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Table of Contents    
LETTER TO EDITOR
Year : 2021  |  Volume : 69  |  Issue : 4  |  Page : 1055-1057

Noncontiguous Radiation-Induced Brain Necrosis (RIBN) in a Patient with Aggressive Pituitary Adenoma and the Utility of Bevacizumab


1 Department of Radiotherapy, Graduate Institute of Medical Education and Research, Chandigarh, India
2 Department of Endocrinology, Graduate Institute of Medical Education and Research, Chandigarh, India
3 Department of Indian Council of Medical Research, Graduate Institute of Medical Education and Research, Chandigarh, India
4 Department of Radiology, Graduate Institute of Medical Education and Research, Chandigarh, India
5 Department of Neurosurgery, Graduate Institute of Medical Education and Research, Chandigarh, India

Date of Submission27-Oct-2017
Date of Decision08-Aug-2019
Date of Acceptance09-May-2020
Date of Web Publication2-Sep-2021

Correspondence Address:
Pinaki Dutta
Department of Endocrinology, Post Graduate Institute of Medical Education and Research, Chandigarh - 160 012
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0028-3886.325385

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How to cite this article:
Kumar N, Rai A, Dutta P, Gupta P, Singh P, Mukherjee KK, Dhandapani S. Noncontiguous Radiation-Induced Brain Necrosis (RIBN) in a Patient with Aggressive Pituitary Adenoma and the Utility of Bevacizumab. Neurol India 2021;69:1055-7

How to cite this URL:
Kumar N, Rai A, Dutta P, Gupta P, Singh P, Mukherjee KK, Dhandapani S. Noncontiguous Radiation-Induced Brain Necrosis (RIBN) in a Patient with Aggressive Pituitary Adenoma and the Utility of Bevacizumab. Neurol India [serial online] 2021 [cited 2021 Nov 30];69:1055-7. Available from: https://www.neurologyindia.com/text.asp?2021/69/4/1055/325385




Sir,

Therapeutic stimulation of angiogenesis is of help in patients with ischemic heart disease, peripheral vascular heart disease, and wound healing.[1] On the contrary, inhibition of angiogenesis is found to be beneficial in various experimental cancer models, such as colon, breast, and kidney as well as in proliferative diabetic retinopathy and senile macular degeneration.[2],[3],[4] More recently, angiogenesis inhibition has also been applied for the management of radiation-induced brain necrosis (RIBN), retinopathy, and optic neuropathy.[5],[6],[7],[8] In this brief communication, we describe the beneficial response to the monoclonal anti-vascular endothelial growth factor (VEGF) antibody for RIBN in a case of aggressive pituitary adenoma who underwent intensity-modulated radiation therapy (IMRT).

A 65-year-old man presented with a history of the headache of 6 months' duration with bitemporal hemianopia. Contrast-enhanced magnetic resonance imaging (MRI) revealed a 3-cm sellar–suprasellar lesion suggestive of pituitary adenoma. There was no hypersecretion in endocrinological investigations. The patient underwent transsphenoidal excision of the tumor. The remnant after surgery showed significant regrowth over four months with an increasing headache. He received IMRT. One year later he presented with a 4-day history of decreased vision in both eyes, weakness in the right upper and lower limbs, and altered sensorium. Biochemical evaluation revealed hyponatremia, hypothyroidism, and hypocortisolemia. MRI showed a residual tumor with noncontiguous left hemispheric edema [Figure 1]a and [Figure 1]b. This was unresponsive to steroids for three weeks. Bevacizumab treatment (10 mg/kg 2 weekly) was started 12 weeks later due to delay in consent to treatment. There was a marked improvement in sensorium, right limb movements, and vision after two cycles with radiological improvement as well [Figure 1 c and d]. He developed right lower limb deep vein thrombosis after the fourth cycle due to prolonged immobilization. It was managed with subcutaneous low molecular weight heparin followed by oral warfarin. The relatives discontinued therapy after four cycles as the patient improved significantly. Two months later he was readmitted with a chest infection, septicemia, and later succumbed to his illness.
Figure 1: T2 flair and post contrast T1 images (a and b) show a large enhancing area of radio-necrosis. Corresponding follow-up images (c and d) after avastin show marked reduction in enhancement and signal changes (a). T2 flair and post contrast T1 images (a and b) show a large enhancing area of radio-necrosis. Corresponding follow-up images (c and d) after avastin show marked reduction in enhancement and signal changes (b). T2 flair and post contrast T1 images (a and b) show a large enhancing area of radio-necrosis. Corresponding follow-up images (c and d) after avastin show marked reduction in enhancement and signal changes (c). T2 flair and post contrast T1 images (a and b) show a large enhancing area of radio-necrosis. Corresponding follow-up images (c and d) after avastin show marked reduction in enhancement and signal changes (d)

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Patients with sellar–suprasellar lesions often face the burden and morbidity of recurrence, necessitating radiation or gamma knife therapy.[9],[10],[11],[12] Radiation-induced optic nerve injury (RION) and RIBN are devastating side-effects of radiation.[8] RIBN can develop in 3%–20% of the patients with a wide range of timescale (3 months to 10 years after radiotherapy). The disease is dependent on location and dose (25% of the patients develop RIBN if the dose exceeds 62.5 Gy). Early-delayed type of RIBN, presenting 1–6 months after radiation therapy, usually regresses spontaneously. The late-delayed type (onset after 6 months to 3 years, median 11.6 months) is associated with vascular abnormalities, demyelination, and necrosis. In a randomized control trial using bevacizumab, RIBN was more common in patients who receive concomitant chemotherapy.[13],[14]

Our case report shows bevacizumab to be an efficacious novel option for the management of RIBN in recurrent pituitary adenoma. VEGFs induce endothelial cell proliferation, cell survival, chemotaxis, increases vascular permeability, and cause neoangiogenesis. Targeting VEGF can be through using neutralizing antibodies for the ligand VEGF itself, targeting its receptor or inhibiting its activation and signaling through blockade of downstream pathways. Bevacizumab is a recombinant humanized anti-VEGF monoclonal antibody. It competes with VEGF for binding to capillary endothelial cells.[14],[15]

Bevacizumab by blocking VEGF from reaching its capillary targets reduces the movement of plasma through leaky capillary endothelium to extracellular space.[16],[17] Bevacizumab by reducing the vascular permeability of inflammatory cells and radiation-associated vasogenic edema has a potential key role in radiation-associated optic neuropathy and RIBN.[8]

Intervention with anti-VEGF antibody resulted in neuro-cognitive and radiological improvements in experimental animal models, case reports, and a single randomized clinical trial. [5, 14, 15, 18, 19] Diffusion tensor MRI, which measures the diffusion of water in three-dimensional space, is the best modality to differentiate demyelination from axonal injury.[14],[15] However, these mechanisms are conjectural only, as there is no correlation with time-course, and MRI observations and histopathological evidence from human biopsy or autopsy. The improvement usually happens after four courses of therapy.[5] Though Bevacizumab has been used for the management of RIBN, larger studies are needed to confirm its efficacy.[5],[15],[20],[21]

Bevacizumab treatment is not free from adverse events, which include hypotension, hemorrhagic, thrombotic, and embolic vascular events. Cerebellar ischemia, gastrointestinal perforation, and impaired wound healing are also known complications.[20],[21] Our case developed deep vein thrombosis after the second dose of Bevacizumab. We postulate that it may have been precipitated by the drug in the immobile paralytic lower limb and VEGF induced reduction in immunity.[22] Therefore, one of the studies had suggested routine low dose anticoagulant therapy in patients receiving anti-VEGF therapy.

Though the conventional medical treatment for RIBN includes glucocorticoids, vitamin E, pentoxyphylline, and hyperbaric oxygen, around 20% of them refractory to all these measures, may benefit from bevacizumab.[20],[21] To conclude, anti-VEGF therapy may be beneficial in the management of patients with RIBN which is refractory to steroids. The current findings may open a new vista in the management of aggressive residual/recurrent suprasellar tumors undergoing some form of radiation therapy.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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Nonoguchi N, Miyatake S, Fukumoto M, Furuse M, Hiramatsu R, Kawabata S, et al. The distribution of vascular endothelial growth factor-producing cells in clinical radiation necrosis of the brain: Pathological consideration of their potential roles. J Neurooncol 2011;105:423-31.  Back to cited text no. 6
    
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Dashti SR, Spalding A, Kadner RJ, Yao T, Kumar A, Sun DA, et al. Targeted intraarterial anti-VEGF therapy for medically refractory radiation necrosis in the brain. J Neurosurg Pediatr 2015;15:20-5.  Back to cited text no. 7
    
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Dutta P, Dhandapani S, Kumar N, Gupta P, Ahuja C, Mukherjee KK. Bevacizumab for radiation associated visual decline among aggressive residual/recurrent suprasellar tumors: More than a mere anti-neoplastic effect. World Neurosurg 2017;107:1044.e5--10.  Back to cited text no. 8
    
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Gupta P, Rai A, Mukherjee KK, Sachdeva N, Radotra BD, Punia RP, et al. Imatinib inhibits GH secretion from somatotropinomas. Frontiers in endocrinology 2018;9:453.  Back to cited text no. 12
    
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Tebbutt NC, Murphy F, Zannino D, Wilson K, Cummins MM, Abdi E, et al. Risk of arterial thromboembolic events in patients with advanced colorectal cancer receiving bevacizumab. Ann Oncol 2011;22:1834-8.  Back to cited text no. 21
    
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