Home About us Editorial board Ahead of print Current issue Search Archives Submit article Instructions Subscribe Contacts Login 

 Table of Contents  
Year : 2011  |  Volume : 7  |  Issue : 1  |  Page : 58-63

Intensity-modulated radiation to spare neural stem cells in brain tumors: A computational platform for evaluation of physical and biological dose metrics

Department of Advanced Centre for Radiation Oncology, Dr. Balabhai Nanavati Hospital, Mumbai - 400 056, Maharashtra, India

Date of Web Publication5-May-2011

Correspondence Address:
Arun Jaganathan
Advance Centre for Radiation Oncology, Dr. Balabhai Nanavati Hospital, S. V. Road, Vile Parle West, Mumbai - 400 056, Maharashtra
Login to access the Email id

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0973-1482.80463

Rights and Permissions
 > Abstract 

Background: Neurocognitive effects following whole-brain and partial-brain irradiation can cause considerable morbidity. Sparing of neural stem cells (NSCs) is proposed as an avenue for reducing the long-term radiation-induced defects in learning, memory, and intelligence. We performed an analytical study to spare the NSC from partial-brain irradiation by intensity-modulated radiotherapy (IMRT).
Objective: The aim of this study is to achieve maximal sparing of NSC during irradiation of brain tumors using biologically equivalent dose (BED) for all plans. The consequent clinical benefit will possibly be in terms of acute effects on stem cells and delayed neurologic sequelae to brain. A tool to modulate various physical and biological dose metrics has been used to study the optimization of radiation therapy for brain tumors with constraints imposed on total radiation to NSC.
Materials and Methods: A total of 10 successive patients of grade III and IV gliomas of brain, who underwent total or near total excision of brain tumors, were included in the study. Patients underwent computed tomography and magnetic resonance imaging fusion for contouring. Computational codes used to analyze the efficacy of the plan are quality of coverage, homogeneity index, and conformity index. Wide range of radiosensitivity parameters were evaluated by using equivalent uniform dose and tumor control probability (TCP) to predict tumor control with and without sparing of NSC.
Results: The physical and biological dose metrics were modulated by fitting standard deviation of 0.3% for all plans. The maximum NSC sparing was achieved in IMRT plans with constraints applied to local TCP. Similarly, for BED of plans with and without constraints, the estimated mean reduction in acute complications of NSC achieved was 12.23% (range, 4.27-28.33%). The estimated mean reduction in BED for late complications of late-reacting brain tissue is 14.69% (range, 7.39-33.56%).

Keywords: EUD, intensity-modulated radiotherapy, Matlab, neural stem cell, TCP

How to cite this article:
Jaganathan A, Tiwari M, Phansekar R, Panta R, Huilgol N. Intensity-modulated radiation to spare neural stem cells in brain tumors: A computational platform for evaluation of physical and biological dose metrics. J Can Res Ther 2011;7:58-63

How to cite this URL:
Jaganathan A, Tiwari M, Phansekar R, Panta R, Huilgol N. Intensity-modulated radiation to spare neural stem cells in brain tumors: A computational platform for evaluation of physical and biological dose metrics. J Can Res Ther [serial online] 2011 [cited 2021 Sep 23];7:58-63. Available from: https://www.cancerjournal.net/text.asp?2011/7/1/58/80463

 > Introduction Top

In recent years, the concept of neural stem cell (NSC) has ignited a great deal of interest largely due to potential clinical benefit associated with sparing stem cells during irradiation. It is now known that the human brain contains regions of mitotically active cells which retain the ability to divide and differentiate along either neural or glial cell lines throughout life. These neural stem cells are located in two specific areas of the brain: the subgranular zone within the dentate gyrus (part of the hippocampus), [1],[2] which allows permanent and irreparable damage during radiation, and the subventricular zone adjacent to the lateral aspect of the temporal horn and the occipital trigone region of the lateral ventricles that have capacity to regenerate to some extent from the effects of ionizing radiation. [3],[4],[5] These cells are capable of increasing their mitotic rate under the influence of appropriate stimuli (e.g., brain trauma, stroke, radiation exposure, etc.), and can migrate through the brain to damaged areas and repopulate areas of cortical neuronal loss or white matter damage. [6],[7] They are also involved in replacing the neurons that are lost as a result of neurodegenerative disorders, and are important in learning. There is lack of adequate survival statistics or models to extrapolate the hypothetical clinical benefit by sparing NSC.

Extensive laboratory data published recently suggest significant impact of radiation on brain tissue leading to altered cognitive function. [8] However, there is considerable uncertainty about the development of these changes. New in vitro and in vivo approaches have provided the means by which new mechanistic insights can be gained relevant to the topic. Irradiation of brain leads to acute and late sequelae resulting in neurological morbidity. Acute effects of radiation to brain mainly manifests clinically as nausea and/or vomiting, irrespective of the site of radiation. Marsh et al. have reported that it is dosimetrically feasible to spare NSC using helical tomotherapy with 65.8% reduction in biologically equivalent dose (BED) (α/β=10Gy) for the NSC compartment in the prophylactic cranial irradiation (PCI) plans and a 70.8% reduction in the whole-brain radiotherapy (WBRT) plans. [9] Preservation of the NSC compartments during the administration of PCI should result in maintenance of the ability of the brain to repair the damage generated by cranial irradiation and help preserve neurocognitive function. Barani et al. have shown that it is possible to identify and dosimetrically reduce dose to these regions using intensity-modulated radiotherapy (IMRT) while treating a patient using treatment schedules applicable to WBRT and a primary high-grade glioma. [10]

 > Materials and Methods Top

This is a retrospective analysis of patients with grade III and IV gliomas of brain who underwent postoperative radiation therapy using IMRT technique and 6MV photon energy. The radiation dose schedule included 50 Gy delivered in 25 fractions with 200 cGy daily fraction size delivered over 5 weeks for phase 1. A boost of 10 Gy was delivered for phase 2, which was not included in the present dosimetric study. Patients were immobilized using thermoplastic mold in treatment position before computed tomography (CT) and magnetic resonance imaging (MRI). CT and MRI images thus obtained were fused on Tomocon (Tomocon 3.0.13, Slovak Republic) and contouring of NSC done by the radiologist, as shown in [Figure 1]. Radiation oncologists assigned constraints to various sites like eye, lens, optic nerve, and NSC. Levels of constraints assigned to various subvolumes are shown in [Figure 2].
Figure 1: Constraints assigned for different PTV, OAR & NSC

Click here to view
Figure 2: PTV (Red in color) & NSC (Brown in color) contours are shown in transverse, sagittal & coronal view

Click here to view

All the plans were carefully designed on precise planning system using aperture-based inverse planning algorithm (ELEKTA Ltd, West Sussex, UK). An attempt was made to reduce the number of segments per plan conceptually to 80 segments with maximum of seven beams. Reduction of segments was attempted to reduce time without compromising plan quality. Plans were generated for all patients with and without constraints to NSC. The session of IMRT planning was grouped as Group 1, with NSC as a constraint in optimization process, and Group 2, without including NSC as constraint in IMRT segmentation. The goal of grouping group 1 and group 2 for the current study was to demonstrate the onset of acute toxicity of NSC in terms of BED (α/β = 10.0 Gy) and (α/β = 2.0 Gy) [11] for late-responding tissues of the brain.

Plan analysis

Plans in Group 1 and 2 were compared against multiple indices bridged with functional database of computational model. This model functions by using Matlab Version, Microsoft office Excel 2007, and Statistical Analysis Software SAS (Cary, NC) to assess the physical dose metrics as RTOG indices and biological dose metrics such as BED, generalized equivalent uniform dose (EUD), tumor control probability (TCP), NTCP, and physical dose volume histogram (DVH) vs BED-DVH analysis.

The plan quality was deemed acceptable if SD of all the above indices calculated individually were within 0.3% against Group 2 plans. For DVH as an input function, the plan in Group 1 would undergo reiteration till the acceptability criteria are met.

The priority of constraint to NSC is assigned as "x" magnitude varies from +x to -x values as per the model output log files and get into reiteration of plans in Group 1 eventually are within acceptable limits, as shown in flowchart of NSC Model from [Figure 3].
Figure 3: Flowchart for the NSC Model

Click here to view

Physical and biological dose metrics

(a) Physical indices--Radiation Therapy Oncology Group criteria:

To rank the treatment plans, Radiation Therapy Oncology Group (RTOG) proposed certain criteria based on reference isodose (V RI ) and the target volume (TV) of the treatment plan.

Where, V RI - reference isodose volume and TV - target volume.

To evaluate precisely and compensate for the defects in above indices, van't Riet et al. proposed an index called conformation number (CN). [12] Calculation of this CN simultaneously takes into account irradiation of the TV and irradiation of healthy tissues.

Where, CN - conformation number, TVRI - target volume covered by the reference isodose, TV - target volume, and VRI - volume of the reference isodose.

(b) Biological indices

Niemierko phenomenological model of EUD is able to address tumors and Organ at Risk (OAR). [13] EUD is normalized at 2 Gy per fraction and combines the effects of both sensitivity to fractionation and volume effects of target or OAR.

'a' is a unitless model parameter that is specific to the tumor (<0) and OAR (>0) and v i is unitless and represents the i'th partial volume receiving dose D i in Gy. Tissue-specific parameter is "a =-8" for brain tumors. [14]

To calculate the TCP, the EUD is substituted in the following equation:

The TCD 50 is the tumor dose to control 50% of the tumors when the tumor is homogeneously irradiated. radiated. γ50 value used for postoperative brain tumors was"0.75" and TCD 50 as 27.04 Gy [15] was used for this study. For NTCP, appropriate model is required to analyze the effects extensively. This study limits up to evaluate injury in terms of BED acute toxicity of NSC and BED late effects of brain without compromising plan quality.

BED is expressed as

Based on study by Marsh et al., [16] BED were calculated by using mean dose "d" per fraction because the goal of current investigation is to use DVH as a relative measure of biological response for assessing acute effects of NSC and late effects of non-NSC parts of brain and brainstem. [17]

 > Results Top

(a) Physical indices

The extracted header files of group 1 plans are modulated by changing the priority values from -x to +x for NSC in the optimization schemes, which corresponds to the group 2 planning indices less than standard deviation (SD) 0.3%. The objective of the model is to figure out the output file, and it implies upon the equipoise between group 1 and group 2 plans to elucidate the potential sparing without compromising plan quality. In this action of the RTOG indices, the calculated value of QC mean is 0.878 and 0.883, HI mean is 1.088 and 1.074, CI mean is 1.146 and 1.144, and CNmean is 0.613 and 0.611, as shown in [Figure 4] and [Table 1]. The acceptable SDs for various physical indices are shown in [Table 2]. We found that the computation model is well within the limit in terms of equipoise criteria adopted for the model.
Figure 4: Graphical distribution of physical Indices fed in to Matlab environment

Click here to view
Table 1: Physical Indices objective limits without and with sparing Stem cell plans

Click here to view
Table 2: The physical Index objective limits with mean SD values of Group 1 and Group 2 Plans.

Click here to view

(b) Biological indices

[Table 3] clearly shows a reduction in acute and late reaction of NSC acute effects and brain while achieving similar EUD and TCP in both groups. Mean EUD in group 1 is 51.47 and it is 51.60 in group 2. Mean variation is 0.10% for TCP and shows agreement for the control probability for the adopted model. The mean and maximum reduction of 12.23% and 28.33% respectively on stem cells and 14.69% and 33.56% respectively on late effects of brain were observed, as shown in [Table 3]; BED-DVH Histogram of NSC and Target and isodose distribution of transverse view are shown in [Figure 5] and [Figure 6].
Figure 5: Graphical representation of Physical and BED-DVH of maximum sparing of neural stem cell

Click here to view
Figure 6: Isodose distribution of neural stem cell sparing in Transverse view

Click here to view
Table 3: Biological Indices of Group1 and Group 2 objective oriented plans and Optimized reduction of neural stem cell and other parts of brain

Click here to view

 > Discussion Top

The overall goal of this study is to incorporate patient-specific biological information and plan-specific indices on to multivariative analysis platform. The current model was applied in the stem cell sparing IMRT plans for Glioblastoma Multiforme (GBM). It has been speculated that the irradiation of NSC results in the inability to repair radiation-induced damage to normal brain tissue. The phenotypic expression of damage due to normal tissue may manifest as memory loss and loss of executive function. [11],[18] Pediatric patients undergoing brain irradiation may lead to hearing loss, severe global cognitive deficiencies, and neuroendocrine deficits. [19],[20],[21],[22] Involvement of NSC in this series varies from 18 to 87% in tumor volume, depending on the volume and site of the tumor, and OAR dose limits are maintained during the plans, as represented in [Figure 2]. There is dearth of evidence about objective and quantitative correlation regarding neurocognitive decline in 5-year survival statistics. There is a lack of information regarding TD 50/5 for human NSC's. Hence, it is difficult to generate accurate NTCP models for this population. [16] Predicting local control for the planned distribution is unique for each plan.

Our study demonstrates the feasibility of creating nonhomogenous distribution using IMRT techniques such that higher therapeutic ratio was achieved while aiming for higher EUD and TCP. The design of nonuniform dose distribution was aided by information gleaned from various physical and biological indices. This basic version of computational tool is not a stand-alone executable environment. It requires repeated DVH input files at each phase to run this tool. It establishes a useful platform for sparing of NSC with benefits of steep dose gradients using IMRT planning. Similar planning can also be carried out by this tool. Extended works of NSC includes more patient data points, and tools need to be modified with additional features to analyze patient response, neurocognitive tests, updated scoring system like National Cancer Institute Common Toxicity Criteria version, RTOG/ European Organization for Research and Treatment of Cancer (EORTC) protocols, [23] and multi-institutional clinical trial results.

 > Conclusions Top

Based on the evidence from in vitro animal and human studies which support the hypothesis of radiation-induced damage to NSC compartment, [24],[25],[26],[27],[28],[29],[30],[31] our results support the recent investigators [32] to emphasize the avoidance of NSC compartment. Its validation is recommended as an important parameter to be included in IMRT plans for partial-brain irradiation. The pilot study has shown that it is feasible to use RTOG-recommended indices and biological indices in planning on this platform. It is however necessary to validate this model as well on a larger cohort of patients and correlate it to subsequent clinical benefits.

 > References Top

1.Tada E, Parent JM, Lowenstein DH, Fike JR. X-irradiation causes a prolonged reduction in cell proliferation in the dentate gyrus of adult rats. Neuroscience 2000;99:33-41.  Back to cited text no. 1
2.Peissner W, Kocher M, Treuer H, Gillardon F. Ionizing radiation induced apoptosis of proliferating stem cells in the dentate gyrus of the adult rat hippocampus. Brain Res Mol Brain Res 1999;71:61-8.  Back to cited text no. 2
3.Hellström NA, Björk-Eriksson T, Blomgren K, Kuhn HG. Differential recovery of neural stem cells in the subventricular zone and dentate gyrus after ionizing radiation. Stem Cells 2009;27:634-41.  Back to cited text no. 3
4.Reynolds BA, Weiss S. Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system. Science 1992;255:1707-10.   Back to cited text no. 4
5.Taupin P, Gage FH. Adult neurogenesis and neural stem cells of the central nervous system in mammals. J Neurosci Res 2002;69:745-9.   Back to cited text no. 5
6.Doetsch F, Caillé I, Lim DA, García-Verdugo JM, Alvarez-Buylla A. Subventricular zone astrocytes are neural stem cells in the adult mammalian brain. Cell 1999;97:703-16.   Back to cited text no. 6
7.Morshead CM, Reynolds BA, Craig CG, McBurney MW, Staines WA, Morassutti D, et al. Neural stem cells in the adult mammalian forebrain: A relatively quiescent subpopulation of subependymal cells. Neuron 1994;13:1071-82.  Back to cited text no. 7
8.Butler JM, Rapp SR, Shaw EG. Managing the cognitive effects of brain tumor radiation therapy. Curr Treat Options Oncol 2006;7:517-23.   Back to cited text no. 8
9.Marsh JC, Gielda BT, Herskovic AM, Abrams RA. Cognitive Sparing during the Administration of Whole Brain Radiotherapy and Prophylactic Cranial Irradiation: Current Concepts and Approaches. J Oncol 2010;2010:198208.   Back to cited text no. 9
10.Barani IJ, Cuttino LW, Benedict SH, Todor D, Bump EA, Wu Y, et al. Neural stem cell-preserving external-beam radiotherapy of central nervous system malignancies. Int J Radiat Oncol Biol Phys 2007;68:978-85.  Back to cited text no. 10
11.Barani IJ, Benedict SH, Lin PS. Neural stem cells: implications for the conventional radiotherapy of central nervous system malignancies. Int J Radiat Oncol Biol Phys 2007;68:324-33.  Back to cited text no. 11
12.van't Riet A, Mak AC, Moerland MA, Elders LH, van der Zee W. A conformation number to quantify the degree of conformality in brachytherapy and external beam irradiation: Application to the prostate. Int J Radiat Oncol Biol Phys 1997;37:731-6.  Back to cited text no. 12
13.Niemierko A. A generalized concept of equivalent uniform dose (EUD). Med Phys 1999;26:1100.  Back to cited text no. 13
14.Thieke C, Bortfeld T, Niemierko A, Nill S. From physical dose constraints to equivalent uniform dose constraints in inverse radiotherapy planning. Med Phys 2003;30:2559-60.  Back to cited text no. 14
15.Okunieff P, Morgan D, Niemierko A, Suit HD. Radiation dose-response of human tumours. Int J Radiat Oncol Biol Phys 1995;32:1227-37.  Back to cited text no. 15
16.Marsh JC, Godbole RH, Herskovic AM, Gielda BT, Turian JV. Sparing of the neural stem cell compartment during whole brain radiation therapy: A dosimetric study using helical tomotherapy. Int J Radiat Oncol Biol Phys 2010;78:946-54.  Back to cited text no. 16
17.Sienkiewicz ZJ, Haylock RG, Saunders RD. Prenatal irradiation and spatial memory in mice: Investigation of dose-response relationship. Int J Radiat Biol 1994;65:611-8.  Back to cited text no. 17
18.Hodges H, Katzung N, Sowinski P, Hopewell JW, Wilkinson JH, Bywaters T, et al. Late behavioural and neuropathological effects of local brain irradiation in the rat. Behav Brain Res 1998;91:99-114.  Back to cited text no. 18
19.Parent JM, Tada E, Fike JR, Lowenstein DH. Inhibition of dentate granule cell neurogenesis with brain irradiation does not prevent seizure- induced mossy fiber synaptic reorganization in the rat. J Neurosci 1999;19:4508-19.  Back to cited text no. 19
20.Paulino AC, Saw CB, Wen BC. Comparison of posterior fossa and tumor bed boost in medulloblastoma. Am J Clin Oncol 2000;23:487-90.  Back to cited text no. 20
21.Palmer SL, Goloubeva O, Reddick WE, Glass JO, Gajjar A, Kun L, et al. Patterns of intellectual development among survivors of pediatric medulloblastoma: a longitudinal analysis. J Clin Oncol 2001;19:2302-8.  Back to cited text no. 21
22.Nandagopal R, Laverdière C, Mulrooney D, Hudson MM, Meacham L. Endocrine late effects of childhood cancer therapy: A report from the children's oncology group. Horm Res 2008;69:65-74.  Back to cited text no. 22
23.Power DA. Late effects of radiotherapy: How to assess and improve outcomes. Br J Radiol 2005;78:150-2.  Back to cited text no. 23
24.Rola R, Raber J, Rizk A, Otsuka S, VandenBerg SR, Morhardt DR, et al. Radiation-induced impairment of hippocampal neurogenesis is associated with cognitive deficits in young mice. Exp Neurol 2004;188:316-30.  Back to cited text no. 24
25.Winocur G, Wojtowicz JM, Sekeres M, Snyder JS, Wang S. Inhibition of neurogenesis interferes with hippocampus-dependent memory function. Hippocampus 2006;16:296-304.  Back to cited text no. 25
26.Raber J, Fan Y, Matsumori Y, Liu Z, Weinstein PR, Fike JR, et al. Irradiation attenuates neurogenesis and exacerbates ischemia-induced deficits. Ann Neurol 2004;55:381-9.  Back to cited text no. 26
27.Raber J, Rola R, LeFevour A, Morhardt D, Curley J, Mizumatsu S, et al. Radiation-induced cognitive impairments are associated with changes in indicators of hippocampal neurogenesis. Radiat Res 2004;162:39-47.  Back to cited text no. 27
28.Madsen TM, Kristjansen PE, Bolwig TG, Wortwein G. Arrested neuronal proliferation and impaired hippocampal function following fractionated brain irradiation in the adult rat. Neuroscience 2003;119:635-42.  Back to cited text no. 28
29.Fike JR, Rosi S, Limoli CL. Neural precursor cells and central nervous system radiation sensitivity. Semin Radiat Oncol 2009;19:122-32.  Back to cited text no. 29
30.Gage FH. Mammalian neural stem cells. Science 2000;287:1433-8.  Back to cited text no. 30
31.Monje ML, Vogel H, Masek M, Ligon KL, Fisher PG, Palmer TD. Impaired human hippocampal neurogenesis after treatment for central nervous system malignancies. Ann Neurol 2007;62:515-20.  Back to cited text no. 31
32.Marsh JC, Gielda BT, Herskovic AM, Abrams RA. Cognitive Sparing during the Administration of Whole Brain Radiotherapy and Prophylactic Cranial Irradiation: Current Concepts and Approaches. J Oncol 2010;2010:198208.  Back to cited text no. 32


  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]

  [Table 1], [Table 2], [Table 3]

This article has been cited by
1 Monitoring and optimising cognitive function in cancer patients: Present knowledge and future directions
S.B. Schagen,M. Klein,J.C. Reijneveld,E. Brain,S. Deprez,F. Joly,A. Scherwath,W. Schrauwen,J.S. Wefel
European Journal of Cancer Supplements. 2014;
[Pubmed] | [DOI]


Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
Access Statistics
Email Alert *
Add to My List *
* Registration required (free)

  >Abstract>Introduction>Materials and Me...>Results>Discussion>Conclusions>Article Figures>Article Tables
  In this article

 Article Access Statistics
    PDF Downloaded345    
    Comments [Add]    
    Cited by others 1    

Recommend this journal