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Table of Contents
Year : 2020  |  Volume : 3  |  Issue : 2  |  Page : 413-414

Brain radionecrosis in the present multiagent systemic therapy era: Time to redefine brain radiotherapy tolerance?

Department of Radiation Oncology, Manipal Hospital, New Delhi, India

Date of Submission04-Mar-2020
Date of Decision05-Mar-2020
Date of Acceptance05-Mar-2020
Date of Web Publication19-Jun-2020

Correspondence Address:
Anusheel Munshi
Department of Radiation Oncology, Manipal Hospital, Dwarka, New Delhi - 110 075
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/CRST.CRST_63_20

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How to cite this article:
Munshi A. Brain radionecrosis in the present multiagent systemic therapy era: Time to redefine brain radiotherapy tolerance?. Cancer Res Stat Treat 2020;3:413-4

How to cite this URL:
Munshi A. Brain radionecrosis in the present multiagent systemic therapy era: Time to redefine brain radiotherapy tolerance?. Cancer Res Stat Treat [serial online] 2020 [cited 2021 Apr 19];3:413-4. Available from: https://www.crstonline.com/text.asp?2020/3/2/413/287255

In the previous issue of the Journal, Madala et al. presented a case of epidermal growth factor receptor (EGFR)-positive cT2N3M1a lung adenocarcinoma who was initially managed with a combination of anti-EGFR therapy and chemotherapy, developed a solitary brain metastasis, and received whole-brain radiotherapy for the same.[1] This was followed by maintenance pemetrexed/gefitinib. After 9 months, the patient was diagnosed with radionecrosis (RN) at the erstwhile site of brain metastasis. The authors have discussed the critical factors related to RN following radiotherapy to the brain, most of these being well known to the scientific world.[2]

When faced with a larger metastatic brain lesion, radiation oncologists face two broad options, in the context of stereotactic radiosurgery (SRS): (1) delivering the entire dose in a single fraction, compromising on the overall dose, and (2) fractionating the SRS dose in 3–5 fractions. In the context of SRS, a retrospective analysis strongly suggests a lower rate of RN with the use of 3-fraction SRS as compared to single-fraction SRS while treating larger lesions.[3] In the same context, two prospective randomized trials are addressing: (1) using single fraction versus 3–5 fractions after surgery in brain metastasis comparison of preoperative versus postoperative SRS (ALLIANCE Cooperative Group Phase III RCT NCT0411981); (2) preoperative versus postoperative SRS (Phase III RCT NCT 03741673). The hypothesis of the latter is the likelihood of irradiating a smaller volume in the preoperative setting (when the lesion is well defined) as compared to the postoperative cavity, which is generally larger in size. A smaller volume intuitively could also result in a lower risk of RN.

What was a bit odd in the present case was the development of RN after a relatively mild dose (whole brain) fractionation of 20 Gy in 5 fractions. Interestingly, while uniform radiotherapy was given to the entire brain, RN developed only in the lesion area. While not unknown, this differs from stereotactic radiotherapy where necrosis is found in the area of dose deposition. Is the brain metastasis site more prone to RN than the normal parenchyma? Further, does the development of RN with a moderate dose of radiotherapy have prognostic implication? (akin to prognostic implication of pseudoprogression). These are critical questions with no clear answers as of now.

However, this case also brings into question the role of other systemic agents and their influence of the development of RN in irradiated patients.[4] Systemic therapy agents have long been known to have radiosensitizing properties, and this has led to the concept of using concurrent radiochemotherapy for several cancer sites. However, in the context of the central nervous system, these agents have also been contributors in augmenting the rate and the risk of RN. In a study of 180 patients, authors observed higher rates of RN in patients who received both SRS and immunotherapy or targeted therapies compared to those who had SRS alone or with concurrent cytotoxic chemotherapy.[5] Another study comparing the rates of RN in melanoma patients who underwent SRS alone with those who were treated with cytotoxic T-lymphocyte-associated protein 4 blockade and programmed death-1 inhibition showed an increase in the occurrence of RN in those who received these systemic therapy agents.[6],[7]

Does the type of equipment used for the delivery of radiotherapy have a bearing on the development of RN? The Gadget Phase III Randomized Trial presented in ASTRO 2018 compared SRS patients treated with linear accelerator versus those with Gamma Knife. There was no difference in local control, disease-free survival, overall survival, or rate of RN in either arm. In multivariate analysis, the volume of brain metastasis was the only factor impacting on RN occurrence (P < 0.03).[8]

The key message for the radiation oncologists, in the era of multiple systemic therapy agents, would be to remain ever more cognizant of the risk of RN. A wake-up call to the radiobiologists needs to be done to redefine the tolerance of brain in such situations and probably remark the dose effect threshold for onset of RN.

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Conflicts of interest

There are no conflicts of interest.

  References Top

Madala RK, Krishnatry R, Noronha V, et al. Neurological deterioration in a patient with lung cancer and brain metastasis. Cancer Res Stat Treat 2020;3:97-9.  Back to cited text no. 1
  [Full text]  
Winter SF, Loebel F, Loeffler J, Batchelor TT, Martinez-Lage M, Vajkoczy P, et al. Treatment-induced brain tissue necrosis: A clinical challenge in neuro-oncology. Neuro Oncol 2019. pii: Noz048.  Back to cited text no. 2
Minniti G, Scaringi C, Paolini S, Lanzetta G, Romano A, Cicone F, et al. Single-fraction versus multifraction (3 × 9 Gy) stereotactic radiosurgery for large (>2cm) brain metastases: A comparative analysis of local control and risk of radiation-induced brain necrosis. Int J Radiat Oncol Biol Phys 2016;95:1142-8.  Back to cited text no. 3
Furuse M, Nonoguchi N, Yamada K, Shiga T, Combes JD, Ikeda N, et al. Radiological diagnosis of brain radiation necrosis after cranial irradiation for brain tumor: A systematic review. Radiat Oncol 2019;14:28.  Back to cited text no. 4
Colaco RJ, Martin P, Kluger HM, Yu JB, Chiang VL. Does immunotherapy increase the rate of radiation necrosis after radiosurgical treatment of brain metastases? J Neurosurg 2016;125:17-23.  Back to cited text no. 5
Fang P, Jiang W, Allen P, Glitza I, Guha N, Hwu P, et al. Radiation necrosis with stereotactic radiosurgery combined with CTLA-4 blockade and PD-1 inhibition for treatment of intracranial disease in metastatic melanoma. J Neurooncol 2017;133:595-602.  Back to cited text no. 6
Song YP, Colaco RJ. Radiation necrosis – A growing problem in a case of brain metastases following whole brain radiotherapy and stereotactic radiosurgery. Cureus 2018;10:e2037.  Back to cited text no. 7
Navarria P, Clerici E, Carta G, Attuati L, Picozzi P, Franzese C. Randomized Phase III Trial Comparing Gamma Knife and Linac Based (EDGE) Approaches for Brain Metastases Radiosurgery: Results from the Gadget Trial. Abs 295. Int. J. Radiat. Oncol. 2018.  Back to cited text no. 8

This article has been cited by
1 Authorsę reply to Gaikwad et al., Munshi, and Pandey et al.
Rahul Krishnatry,RaviKrishna Madala
Cancer Research, Statistics, and Treatment. 2020; 3(2): 417
[Pubmed] | [DOI]


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