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Table of Contents
REVIEW ARTICLE
Year : 2018  |  Volume : 1  |  Issue : 1  |  Page : 40-42

Re-irradiation in central nervous system tumors


1 Department of Radiation Oncology, Apollo Cancer Institute, Hyderabad, Telangana, India
2 Department of Radiation Oncology, Mahatma Gandhi Cancer Hospital, Vishakhapatnam, Andhra Pradesh, India

Date of Web Publication18-Jun-2018

Correspondence Address:
Dr. Sayan Paul
Apollo Health City Hospital, Jubilee Hills, Hyderabad
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jco.jco_11_17

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  Abstract 


Radiotherapy (RT) in relapsed brain tumors has been used sparingly because of the risk of toxicity, particularly white matter necrosis. However, evidence from preclinical animal models and increasing data from clinical series show that brain and spinal cord have marked repair potential, and re irradiation should be considered a valid option in selected patients. The choice of technique and dose fractionation for re irradiation depends on tumor characteristics (volume and location), previous RT dose and volume, and patient characteristics (age and performance status). For small volume tumors in noneloquent areas, single fraction SRS and brachytherapy may be good options. For small and intermediate volume tumors in eloquent areas, FSRT or hypofractionated RT may be used. For large volume recurrences, requiring partial brain irradiation, conventional fractionation is safer and offers palliation with minimal risk of radiation induced toxicitie.

Keywords: Brain tumor, re-irradiation, central nervous system


How to cite this article:
Paul S, Sesikeran B N, Patro KC, Bhattacharya K, Palkonda VA. Re-irradiation in central nervous system tumors. J Curr Oncol 2018;1:40-2

How to cite this URL:
Paul S, Sesikeran B N, Patro KC, Bhattacharya K, Palkonda VA. Re-irradiation in central nervous system tumors. J Curr Oncol [serial online] 2018 [cited 2018 Dec 14];1:40-2. Available from: http://www.journalofcurrentoncology.org/text.asp?2018/1/1/40/234539




  Introduction Top


Radiotherapy (RT) in relapsed brain tumors has been used sparingly because of the risk of toxicity, particularly white matter necrosis. However, evidence from preclinical animal models and increasing data from clinical series show that brain and spinal cord have marked repair potential, and re-irradiation should be considered a valid option in selected patients.


  Radiobiology of Central Nervous System Toxicity Top


The mechanism of central nervous system (CNS) damage involves different functional and structural components. The neurons, glial cells (oligodendrocytes and astrocytes), and vascular tissue are the key players in radiation-induced damage. The phases of CNS toxicity are classified as early (days-weeks), early delayed (1–6 months), and late (>6 months). Early and early delayed phases occur due to transient demyelination due to apoptosis of oligodendrocytes. However, this damage is repaired by the stem cell compartment consisting of oligodendrocyte Type 2 astrocyte cell (O2A).[1] Late damage is a complex interplay of demyelination due to O2A cell damage and vascular changes due to endothelial damage. A critical depopulation of cells and permeability changes in the vasculature lead to hemorrhage and infarcts, which precipitates white matter necrosis.[2]

Studies regarding recovery of CNS structures come from preclinical evidence of radiation-induced myelopathy after re-irradiation at different intervals in animal models. Brain and spinal cord are known to have a low α/β. Although sensitive to large fraction sizes, the CNS has remarkable recovery potential and can withstand up to 50% of tolerance dose after 1 year and 65%–70% of tolerance dose after 3-year interval from the first course of radiation.[3] This study comes close to clinical scenarios of head-and-neck RT where the cord has initially received a dose of around 45 Gy at conventional fractionation, and there is a requirement of a second course after ≥1 year. A risk model proposed by Nieder et al. suggested that an interval of <6 months and a cumulative biologically effective dose of any one course of >102 Gy were significant contributors to myelopathy risk.[4]


  Re-Irradiation Tolerance Top


Re-irradiation tolerance of brain has been extrapolated to a large extent from the preclinical studies of spinal cord. In a meta-analysis of 21 re-irradiation studies of gliomas, Mayer and Sminiaattempted to compile information regarding cumulative dose, interval, fractionation, and effect of concurrent therapies on brain tolerance. An NTDcumulative (normalized total dose = sum of 2 Gy equivalent doses of both courses) of >100 Gy for conventionally fractionated three-dimensional conformal RT was associated with radiation-induced white matter necrosis. Smaller volumes and more conformal techniques such as fractionated stereotactic RT (FSRT) and linear accelerator-based single-fraction stereotactic radiosurgery (SRS) allow safe delivery of higher NTDcumulative doses (90–133.9 Gy for FSRT and 111.6–137.2 Gy for SRS). However, they found no correlation between time interval of the RT courses and incidence of complications. There was an unusually high rate of necrosis of 6% when hyperfractionated RT was used with a conservative cumulative dose of 87.5 Gy, indicating that complete recovery probably does not occur within 6 h.[5]

Radiation tolerance of other critical structures, however, has not been documented in as much details and recommendations cannot be made based on these few small studies. Radiation-induced optic neuropathy was reported to occur in one every ten patients who received a cumulative NTD of 86 Gy.[6]

Studies on brainstem tolerance have been reported in patients of relapsed carcinoma nasopharynx, who received re-irradiation. Brainstem was found to tolerate a cumulative Dmax of 79 Gy, D0.1cc of 71 Gy, D0.5cc of 65 Gy, and D1.0cc of 60 Gy [Table 1].[7]
Table 1: Practical considerations

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  Concurrent Treatment Top


Higher incidence of necrosis was also reported with the use of hyperbaric oxygen in a study by Koshi et al., where patients received hyperbaric oxygen immediately followed by gamma knife radiosurgery. A relatively low median cumulative dose of 86 Gy was associated with an incidence of brain necrosis of 28%. This was suggested to be due to the radiosensitivity of the well-perfused surrounding normal tissue.[8] Concurrent weekly paclitaxel with fractionated SRS delivered once a week also showed high rates of necrosis of 10%.[9] Temozolomide used concurrently has not demonstrated additional late toxicity.[10] Bevacizumab in recurrent high-grade glioma used concurrently with RT (median dose 36 Gy) was found to be superior in terms of progression-free survival and overall survival in a retrospective series. Bevacizumab was also associated with lower incidence of radiation-related adverse events.[11]


  Role of Brachytherapy Top


Brachytherapy in various forms has been explored as an option for recurrent gliomas. Low-dose rate interstitial brachytherapy with I-125 permanent seeds (15 cGy/h, lifetime dose of 100–400 Gy), temporary implants (30–60 cGy/h, 4–6 days, and 50–65 Gy) gliaSite and high dose rate Ir-192 (15–60 Gy, 7–12 days) have been used in recurrent glioblastomas (GBMs) with varying success. Patients with good Karnofsky performance status and volume <30 cc were found to benefit more from these techniques. Median survival of 10.5–12 months has been reported. However, high rates of complications including radionecrosis, meningitis, and cerebrospinal fluid leak have been reported.[12]


  Target Volume Delineation Top


Consensus guidelines have been compiled by the American Society for Therapeutic Radiology and Oncology, with regard to volume delineation and dose prescription for re-irradiation of GBMs. Tumors <2 cm can be treated with single-fraction 24 Gy, 2–3 cm tumors with single-fraction 18 Gy, and larger tumors may be treated with FSRT at 5–6 Gy per fraction/day in 5 days. Target volume is defined as contrast-enhancing tumor on magnetic resonance imaging (MRI) + 5 mm. When conventional fractionation of 1.8–2 Gy/day is used, larger volumes may be treated safely.[13]


  Imaging Challenges Top


Post-RT relapses can be challenging to accurately delineate on an MRI. Areas of necrosis, gliosis, and nonspecific blood–brain barrier disturbances represent challenges in identifying the tumor accurately. Biological imaging with C11 methionine positron emission tomography aids in these diagnostic dilemmas and can be used for target delineation.[14]


  Quality of Life After Re-Irradiation Top


Very few studies of brain tumor re-irradiation have reported quality of life (QOL) data. A case series reported data in patients of Grade II glioma, who received concurrent temozolomide with re-irradiation. The trial applied The Functional Assessment of Cancer Therapy/National Cancer comprehensive network brain symptom index (FBrSI)-15 questionnaires to assess the QOL and showed significant improvement in scores 8 weeks after completion of treatment.[15] Other studies report indirect measures of QOL in the form of neurological function and steroid dependence. A review of over 300 patients of GBM who received re-irradiation showed that 24%–45% had improvement in neurological status, 20%–60% had reduction in steroid requirement, and most patients recorded stabilization of performance status until progression.[16],[17]


  Newer Radiotherapeutic Modalities Top


High linear energy transfer radiation-like proton therapy, boron neutron capture therapy, and intraoperative RT have been tried with varying results in the setting of recurrent GBMs.[18]


  Conclusion Top


The choice of technique and dose fractionation for re-irradiation depends on tumor characteristics (volume and location), previous RT dose and volume, and patient characteristics (age and performance status). For small-volume tumors in noneloquent areas, single-fraction SRS and brachytherapy may be good options. For small- and intermediate-volume tumors in eloquent areas, FSRT or hypofractionated RT may be used. For large-volume recurrences, requiring partial brain irradiation, conventional fractionation is safer and offers palliation with minimal risk of radiation-induced toxicities.[19]

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Belka C, Budach W, Kortmann RD, Bamberg M. Radiation induced CNS toxicity-Molecular and cellular mechanisms. Br J Cancer 2001;85:1233-9.  Back to cited text no. 1
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2.
van der Kogel AJ. Radiation-induced damage in the central nervous system: An interpretation of target cell responses. Br J Cancer Suppl 1986;7:207-17.  Back to cited text no. 2
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3.
Ang KK, Jiang GL, Feng Y, Stephens LC, Tucker SL, Price RE, et al. Extent and kinetics of recovery of occult spinal cord injury. Int J Radiat Oncol Biol Phys 2001;50:1013-20.  Back to cited text no. 3
    
4.
Nieder C, Grosu AL, Andratschke NH, Molls M. Proposal of human spinal cord reirradiation dose based on collection of data from 40 patients. Int J Radiat Oncol Biol Phys 2005;61:851-5.  Back to cited text no. 4
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5.
Mayer R, Sminia P. Reirradiation tolerance of the human brain. Int J Radiat Oncol Biol Phys 2008;70:1350-60.  Back to cited text no. 5
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6.
Mayo C, Martel MK, Marks LB, Flickinger J, Nam J, Kirkpatrick J, et al. Radiation dose-volume effects of optic nerves and chiasm. Int J Radiat Oncol Biol Phys 2010;76:S28-35.  Back to cited text no. 6
    
7.
Wang HZ, Luo JW, Yi JL, Huang XD, Zhang SP, Wang K, et al. The tolerance of brainstem in reirradiation with intensity modulated radiation therapy in recurrent nasopharyngeal carcinoma. Int J Radiat Oncol Biol physics 2016;96:E340.  Back to cited text no. 7
    
8.
Brady LW. Medical Radiology Radiation Oncology Series Editors. Radiation Oncology 2011. Available from: http://www.springerlink.com/index/10.1007/978-3-642-12468-6. [Last accessed on 2016 Aug 01].  Back to cited text no. 8
    
9.
Lederman G, Wronski M, Arbit E, Odaimi M, Wertheim S, Lombardi E, et al. Treatment of recurrent glioblastoma multiforme using fractionated stereotactic radiosurgery and concurrent paclitaxel. Am J Clin Oncol 2000;23:155-9.  Back to cited text no. 9
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10.
Minniti G, Scaringi C, De Sanctis V, Lanzetta G, Falco T, Di Stefano D, et al. Hypofractionated stereotactic radiotherapy and continuous low-dose temozolomide in patients with recurrent or progressive malignant gliomas. J Neurooncol 2013;111:187-94.  Back to cited text no. 10
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11.
Flieger M, Ganswindt U, Schwarz SB, Kreth FW, Tonn JC, la Fougère C, et al. Re-irradiation and bevacizumab in recurrent high-grade glioma: An effective treatment option. J Neurooncol 2014;117:337-45.  Back to cited text no. 11
    
12.
Combs SE, Debus J, Schulz-Ertner D. Radiotherapeutic alternatives for previously irradiated recurrent gliomas. BMC Cancer 2007;7:167. Available from: http://www.biomedcentral.com/1471-2407/7/167%5Cn; http://www.embase.com/search/results?subaction=viewrecord& from=export&id=L351165862%5Cn; http://www.dx.doi.org/10.1186/1471-2407-7-167%5Cn; http://www.sfx.library.uu.nl/utrecht?sid=EMBASE&issn=14712407&id=doi: 10.1186%2F. [Last accessed on 2016 Aug 01].  Back to cited text no. 12
    
13.
Cabrera AR, Kirkpatrick JP, Fiveash JB, Shih HA, Koay EJ, Lutz S, et al. Radiation therapy for glioblastoma: Executive summary of an american society for radiation oncology evidence-based clinical practice guideline. Pract Radiat Oncol 2016;6:217-25.  Back to cited text no. 13
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14.
Miwa K, Matsuo M, Ogawa S, Shinoda J, Yokoyama K, Yamada J, et al. Re-irradiation of recurrent glioblastoma multiforme using 11C-methionine PET/CT/MRI image fusion for hypofractionated stereotactic radiotherapy by intensity modulated radiation therapy. Radiat Oncol 2014;9:181.  Back to cited text no. 14
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15.
Osman MA. Temozolomide and reirradiation in recurrent grade II brain glioma. World J Oncol 2014;5:118-25. Available from: http://www.wjon.org/index.php/wjon/article/view/838. [Last accessed on 2016 Aug 01].  Back to cited text no. 15
    
16.
Nieder C, Astner ST, Mehta MP, Grosu AL, Molls M. Improvement, clinical course, and quality of life after palliative radiotherapy for recurrent glioblastoma. Am J Clin Oncol 2008;31:300-5. Available from: http://www.journals.lww.com/amjclinicaloncology/Fulltext/2008/06000/Improvement,_Clinical_Course,_and_Quality_of_Life. 16.aspx. [Last accessed on 2016 Aug 01].  Back to cited text no. 16
    
17.
Ryu S, Buatti JM, Morris A, Kalkanis SN, Ryken TC, Olson JJ, et al. The role of radiotherapy in the management of progressive glioblastoma: A systematic review and evidence-based clinical practice guideline. J Neurooncol 2014;118:489-99.  Back to cited text no. 17
    
18.
Miyatake S, Kawabata S, Hiramatsu R, Kuroiwa T, Suzuki M, Kondo N, et al. Boron neutron capture therapy for malignant brain tumors. Neurol Med Chir (Tokyo) 2016;56:361-71.  Back to cited text no. 18
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19.
Amichetti M, Amelio D. A review of the role of re-irradiation in recurrent high-grade glioma (HGG). Cancers (Basel) 2011;3:4061-89.  Back to cited text no. 19
[PUBMED]    



 
 
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  In this article
Abstract
Introduction
Radiobiology of ...
Re-Irradiation T...
Concurrent Treatment
Role of Brachyth...
Target Volume De...
Imaging Challenges
Quality of Life ...
Newer Radiothera...
Conclusion
References
Article Tables

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