfusion. The perfusion technique differentiates between low- and high-grade tumors. It is helpful in the differentiation of radiation necrosis (decreased perfusion) from tumor recurrence (normal to elevated perfusion) and in defining the ideal area for surgical biopsy, avoiding areas of necrosis.

#### *1.3.1. PET scan and future molecular imaging*

Radiotherapy evolved tremendously in the last three to four decades, depending upon the advances in physics, atomic sciences, materials, engineering, computer science, and telecom‐ munication. Linear accelerator-based RT became the backbone technology. This phase represented a megavoltage (MV) power race, which would have skin-sparing properties, while delivering a high dose of radiation at depth. Linear accelerators initiated the new technolo‐ gies of 3D conformal RT, IMRT, and image-guided radiotherapy including the helical tomotherapy and others [7]. The technique of radiosurgery was developed through com‐ bined efforts of multiple specialties, where multiple cobalt-60 sources were fitted into a helmetlike configuration with precision beam collimation to produce remarkably tiny and accurate beams, resulting in the concept of using single-fraction radiation doses for the purposes of target ablation, which expanded the clinical utility beyond neoplasms into the field of benign

Neuroimaging is a key tool in the diagnosis and follow-up of neuro-oncologic patients. MRI and CT are the main imaging modalities involved in neuroimaging diagnosis of these patients. Nevertheless, in pediatric neuro-oncology MRI ranked superior not only due to lack of radiation exposure provided by CT but also due to the more significant details of the brain parenchyma offered by MRI. The standard MRI sequences (T1- and T2-weighted spin-echo in three planes; axial, coronal, and sagittal). Fluid attenuation inversion recovery (FLAIRE) sequences followed by post-contrast are usually adopted. These sequences are usually enough for an accurate differential diagnosis. However, newer sequences and techniques provide additional information for both the diagnosis and treatment management of difficult and/or atypical cases [8]. Although gadolinium-based contrast media is not nephrotoxic yet, it is not

Ideally, post-surgery studies should be performed within the first 48 h after neurosurgical procedure in order to avoid misinterpretations of residual tumor enhancement with blood leakage across the blood-brain barrier. Diffusion study, describing the random thermal motion of the water molecule in tissues, detects the tissue cellularity. It gives a clue about the grade of the tumor and its cellularity. Diffusion tensor imaging (DTI) allows determination of fiber

In neuro-oncology, 3D imaging is used for stereotaxy, a technique creating a coordinate system to guide lesion localization in a surgical procedure or radiotherapy treatment. In order to reduce morbidity in CNS tumor resection, this technique is usually supplemented by other

MR spectroscopy (MRS) is a technique widely used to assess metabolites in the brain paren‐ chyma and lesions. The results of an MRS acquisition are typically displayed in a graphic of metabolite peaks. The assessed metabolites are choline, creatine, N-acetylaspartate (NAA), and lactate. Perfusion technique can be applied with both MRI and CT. Nevertheless, there is a new MRI sequence called arterial spin labeling (ASL) that can be used to study brain perfu‐ sion without the use of contrast media [10]. The perfusion images are frequently interpreted

maneuvers and techniques such as functional MRI and direct cortical stimulation [8].

and functional indications.

450 Neurooncology - Newer Developments

advisable for children younger than 2 years [8].

bundle directionality (tractography) study [9].

**1.3. Neuroimaging**

Positron emission tomography (PET) and molecular imaging are rapidly developing as new techniques to evaluate brain tumor. The results provided by PET and molecular imaging appear to corroborate the findings of MRI studies for decision making in the treatment and follow-up. The use of a PET scan is often carried out together with low-dose CT images or MRI to improve the anatomical localization. Common radiopharmaceuticals applied in brain imaging are fludeoxyglucose (FDG), L-[methyl-11 C] methionine ([11 C]MET), and 3′ deoxy-3′- [18 F]fluorothymidine ([18 F]FLT). However, FDG applicability in clinical practice is low as the normal gray matter also demonstrates increased glucose metabolism, effacing lesions [11].

#### **1.4. Neuropathological services**

Experienced pathologists able to differentiate subtypes of pediatric neurological tumors are deficient in many LMICs. Some diagnoses can be promptly made on standard hematoxylin and eosin stains based on classic architectural features alone, while more challenging cases often require ancillary studies including immunohistochemistry, electron microscopy, cytogenetics, and/or molecular studies. The lack of trained personal and inadequate techni‐ cal equipment is therefore limiting the possibility to achieve an accurate diagnosis in many places. It is likely that a significant number of children are treated without an adequate diagnosis that may lead to inadequate or even improper treatment. Microscopic examina‐ tion combined with molecular signatures of these tumors continues to identify and define features specific to CNS tumor subtypes mostly of great importance, to reach to the proper diagnosis or the appropriate subtype [12]. Neuro-oncologic telepathology and twinning between centers in both LMICs and HICs can improve the capacity of accurate histopatho‐ logical diagnosis with little burden on centers shared in these programs [13].

#### **1.5. Radiotherapy services**

RT is one of the main critical components of treatment of many pediatric CNS tumors; however, limited radiotherapy machines and personnel in LMICs make them available only at large centers with long waiting lists. Delay in starting radiotherapy has a negative impact on survival. Radiation indications, treatment volumes, and doses are determined according to the extent of disease, magnitude of excision, tumor histology, pattern of spread, and pattern of failure in each tumor type and grade. In malignant CNS tumors such as medulloblastoma and ependymoma, excellent clinical end results have been reported, particularly in patients with

features denoting standard risk (complete resection, absence of metastatic disease, and no anaplastic features). The overall survival rates are above 90% in patients with pure germino‐ ma, regardless of metastatic stage, with a combination of chemotherapy and radiation. However, access to radiation oncology services and the number of functioning radiotherapy machines available in most LMICs is the main barrier to optimal patient care. It is obvious that pediatric neuro-oncology programs cannot be implemented in countries, which have no radiation oncology services. Based on World Bank classification, 139 countries are defined in the category of LMICs. Out of these, only four (2.9%) have the requisite number of telethera‐ py units and 55 (39.5%) have no RT facilities. It is also worth mentioning that LMICs have 0.71 teletherapy units per million population in contrast to 7.62 teletherapy units per million population for HICs [14]. A survey of radiotherapy equipment in Africa reported that 52% (29/56) of their countries had no radiotherapy at all and two-thirds of the MV equipment available in the continent were located in two countries (Egypt and South Africa) [15]. Moreover, many countries rely on machines that are more than 20 years old, which ques‐ tions their functionality and reliability. The available radiation oncology equipment in the continent represented 18% of the estimated needs, at time of reporting. The needs increased more due to rapid increase in the population in many African countries without simultane‐ ous increase in the facilities. Furthermore, appropriate maintenance of the radiation equip‐ ment is a major, problematic issue in countries wherever only one radiotherapy machine is the case. The treatment could get interrupted for an undetermined period of time and the waiting times can be prolonged considerably with the machine going out of service. It was estimated that the LMIC deficit in the teletherapy units was 61.4%, in radiation oncologists 38.9%, radiation physicists 68.4%, and RT technologists was 66.5% to reach the requirement applied in HICs [14]. As a consequence, access to radiation and delay in initiation and/or continua‐ tion of radiation treatment are a major problematic issue in most LMICs.

In several situations, pediatric oncologists on trying to overcome the problem of availability of radiotherapy design protocols that offer postoperative chemotherapy prior to radiation, in particular for medulloblastoma patients. Although this is not the sound or ideal option, it may delay or decrease recurrence or dissemination following initial surgery. Another limiting factor in the management is the number of experienced, well-qualified personnel with an experience in CNS radiation techniques. Several medulloblastoma trials showed that the quality of craniospinal radiotherapy (CSI) affects outcome. Therefore, the deficiency of adequate human resources is another major contributing factor for poor RT capacity in LMICs. Most reports on radiation oncology personnel availability and training confirm the unavaila‐ bility of enough physicians and staff to deal with the number of patients needing radiation treatment. This lack of trained personnel with the high patient volume often leads to long waiting list, disease progression, and poor outcome [16]. In Latin America, a survey report‐ ed the major obstacles for provision of adequate RT as insufficient number of specialists, rather than a lack of equipment [17]. The insufficient number of radiation oncologists, medical physicists, and radiation technologists training programs contributed negatively to efficient number of personnel needed for a decent service. To add to the gloomy picture, it is well estimated that within the next 10 years, 70% of newly diagnosed cancer patients will be living in countries that collectively have only 5% of the global resources for cancer control. It is

estimated that approximately 60% of the world's patients with cancer, including the pedia‐ tric neuro-oncology patients, do not have access to a complete cancer systemic therapy regimen, and the percentage is higher for radiotherapy [18].

features denoting standard risk (complete resection, absence of metastatic disease, and no anaplastic features). The overall survival rates are above 90% in patients with pure germino‐ ma, regardless of metastatic stage, with a combination of chemotherapy and radiation. However, access to radiation oncology services and the number of functioning radiotherapy machines available in most LMICs is the main barrier to optimal patient care. It is obvious that pediatric neuro-oncology programs cannot be implemented in countries, which have no radiation oncology services. Based on World Bank classification, 139 countries are defined in the category of LMICs. Out of these, only four (2.9%) have the requisite number of telethera‐ py units and 55 (39.5%) have no RT facilities. It is also worth mentioning that LMICs have 0.71 teletherapy units per million population in contrast to 7.62 teletherapy units per million population for HICs [14]. A survey of radiotherapy equipment in Africa reported that 52% (29/56) of their countries had no radiotherapy at all and two-thirds of the MV equipment available in the continent were located in two countries (Egypt and South Africa) [15]. Moreover, many countries rely on machines that are more than 20 years old, which ques‐ tions their functionality and reliability. The available radiation oncology equipment in the continent represented 18% of the estimated needs, at time of reporting. The needs increased more due to rapid increase in the population in many African countries without simultane‐ ous increase in the facilities. Furthermore, appropriate maintenance of the radiation equip‐ ment is a major, problematic issue in countries wherever only one radiotherapy machine is the case. The treatment could get interrupted for an undetermined period of time and the waiting times can be prolonged considerably with the machine going out of service. It was estimated that the LMIC deficit in the teletherapy units was 61.4%, in radiation oncologists 38.9%, radiation physicists 68.4%, and RT technologists was 66.5% to reach the requirement applied in HICs [14]. As a consequence, access to radiation and delay in initiation and/or continua‐

452 Neurooncology - Newer Developments

tion of radiation treatment are a major problematic issue in most LMICs.

In several situations, pediatric oncologists on trying to overcome the problem of availability of radiotherapy design protocols that offer postoperative chemotherapy prior to radiation, in particular for medulloblastoma patients. Although this is not the sound or ideal option, it may delay or decrease recurrence or dissemination following initial surgery. Another limiting factor in the management is the number of experienced, well-qualified personnel with an experience in CNS radiation techniques. Several medulloblastoma trials showed that the quality of craniospinal radiotherapy (CSI) affects outcome. Therefore, the deficiency of adequate human resources is another major contributing factor for poor RT capacity in LMICs. Most reports on radiation oncology personnel availability and training confirm the unavaila‐ bility of enough physicians and staff to deal with the number of patients needing radiation treatment. This lack of trained personnel with the high patient volume often leads to long waiting list, disease progression, and poor outcome [16]. In Latin America, a survey report‐ ed the major obstacles for provision of adequate RT as insufficient number of specialists, rather than a lack of equipment [17]. The insufficient number of radiation oncologists, medical physicists, and radiation technologists training programs contributed negatively to efficient number of personnel needed for a decent service. To add to the gloomy picture, it is well estimated that within the next 10 years, 70% of newly diagnosed cancer patients will be living in countries that collectively have only 5% of the global resources for cancer control. It is

National cancer control programs, large national or international meetings, or even national treatment guidelines though of extreme importance, were not adequate to improve the current situation of neuro-oncology in LMICs. A survey in 167 countries performed by the WHO found that almost half of these countries had a sort of plan for improving treatment, but national guidelines are generally lacking while the accessibility and affordability of treatment re‐ mained low in LMICs. In many countries, the national cancer control plans had been de‐ signed according to WHO plan without tailoring it to the local conditions, needs, and challenges [19, 20].

Engaging in innovative strategic thinking and finding new ways to mobilize and enforcing local resources to improve the availability and accessibility of cancer care are essential to overall and balanced cancer control in underserved countries. Most LMICs have some local resources; however, they may not be adequately mobilized or used in the appropriate manner. LMICs should not rely entirely on external financial donations. Instead, what is needed is winwin support and adequate assistance from the affluent organizations or countries, as well as the pharmaceutical and radiology industrial companies. Assistance better take the form of technical support for building local capacity, staff training, management guidance, and research cooperation. Other types of support may include provision of information and communication technologies, help with obtaining local funds or international grants, and instructions on how to collaborate on international work in their own countries. (The Win-Win Initiative of ICEDOC's Experts in Cancer Without Borders [21].)

Conducting more clinical trials in LMICs, which have the major bulk of pediatric cancer and neuro-oncologic patients, could shorten the total time needed for conducting clinical trials, may reduce costs, and could enrich the scientific aspects of those trials with more variability. It could also help initiate more cost-effective ways in medical services in LMICs that can be applied even in HICs and could establish a better value cancer care. This may serve double purposes: improve the quality of both health care and research and prevent the brain drain experienced by LMICs when their most highly qualified people immigrate to HICs. Hypofractionation for glioblastoma multiforme (GBM) and diffuse intrinsic pontine glioma (DIPG) are treatment approaches to improve regional tumor control. This has several advantages over conventional RT via increased cell death due to the used higher doses per fraction and reduced tumor repopulation effect consequent to shortening of the overall treatment time. Haas-Kogan et al. [22] assumed that the α/β ratio equals 2 Gy in p53-mutat‐ ed GBM, and not 7–10 as suggested in other malignant tumor types. Shortened treatment time has additional significant benefit for patients and their families, because patients with GBM or DIPG have a limited survival time after the completion of treatment. Shortening treat‐ ment time allows for a better QoL for the patients saving them and their families the burden of prolonged treatment with all its consequent suffering. However, there may be a risk of enhanced radioresistance. Hypofractionated radiation has become a frequent choice in the treatment of GBM and DIPG patients [23–27].
