Review of dose fractionation schemes for pontine glioma irradiation

Brain tumors in the pediatric population constitute a very frequent type of solid childhood cancers and a considerable part of all pediatric malignancies. These tumors are typically classifi ed into supra and infratentorial with respect to their location. Another classifi cation is based on age at diagnosis and includes congenital brain tumors, tumors of infancy period observed at younger than 1 year of age, and tumors observed in older children. Brain tumours account for about 20% of all childhood neoplasms [1-5]. Brainstem comprises a critical location for pediatric Central Nervous System (CNS) malignancies [5]. Critical parts of the brainstem include the medulla oblongata, pons, and the midbrain all of which are involved in critical functions of the human body [5].


Introduction
Brain tumors in the pediatric population constitute a very frequent type of solid childhood cancers and a considerable part of all pediatric malignancies. These tumors are typically classifi ed into supra and infratentorial with respect to their location. Another classifi cation is based on age at diagnosis and includes congenital brain tumors, tumors of infancy period observed at younger than 1 year of age, and tumors observed in older children. Brain tumours account for about 20% of all childhood neoplasms [1][2][3][4][5]. Brainstem comprises a critical location for pediatric Central Nervous System (CNS) malignancies [5]. Critical parts of the brainstem include the medulla oblongata, pons, and the midbrain all of which are involved in critical functions of the human body [5].
Brainstem tumors constitute approximately 10% to 15% of CNS neoplasms in the pediatric population, and most common of brainstem tumors is Diffuse Intrinsic Pontine Glioma (DIPG) [5][6][7]. Children with DIPG are typically diagnosed at the 5th to 10th years of their lives, with tumors being more frequently located in the pons rather than the midbrain or medulla oblongata [5][6][7][8].
Location at the midbrain and medulla oblongata may be associated with a relatively more favorable prognosis compared to pontine location with frequent expansion and diffuse infi ltration of more than half of the pons [5][6][7][8][9][10]. DIPG are typically categorized as World Health Organization (WHO) grade III or IV tumors with typically an aggressive disease course and grim prognosis [5][6][7][8][9][10][11]. Median Overall Survival (OS) is typically in the range of 8 to 11 months, with a low OS rate of about 30% at 1 year, and less than 10% at Citation: Dincoglan   it seems prudent not to opt for hyperfractionated RT regimens which also put forward additional issues including logistics, patient convenience, and potential requirements for repeated anaesthesia [5,9,33].

Reirradiation of pontine gliomas
Despite the poor prognosis of DIPG with limited survival durations, reirradiation may be considered [34]. Reirradiation schemes may include CFRT as well as radiosurgical applications [34,[50][51][52]. Comprehensive studies addressed the utility of reirradiation for DIPG [53][54][55][56][57][58]. Janssens, et al. analyzed the benefi t and toxicity of reirradiation at fi rst progression of DIPG [56]. They treated 31 children aged 2-16 years with DIPG at fi rst progression with a reirradiation dose of 19.8 -30 Gy [56]. Median overall survival was 13.7 months for patients receiving reirradiation, and the authors concluded that majority of DIPG patients responding to upfront RT may benefi t from reirradiation with acceptable toxicity [56]. Massimino, et al. assessed the results of nimotuzumab and vinorelbine, RT and reirradiation for diffuse pontine glioma in childhood [57]. Twenty fi ve patients were enrolled, and 11 out of 16 patients with local relapse received reirradiation to a dose of 19.8 Gy delivered over 11 days [57]. Median progression free survival was 8.5 months and median overall survival was 15 months [57]. The authors concluded that the treatment strategy should be further investigated in view of the interesting results [57]. Wolff et al. reported their experience on treatment of recurrent DIPG including reirradiation as part of management in 7 patients out of the total 31 patients [58]. The authors concluded that reirradiation should be tested in a prospective clinical study in view of the encouraging response rates [58].
Recent years have witnessed signifi cant advances in radiation oncology with widespread adoption of contemporary RT strategies including Image Guided Radiation Therapy (IGRT), Intensity Modulated Radiation Therapy (IMRT), and Adaptive Radiation Therapy [59][60][61][62][63][64][65]. Radiosurgery in the form of Stereotactic Radiosurgery (SRS), Stereotactic Body Radiation Therapy (SBRT) and Hypofractionated Stereotactic Radiation Therapy (HFSRT) may be used for focused irradiation of several CNS disorders as well as several other tumors throughout the human body . Rationale of radiosurgery includes highly focused delivery of high and ablative RT doses to well defi ned targets with optimal normal tissue sparing with stereotactic localization, robust immobilization, and steep dose gradients around the target. Nevertheless, there is relatively limited experience with this relatively newer radiotherapeutic strategy.

Conclusions and future perspectives
RT plays a major role in management of pontine gliomas. Given the limited life expectancy of patients with DIPG, RT may be utilized for achieving at least a transient stabilization of disease and improvement in symptoms and quality of life. Improved understanding of the biology of DIPG may allow for utilization of targeted therapies to achieve an improved therapeutic ratio for pontine gliomas.