Impact of Radiation Dose inSubventricular Zone on Survival in Glioblastoma Multiforme: A Mini Review

Aastha Shah; RajanYadav; Isha Shah; Monik Patel

Impact of Radiation Dose inSubventricular Zone on Survival in Glioblastoma Multiforme: A Mini Review

Aastha Shah^*,RajanYadav, Isha Shah and Monik Patel

Published Date: 2021-01-27

Aastha Shah^*, RajanYadav,Isha Shah and Monik Patel

Gujarat Cancer and Research Institute,MD Radiation Oncology, Ahemdabad,Gujarat

*Corresponding Author:: Aastha Shah
Radiation Oncology,
Gujarat,
India
Email: shahaastha2781994@gmail.com

Received Date:December 02, 2020 Accepted Date:January 19, 2021 Published Date: January 27, 2021

Citation: Shah A (2021) Impact of Radiation Dose inSubventricular Zone on Survival in Glioblastoma Multiforme: A Mini Review. J Neoplasm. Vol. 6 No. 2: 06.

Visit for more related articles at Journal of Neoplasm

Abstract

GlioblastomaMultiforme (WHO GRADE IV) constitutes 75% of all high grade glial cell tumors in the central nervous system.The general management consists of maximal tumor resection followed by adjuvant radiation and chemotherapy. Thereexists a controversial role of neural stem cells residing in subventricular zone and the location of tumor with respect to it and the probability of the recurrence with respect to it. An intense review on literature and studies were found which showed varied results on the pattern of recurrence and the overall survival and time to progression by the irradiation of subventricular zone in patients of Glioblastoma Multiforme to high doses. All these studies incorporated 3 dimensional conformal radiotherapy or Intensity Modulated Radiotherapy as preferred modality for radiation planning modality. They showed that initial contact of primary tumor to Subventricular zone was associated with a high probability of recurrence but prophylactic irradiation of bilateral Subventricular zone to high doses is still questionable keeping in mind its close proximity to hippocampus where studies are going on hippocampal sparing radiation techniques. All of these have not arrived at a common conclusion.GlioblastomaMultiforme tumors involving Subventricular zone can be an independent poor prognostic factor,but prophylactic irradiation of bilateral subventricularzone to high doses is still questionable.

Keywords

Adjuvant radiation; chemotherapy; subventricular zone

Introduction

Glioblastoma Multiforme (WHO GRADE IV) constitutes 75% of all high grade glial cell tumors in the central nervous system.World Health Organization (WHO) classified glial tumors into four grades based on their histopathological features. Any of the three below mentioned histopathological features would suffice to establish diagnosis of Glioblastoma Multiforme (GBM):

• Nuclear atypia

• Mitotic activity

• Vascular proliferation

• Necrosis

The prognosis of GBM remains poor despite use of trimodality therapy in these cases.The median survival of patients with GBM is 14 months.The current approach focuses on improving the quality of life of patients along with the researches going on to introduce adaptations in treatment techniques to improve survival.Curran et al.[1], used non parametric Recursive Partitioning Analysis (RPA), a statistical tool for the identification of significant prognostic factors and further classification of patients with similar outcomes is shown below:

At present the treatment consists of maximal surgical safe resection followed by radiotherapy with concurrent temozolomidechemotherapy and adjuvant temozolomide chemotherapy [2]. Despite this, the survival has not been drastically increased.Thereexists a controversial role of neural stem cells residing in subventricular zone and the location of tumor with respect to it and the probability of the recurrence with respect to it [3]. The tumor is considered to made up of a heterogeneous population of cells.The Subventricular Zone (SVZ) lines the lateral ventricles and it represents the origin of neural stem cells with astrocytes like characteristics.NeuralStem Cells (NSCs) are self-renewing cells that generate the major cell types of the central nervous system, namely neurons, astrocytes and oligodendrocytes, during embryonic development and in the adult brain. This article aims to compile the results of different studies done with the aim of focussing the role of irradiation of SVZ in patients of GBM and their prognosis.

CLASS	Patient Characteristics	Median Survival (months)
I,II	Anaplastic Astrocytoma Age>50 years,normal mental status or age>50 years,KPS>70,symptoms>3 months	40-60
III,IV	Anaplastic Astrocytoma Age<50 years,abnormal mental status Age>50 years,symptoms<3 months Glioblastoma Age<50 years Age>50 years,KPS>70	11-18
V,VI	Glioblastoma Age>50 years,KPS<70 or abnormal mental status	5-9

Table 1: Showing the four classes of recursive partitioning analysis

Study	Study type	N	Cut off dose to SVZ	TTP (months)	OS (months)
Lee. Percy et al. [3]	Retrospective	173	iSVZ>59.4 Gy iSVZ<59.4 Gy	12.6 9.9	25.8 19.2
M Malik et al. [4]	Prospective	54	iSVZ>58 Gy iSVZ<58 Gy		16 14
Linda Chen et al. [5]	Prospective	116	iSVZ>40 Gy	15.1	17.5
Murchison et al. [8]	Retrospective	370	iSVZ<49 Gy bSVZ<40.8 Gy iSVZ>49 Gy bSVZ>40.8 Gy	8.7 9 9 8	16.9 15.7 16.6 16.5
Evers et al. [10]	Retrospective	55	bSVZ>43 Gy bSVZ<43 Gy	15 7.2	Not known
Gupta et al. [11]	Retrospective	40	iSVZ>59.9 Gy iSVZ<59.9 Gy	10 11	17 15
Khalifa et al. [12]	Retrospective	43	V20 to bSVZ>84% V20 to bSVZ<84%	17.7 5.2	20.3 22.7
Adeberg et al. [13]	Retrospective	65	iSVZ>40 Gy iSVZ<40 Gy	8.5 5.2	21.3 18

TTP=Time to Tumor Progression
OS=Overall Survival
N=Number of patients included in study

Table 2:Showing the various studies reviewed during the process.

Review Process

We did an intense review on literature and studies were found which showed varied results on the pattern of recurrence and the overall survival and time to progression by the irradiation of subventricular zone in patients of GBM to high doses [4,5]. The idea behind the lethality of GBM owes to the hypothesis of neurogenic stem cells [6]. The subventricular zone is contoured on planning CT (Computed Tomography) scan of 3 mm slice as 5 mm margin around the lower end of lateral ventricles [7]. The studies focussed in this article contoured GTV (Gross Tumor Volume), CTV (Clinical Target Volume), PTV (Planning Target Volume) with the aid of using pre op T1w MRI (Magnetic Resonance Imaging) and FLAIR (Fluid Attenuated Inversion Recovery) sequences and the planning CT scan. The GTV was contoured as the contrast enhancing lesion on T1w MRI or the post op cavity with rim of enhancement around it on planning CT scan. The CTV was contoured by giving isotropic 20 mm margins around GTV and editing with respect to anatomic barriers and PTV was contoured by giving 30mm isotropic margin around CTV. The response assessment was done using RANO (Response Assessment in Neuro Oncology) criteria. Patients included had either undergone GTR (Gross Total Resection), STR (Sub Total Resection) or biopsy. The studies also showed that prognosis of patients undergoing GTR was significantly better as compared to those undergoing STR and biopsy. The dose of concurrent Temozolomide was 75mg/ m² of BSA (Body Surface Area) given along with radiation for 7 days a week from first to last day of radiation therapy followed by adjuvant Temozolomide for 5 days a week in a 28 day cycle to a dose of 150 to 200 mg/m²BSA.Radiation was given 5 days a week. All thestudies incorporated 3-dimensional conformal radiotherapy or Intensity Modulated Radiotherapy as preferred modality for radiation planning modality.

Identified Studies

All the below mentioned studies incorporated a large cohort of patients. All of these have not arrived at a common conclusion. Lee et al. stated that astrocyte-like neural stem cells leave the SVZ and migrate into distant brain regions to form gliomas thus stressing the point to aggressively irradiation SVZ in GBM patients. The Murchison et al study showed no significant improvement in DFS (Disease Free Survival), PFS (Progression Free Survival), OS (Overall Survival) on patients undergoing SVZ irradiation to high doses after Gross Total Resection of their tumor [8]. One of the study conversely suggest that irradiation of SVZ to high doses may be in fact associated with poorer OS and PFS [9]. The first study Evers et al however found that the mean dose of >43 Gy to BSVZ (bilateral SVZ) was associated with improved DFS but not improved OS [10]. But Gupta et al found that irradiation of iSVZ to mean dose of >59.9 Gy is an independent factor for OS but not to contralateral SVZ [11]. They showed that initial contact of primary tumor to SVZ was associated with a high probability of recurrence but prophylactic irradiation of bSVZ to high doses is still questionable keeping in mind its close proximity to hippocampus where studies are going on hippocampal sparing radiation techniques.

Conventional approaches are limited due to hurdles like the development of therapy resistance coming with a decreasing sensitivity of tumor cells towards radiation, the unspecific targeting of both cancer and healthy brain cells, as well as the recurrence of the tumor after treatment.Recent researches suggest that the failure of therapies might be caused by the belief that the tumor consists of a homogenous group of cells.

The tumor is distinguishable into many subgroups of cells varying on genetics, epigenetics and phenotype as well as their capabilities to replicate and migrate. Thus, elimination of Brain tumor propagating cells is a promising alternative to specifically target the cell of origin of the tumor, which raises the possibility to prevent tumor proliferation, tumor cell differentiation and brain tumor propagating cells regeneration[14].

Conclusion

GBM tumors involving SVZ can be an independent poor prognostic factor but prophylactic irradiation of bSVZ to high doses is still questionable. Further research work at a large scale would help to answer this question precisely.