- © 2010 by American Society of Clinical Oncology
Successful Treatment of Radiation-Induced Temporal Lobe Necrosis With Mouse Nerve Growth Factor
A 51-year-old Chinese woman was diagnosed with undifferentiated nasopharyngeal carcinoma (NPC) confirmed with biopsy. Computed tomography and magnetic resonance imaging (MRI) showed that the primary tumor extended to the clivus, the right foramen lacerum, and the apex of the petrous temporal bone (arrow in Figs 1A and 1B). Her clinical stage was T3N1M0 stage III on the basis of the American Joint Committee on Cancer (AJCC) 2002 staging system. She was treated with concurrent cisplatin and conventional radiation therapy to 70 Gy, with a boost of 4 Gy to the involved skull base, and then followed by an additional three cycles of cisplatin and fluorouracil on the basis of data from the Intergroup 0099 trial1 at Cancer Hospital, Fudan University, Shanghai, China. Three years later, she complained of memory loss, mild imbalance, and fatigue. Neurologic examination showed that there was a notable psychomotor slowing and a deficit in immediate recall. The Folstein and Folstein Mini-Mental State Examination was administered and suggested that the patient had moderate cognitive dysfunction with a score of 25. MRI was performed to evaluate her neurocognitive deficits; gadolinium-enhanced T1-weighted images with fat suppression showed enhancement in the bilateral inferior temporal lobes (Figs 2A and 2B). She also underwent [18F]fluorodeoxyglucose –positron emission tomography, and no uptake of [18F]fluorodeoxyglucose was found at the corresponding region of gadolinium enhancement. The MRI findings showed a typical Swiss cheese pattern, suggesting radiation-induced brain necrosis.2 Examination of the isodose distribution in the planes in which the radiologic abnormalities were observed indicated that the temporal lobe lesions received approximately 70.3 Gy (areas surrounded by the pink isodose line in Figs 1C and 1D). She was treated with the mouse nerve growth factor (mNGF; Enjingfu, Xiamen Beida Road Bioengineering, Xiamen, Fujian Province, China). mNGF was dissolved in 2 mL normal saline and then injected intramuscularly at 18 μg/time, once a day3–5 for 2 months. Her symptoms of fatigue and imbalance disappeared 3 months later and her Folstein and Folstein Mini-Mental State Examination score increased to 30. The Swiss-cheese appearance in the bilateral temporal lobes on MRI completely disappeared (Figs 2C and 2D). These neurocognitive improvements persisted at the time of follow-up 9 months later.
Late temporal lobe necrosis is a severe complication of radiation treatment of NPC and may have a tremendous negative impact on a patient's quality of life. Before the application of intensity-modulated radiation therapy for NPC, cerebral necrosis was common. Long-term follow-up studies showed that the incidence of late temporal necrosis varied from 1.6% to 22% at intervals of 9 months to 16 years after treatment.6,7 The development of temporal lobe necrosis is a function of dose per fraction, total dose, and time after completion of radiation.8 The higher the dose per fraction or total dose, the sooner cerebral radiation necrosis appears. Typical findings of cerebral necrosis on MRI are areas of finger-like or cystic lesions of increased signal intensity in the white matter on T2-weighted fluid-attenuated inversion recovery images, which frequently extend beyond the radiation portals. Rim, nodular, or heterogeneous enhancement might be seen after intravenous administration of gadolinium-diethylenetriamine pentaacetic acid.9
Although cerebral necrosis after radiation is common, the natural course remains poorly understood. It was hypothesized that four factors may finally contribute to the development of radiation-induced CNS toxicity: (1) neural stem-cell damage, (2) oligodendrocyte damage, (3) vessel damage, and (4) alterations of cytokine expression.10
Cerebral necrosis is generally regarded as a progressive and irreversible complication of radiation therapy.11 Treatment of radiation-induced cerebral necrosis has typically been management of symptoms. A common practice is the use of corticosteroids to control edema. However, long-term use of corticosteroids is problematic because of myriad debilitating chronic adverse effects. Antiplatelet agents, anticoagulants, hyperbaric oxygen, high-dose vitamins, and surgery have also been tried as treatments for this condition.12–15 To date, none of these approaches has proved effective in reversing cerebral radiation necrosis, and no patients have been reported to have complete resolution of both symptoms and MRI abnormality. Recently, experience with bevacizumab therapy for radiation necrosis has been reported in four pediatric pontine gliomas; three patients had significant clinical improvement and were able to discontinue steroid use. One patient continued to decline.16 One case report stated that after the use of bevacizumab as a treatment for brain necrosis, the enhancement on MRI was nearly gone,17 which indicated that the process of cerebral radiation necrosis might be reversed. None of the above-mentioned modalities was used in this patient. The fact that the patient achieved complete resolution of both symptoms and MRI enhancement after the use of mNGF suggested the role of mNGF.
Nerve growth factor (NGF) is one of the most important bioactive molecules that act as a neurotrophic factor. NGF has a significant protective effect on both peripheral and central nervous systems, prevents the apoptosis and degeneration of neurons, and promotes the functional recovery and regeneration of injured neurons.18 In our patient, after a continuous injection of mNGF for 2 months, the necrotic disease in bilateral temporal lobes completely disappeared. To our knowledge, this is the first case that demonstrates a potential therapeutic benefit from NGF therapy in cerebral radiation necrosis. The result is promising. However, it is hard to make definitive treatment recommendations for cerebral radiation necrosis following this case only. We are planning a phase II trial to study the safety and efficacy of mNGF in cerebral radiation necrosis.
AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
The author(s) indicated no potential conflicts of interest.
