Soft-tissue radionecrosis of the brain generally occurs in the area of the brain where the tumor was radiated. The resulting brain tissue necrosis can occur as early as 6 months after the radiation treatment. The brain tissue necrosis is a delayed effect of the radiation therapy and can occur several years after the radiation treatment, but it usually occurs within the first 1 to 2 years.
The risk of developing delayed effects of radiation therapy with resulting brain tissue necrosis is dependent upon many factors including the dose of radiation given, the form of the radiation, the area and amount of brain tissue irradiated, genetic host factors, and use of chemotherapy or radiation sensitizing medications. Radiation necrosis is usually confined to the area where the tumor originally occurred in the brain but can also involve any structure in the brain that was in the original field of radiation therapy. Whole brain radiation places the patient at higher risk than if only a small section of the brain was included in the radiation field. The majority of patients who receive radiation therapy do not develop radiation necrosis, but a significant number of patients may develop this serious complication, and in various studies, the range of risk can be as small as 5% to as high as about 37% of the patients.
Radiation therapy induced syndromes are time-dependent and can be divided into acute encephalopathy which occurs within 1 month after therapy and early delayed complications which occur between 1 to 4 months after therapy. The acute phase results in cerebral edema; damage to DNA; damage to vascular structures, especially the smaller arterioles; and damage to progenitor cells, especially oligodendrocytes which leads to demyelination. Endothelial cells are especially prone to damage from radiation therapy. The acute vasogenic edema that develops from radiation therapy is a reversible problem. Also, early delayed damage can be due to neural progenitor cells in the temporal lobe which may be the mechanism that leads to memory problems. The cerebral edema in some of the patients may cause problems with somnolence, headaches, and seizures. Many of these acute and early delayed effects of radiation therapy can reverse on their own or with steroid therapy, but the more delayed effects of radiation therapy, which occur after 6 months, can lead to radiation necrosis which is irreversible and very difficult to treat.
Pathologically, radiation necrosis primarily affects the smaller arterioles and arteries which initially causes a coagulative necrosis and then endothelial thickening and infiltration of lymphocytes and macrophages. The inflammation that develops from the infiltration of these immune cells triggers off a whole host of cytokine activity, activation of fibroblasts, and hyalinization of the tissue. Immune-mediated mechanisms that contribute to neurotoxicity have been hypothesized but have not been fully explained.
The vascular injury stimulates the formation of new microvessels mediated in part through vascular epidermal growth factor (VEGF), a key player in this mechanism. The disorganized vascular growth can lead to telangiectasia formations which are prone to bleeding and thrombotic events which can lead to further tissue necrosis. Recent studies using bevacizumab and MRI imaging showed decreased vascular permeability, but, although promising, the efficacy and longer term risk versus the benefit of this therapy remains to be determined.
The symptoms of radiation necrosis are varied depending upon the area of the brain involved, but common symptoms include headache, drowsiness, memory loss (especially if the temporal lobe is involved), personality changes, and seizures. Whole brain radiation therapy, as is commonly done for treating lymphoma, can result in a diffuse encephalopathy.
The problem with diagnosing radiation necrosis of the brain is that it is difficult to distinguish tumor recurrence versus radiation necrosis. This distinction is especially difficult with glioblastoma multiforme which often may have a palisading pattern of necrosis. Brain MRI perfusion scanning can be helpful in differentiating because in radiation necrosis there is often a lack of T2 flair usually involving the white matter but is commonly present with tumors. MR spectroscopy typically shows low choline and creatine and NAA in radiation necrosis. FDG-PET scanning typically shows lower activity in radiation necrosis, while recurrent tumors typically have increased metabolic activity. Conventional imaging can be misleading and ultimately surgical biopsy may be necessary to distinguish whether the lesion is from radiation necrosis or recurrence of the cancer or secondary primary.
The approach to the treatment of patients with radiation necrosis should be divided into patients who are asymptomatic and symptomatic. In the asymptomatic patients, it would be reasonable to do serial MRI scans to follow the area of suspected necrosis and see if it further evolves or consider the possibility of tumor recurrence. Lesion biopsy ultimately may be necessary to determine whether it is radiation necrosis versus tumor recurrence, especially if the lesion continues to grow. It is very important to establish the diagnosis of radiation necrosis versus tumor recurrence so that the appropriate therapy may be rendered to the patient. If the patient is having neurologic symptoms or increased intracranial pressure, then surgical options, steroids, anticoagulation therapy, and even hyperbaric oxygen therapy will need to be considered. A novel treatment for radiation necrosis using bevacizumab has been studied with just class one evidence available for its efficacy but is not yet considered standard therapy.
Hyperbaric oxygen therapy (HBO2) has no double-blind placebo-controlled trials to prove its efficacy, but many case studies and prospective studies demonstrate some benefit. HBO2 promotes tissue healing by improved angiogenesis that results in better tissue perfusion. Hyperbaric oxygen therapy also can reduce tissue edema and enhance collagen synthesis by fibroblasts which activity is crucial for the healing of damaged tissue. Radiation necrosis is in part caused by a coagulative and ischemic process which leads to cellular death; this is, in essence, an ischemia-reperfusion injury phenomenon. HBO2 helps to restore normal cellular functions to aid the repair of the ischemic damaged tissue. It is important to note that the angiogenesis that occurs with hyperbaric oxygen therapy produces a vascular supply to the radiation damage tissue that is more robust than the telangiectasia that sometimes occurs as a part of the radiation necrosis.
HBO2 usually is delivered at a dose of 2 to 2.4 atmospheres absolute for 90 to 120 minutes daily and may take 20 to 30 treatments before significant angiogenesis occurs with the improvement of the neurologic symptoms. The major disadvantage of hyperbaric oxygen therapy is that it is expensive, time-consuming, and universally not readily available, although this later problem is becoming less of a concern as more facilities are built. More studies on the use of hyperbaric oxygen therapy alone and in conjunction with other therapies, such as concomitant steroid and surgery, are needed to determine the best treatment practices. An interesting study using bevacizumab (which inhibits VEGF) and HBO2 (which enhances VEGF) in combination would be interesting to do. This would be helpful to elucidate some of the other mechanisms by which the HBO2 is working.
HBO2 does have undesirable side effects which include enhancement of cataracts; ear barotrauma; pneumothorax formation with pressure changes during the treatment, which can become life-threatening; hypoglycemia in diabetic patients, especially if taking insulin and/or oral hypoglycemic agents; and oxygen associated seizures. Because the patient is being treated in an environment with 100% oxygen under pressure, there is always the risk of fire and failure of the chamber. The risk of the hyperbaric oxygen treatment is relatively low, and the benefit of the therapy generally outweighs the risk. It is important that safety precautions are followed and strongly recommended that the facility considered for treatment have appropriate certification.