Intensity modulated radiotherapy (IMRT) and image-guided radiotherapy (IGRT) have improved radiotherapeutic sparing of healthy nontarget brain tissue, theoretically reducing CRN risk.6 However, brachytherapy is associated with up to a 50% risk of CRN, and CRN remains a significant dose-limiting toxicity for stereotactic radiotherapy (SRT).5,6

CRN is a diagnostic challenge because symptomatology can vary dramatically and radiographic imaging modalities do not always allow differentiation between it and recurrent brain metastases.4,5 Therefore, magnetic resonance imaging (MRI) has become a preferred imaging modality for detecting and characterizing CRN.6 Advanced MRI and positron-emission tomography (PET) brain tumor imaging protocols have been developed that can identify and differentiate brain tumor, necrosis, and edema.6 Diagnostic peripheral blood sample (“liquid biopsy”) tests that detect glioblastoma-shed tumor cells and expression of inflammatory molecules with which CRN might be detected, are also under development.6 Neuropsychiatric assessments should be undertaken when CRN is suspected.3

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Treatment

First-line palliative corticosteroid therapy can mitigate inflammatory cytokine pathways and reduce edema, although no clinical trials have been undertaken to validate this strategy.6 Pulsed corticosteroid therapy (eg, dexamethasone 4-16 mg/day in 1 or 2 fractions for 4 to 6 weeks with gradual tapering) reportedly can ameliorate CRN symptoms, but benefits tend to decline over time.6 Prolonged corticosteroid therapy can cause gastrointestinal bleeding and infectious complications like thrush or pneumonia.6 It can also compound CRN-associated neuropsychiatric symptoms because of steroid-induced psychosis.6

Corticosteroid-refractory CRN sometimes requires surgical resection of necrotic foci but edema must be monitored for several weeks after surgery.6 Surgical biopsy allows histopathological confirmation of CRN or recurrent tumor tissue.

Other investigational treatments employed for steroid-refractory CRN include anticoagulants, pentoxifylline, vitamin E, hyperbaric oxygen therapy, and laser interstitial thermal ablation, but no clinical trials have been completed for these strategies.6

In contrast, a nascent clinical trial evidence base is emerging for low-dose bevacizumab.6,7 Bevacizumab appears to slow CRN progression by disrupting vascular endothelial growth factor (VEGF) but patients should be monitored for hypertension, thrombosis, ischemia, and renal dysfunction.6 Preliminary findings from a small, recently reported phase 2 clinical study conducted at Stanford University in California and Peking University Third Hospital in China concluded that ultra-low-dose bevacizumab (1 mg/kg once every 3 weeks for 3 or more cycles) is an effective alternative to standard-dose bevacizumab therapy.7 The study enrolled only 21 CRN-symptomatic patients, all of whom had undergone SRT between December 2016 and February 2019; all but one had cerebral edema, which improved for 19 patients (95%) with ultra-low-dose bevacizumab.7 MRI CRN image intensity also declined significantly (P =.001).7 No grade 3 or higher adverse events were reported for this regimen.7

Additional, larger studies with longer follow-up are needed to validate those hopeful but preliminary findings, the authors emphasized.7

References

1. Giglio P, Gilbert MR. Cerebral radiation necrosis. Neurologist. 2003;9(4):180-188.

2. Gil-Salu JL. Comments on the review article “Cerebral radiation necrosis: diagnostic challenge and clinical management” [English edition]. Neurologia. 2018;33(4):275-276.

3. Holmes EG, Holmes JA, Park EM. Psychiatric care of the radiation oncology patient. Psychosomatics. 2017;58(5):457-465.

4. Rahmathulla G, Marko NF, Weil RJ. Cerebral radiation necrosis: a review of the pathobiology, diagnosis and management considerations. J Clin Neurosci. 2013;20(4):485-502.

5. Loganadane G, Dherman F, Louvel G, et al. Brain radiation necrosis: current management with a focus on non-small cell lung cancer patients. Front Oncol. 2018;8:336.

6. Ali FS, Arevalo O, Zorofchian S, et al. Cerebral radiation necrosis: incidence, pathogenesis, diagnostic challenges, and future opportunities. Curr Oncol Rep. 2019;21(8):66.

7. Zhuang H, Zhuang H, Shi S, Wang Y. Ultra-low-dose bevacizumab for cerebral radiation necrosis: a prospective phase II clinical study. Onco Targets Ther. 2019;12:8447-8453.