Bevacizumab reverses cerebral radiation necrosis.

A 43-year-old Chinese woman, with a 6-month history of hearing loss, was diagnosed with biopsy-proven T3, N1, M0, stage III undifferentiated nasopharyngeal carcinoma. Her initial head magnetic resonance imaging (MRI) scan showed a mass in the nasopharynx (Fig 1A, asterisk) extending into the left sphenoid sinus (Fig 1B, arrow), and there was fluid accumulation in the left mastoid process. She received cisplatin and involved-field intensity-modulated radiotherapy (IMRT) to 70 Gy, followed by an additional three cycles of cisplatin and fluorouracil. Her inferior temporal lobes received up to 68.5 Gy of radiation (Fig 1C, red isodose line). Two years later, she experienced verbal memory loss, together with fatigue and mild imbalance. Her neurological examination was notable for psychomotor slowing and deficit in immediate recall. She also had a mini–mental status examination score of 26 (from a total of 30), suggesting moderate cognitive dysfunction. A gadolinium-enhanced head MRI, taken for evaluation of her neurocognitive deficits, showed enhancement in the inferior left temporal lobe with increased fluid-attenuated inversion recovery signals in the surrounding brain parenchyma (Figs 2A and 2B). She underwent [F]fluorodeoxyglucose (FDG)–positron emission tomography and thallium–single photon emission computed tomography, and revealed no uptake of either radionuclide in the corresponding region of gadolinium enhancement. The inferior left temporal lobe did not have increased blood flow, as measured by arterial spin labeling. Because the findings suggest radiation necrosis of the brain, she was treated with 5 mg/kg of bevacizumab every other week. After four doses, the enhancement on MRI was nearly gone (Fig 3A & 3B) and her mini–mental status examination score increased to 30. Her imbalance and fatigue disappeared. These neurocognitive improvements persisted at the time of follow-up 6 months later. Temporal lobe radiation necrosis was common before the adoption of IMRT for head and neck cancer. The spectrum of this disorder ranged from edema noted as hyperintense fluid-attenuated inversion recovery, T2 signals in the temporal lobes, and hemorrhagic transformation, to necrotic cysts causing mass effect. The development of cerebral radiation necrosis from fractionated radiotherapy is a function of total dose, dose per fraction, and time from completion of radiation. The higher the total dose or dose per fraction, the sooner cerebral radiation necrosis would appear in patients. The mechanism appears to be a result of radiation damage to vascular endothelial cells, causing endothelial cell proliferation, telangiectatic vessels, and fibrinoid necrosis with accompanying perivascular exudation and edema. In experimental settings, microhemorrhages was noted in the brains of rabbits when they were treated with proton stereotaxic radiosurgery. Similarly, in the gastrointestinal tract of mice treated with 15 Gy of whole-body irradiation, radiation-induced endothelial cell apoptosis was the primary mechanism leading to stem-cell dysfunction, crypts damage, and death. The secondary stem-cell dysfunction was probably a result of damage to the vascular niche where the stem cells reside. Although the kinetics of this damage is unknown in experimental animals, patients who received radiation at 62.5 Gy or more have greater than 25% probability of radiation necrosis within 5 years. Our patient received a dose of up to 68.5 Gy in the inferior temporal lobe, making her high risk for developing radiation necrosis despite the tight conformality of IMRT-limiting scattered radiation to the temporal lobes. The gadolinium-enhancing abnormality was not FDG or thallium avid, suggesting that it was unlikely to be tumor or infection. A diagnosis of cerebral radiation necrosis was also supported by more than 2 years of delayed development of her temporal abnormality. Conventional treatment consisted of corticosteroid to limit the extent of cerebral edema and, if necessary, drainage of compressive cysts. Unfortunately, due to the unrelenting process of necrosis, patients in the past typically succumbed to complications of