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TREATMENT OF BRAIN TUMORS AND AVMS In the United States, approximately 35,000 new intracranial tumor cases are diagnosed each year—15,000 are primary brain tumors, the remainder metastasize from tumors in other locations. Many of the brain tumors diagnosed each year are treated with radiation therapy to destroy or shrink the tumor. (Radiation is also used to eliminate arteriovenous malformations (AVMs), defective blood vessel formations.)
Radiation therapy may be a critical component of intracranial tumor management.
While it is invaluable in treating malignancies, the potential for long term side effects raises questions
for benign (non-cancerous) tumors, with the incidence of visual, pituitary and brain tissue damage as high
as 38%. For malignant tumors, new or continuing symptoms may be the result of the original tumor spreading
(metastasis), radiation damage, or the development of new cancer. Chemotherapy seems to aggravate the
deleterious effects of radiation.
Radiation treatment of large brain areas can result in memory loss, impaired thinking ability (cognition), reduced sexual desire, hormonal changes, personality disturbance, sleep disruption, poor cold tolerance, nausea, unsteadiness, and visual changes. Half of these patients will show brain shrinkage or increase in the non-tissue (ventricle) space. Radiation necrosis, an area of dead cells within the radiation site in the brain, may occur months or years after radiation. The actual damage can be very focused (focal necrosis), or throughout the white matter of the brain. Demyelination (the stripping away of the protective nerve covering), reactive gliosis (brain-specific inflammatory reactions), and coagulation necrosis (the clumping of body proteins into an inert, non-functioning mass) are observed responses. Both chromosomal cell damage (probably the cause of new cancers) and blood vessel damage (leading to tissue death and atrophy) may result from treatment. Less predictable is the deterioration that occurs over time, affecting not just localized brain tissue, but the death of a larger area than originally treated. Treatment-caused lesions increase from 3 to 23 months after radiation has ended—the lesions may regress, but then re-occur. Often the radiation-damaged brain shrinks in size. One theory for the continuing damage notes its similarity to the brain death cascade seen in stroke victims, where the death of cells in the brain triggers the death of adjacent cells. Radiation treatment of the brain inflames and damages the protective blood-brain barrier, allowing more fluid into the brain than is normal. The imbalance and presence of the fluid triggers more swelling in the enclosed skull space, building pressure. With increased pressure, blood flow is restricted, starving the portion of the brain served by the restricted blood vessels of oxygen. Without adequate oxygen, that portion of the brain begins to die. Most commonly, brain radionecrosis is attributed to damage within the cells lining blood vessels. Arteries narrow and become blocked—the lining thickens, loses elasticity, atrophies, and dies. The result is increased swelling and pressure, the obliteration of blood vessels, and blood supply interruption. This post-treatment blood vessel shrinking and scarring has been observed, and by itself would account for symptoms—it is the most devastating side effect of radiation therapy. Whole brain irradiation is not a preferred treatment for patients with a single brain metastasis, because its side effects—neurological deterioration and dementia—are devastating, particularly in patients over age 60, where it affects up to 90% of radiation-treated patients. Journal of the American Medical Association researchers reported that patients receiving whole brain radiation do not remain functionally independent longer, nor do they live longer than those that have surgery alone. Cognition and hormone production abnormalities can be debilitating, potentially life threatening, and an increasingly frequent problem in brain tumor patients. These symptoms can be from progression of cancer or caused by the side effects of whole brain radiation. When permanent Iodine-125 seeds are implanted, up to 50% of patients suffer delayed radiation damage and radiation necrosis. Rapid tumor shrinkage can result in a greater amount of non-tumor tissue being exposed to radiation. In current clinical practice, focused radiation (Radiotherapy), which extends only 2-3cm beyond the periphery of the tumor site, begins immediately after surgical incision healing. Radiosurgery techniques, including Stereotatic, Gamma-Knife, Brachyradiation, and IMRT, access most areas of the brain and because of their precision, are quite suitable for treatment of metastases. Precisely targeted radiation (stereotactic therapy), supported by constantly updated CT scans, enables physicians to deliver high-dose, non-invasive, relatively well-tolerated irradiation. Boron neutron capture therapy may also be effective, but only when conventional radiotherapy has not already been used.
Radiation of structures outside the brain may result in brain exposure. Treatment
of cancers of the facial skin, nose, mouth, ears, and eyes may lead to late-onset brain effects and dementia.
SYMPTOMS OF RADIATION-INDUCED BRAIN NECROSIS There is extreme difficulty in determining whether a patient’s symptoms are the result of tumor recurrence, metastasis (spreading outside of the original site), or radiation necrosis. Identifiable radiation-induced necrosis occurs in 20% to 25% of patients treated for cancerous brain tumors. For large volume tumors or whole brain radiation, 40% of patients, and for localized irradiation, 3% to 9% of patients, may suffer such necrosis, seen 3 months to years after completion of treatment. Significant neurological damage can result even when treatment is not extensive. The extent of brain radionecrosis symptoms depends on the location of the brain which required radiation, the size of the treatment area, the total radiation dose the person was exposed to, the period of time over which treatment was administered, whether the treatment was concurrent with other treatments (e.g., chemotherapy), and individual response to therapy. The most affected areas of the brain are in the white matter. The individual response component is probably the contributing factor to the difficulty of predetermining optimal treatment.
Long-term radiation damage is most common in children less than 2 years of age and adults over 50. Treatment-induced destruction of the myelin sheath, cancer of the central nervous lymph system, compromise of the blood-brain barrier, and chemotherapeutic damage of the blood vessels may be seen in more than 90% of combination chemotherapy and whole-brain radiation patients older than 60 years.
Acute brain dysfunction occurs during and up to 1 month after radiotherapy due to blood-brain barrier disruption. Chemicals in blood are extremely toxic to brain tissue. The blood-brain barrier is a protective membrane (blood vessel endothelial cells) which allows the transfer of oxygen and nutrients from the blood to the brain without intermingling blood and cerebral-spinal fluid. One to 4 months after radiotherapy, early delayed complications may occur. These are caused by white matter injury, nerve demyelination, and the accumulation of fluid in the brain. Symptoms include drowsiness in children, the reappearance of the initial tumor's symptoms, a temporary long-term memory deficit, and overall brain dysfunction. Both the acute and early delayed complications are steroid responsive. Up until 6 months after the initiation of radiation therapy, acute organ damage, often clinically silent, accumulates.
During the second six months, the sub-acute period, permanent damage may start to
become evident. In the chronic period, 2 to 5 years after treatment, residual damage continues and 5 years
after treatment, in the late clinical period, premature aging and the development of new cancers becomes
evident.
DIAGNOSIS OF RADIATION-INDUCED BRAIN NECROSIS It is often difficult to determine if the symptoms are caused by recurrence of the tumor, spreading of the cancer from the original site (metastasis), or the death of otherwise healthy tissue (necrosis). Because the site where necrosis most frequently occurs is where radiation was used to destroy tumor tissue, the symptoms often mimic those previously experienced before tumor treatment. Whether there is an autoimmune component to the necrosis process is unknown. A radiation-induced necrosis diagnosis is difficult to confirm without surgical tissue sampling (craniotomy or biopsy). Even more complex is that fact that symptoms may not be caused by tumor or necrosis alone, but often by a combination of active tumor tissue and radiation necrosis together. CT and MRI scans are inconclusive. Although patients who show radiographic changes may have no symptoms, the converse is not true. For patients who suffer impairments, MRIs mirror the severity of symptoms. Sometimes a FDG-PET Scan or T1-SPECT studies can tell the difference by measuring metabolic levels (higher than normal for tumor, lower than normal for necrotic tissue), but again, if both types of tissue are present, they may provide a metabolic profile very close to normal. Also, the increased metabolic activity in inflammatory “edges” surrounding necrotic tissue may give a false positive for the presence of tumor tissue. A PET scan can provide useful targeting information for further biopsy, the appropiateness and scope of further surgery, and quickly monitor patient response to a particular course of treatment.
Magnetic resonance spectroscopy (MRS) measures metabolic markers, including
creatine (cellular bioenergetics), choline (membrane metabolism), lactate (anaerobic metabolism), and
N-acetylaspartate (neuron function). Cancerous gliomas have very high creatine and choline levels.
Necrotic tissue has low creatine, choline, and N-acetylaspartate, which could be expected since necrotic
cells are not functioning. MRS may be particularly useful in distinguishing pure tumor from pure necrosis.
TREATMENT OF RADIATION-INDUCED BRAIN NECROSIS
Traditional treatments (usually corticosteroids) for radionecrosis are also
dangerous, and typically not administered until the patient complains of symptoms, with dosage increased as
required to stabilize the condition. How corticosteroids actually work is uncertain, but doctors believe
they reduce the response of the body to injury and thus diminish the flow of fluid into tissues. When
corticosteroids are used to control swelling, only about 35% of patients respond. Long term usage of
corticosteroids results most notably in osteoporosis, the thinning and weakening of bones.
If steroids fail, surgical removal of the damaged portion of the brain may be an option. This not only allows diagnostic verification, but the reduction in tumor size can relieve intracranial pressure and improve disability. Surgery itself carries a high risk of complications and the potential for further neurological deficit. Even then, surgery is not always possible due to injury size or location or the presence of tumors in multiple sites.
If steroids are not effective, and surgery is not a choice, treating symptoms
used to be the only choice—and one that did not stop the underlying damage process. The objective of any
treatment has to be evaluated—success, often described as the ‘not having the tumor recur,’ is probably
more accurately described in terms of longevity and quality of life.
HYPERBARIC OXYGEN TREATMENT FOR RADIATION-INDUCED BRAIN NECROSIS Traditional radiation injury treatment has focused on control of intracranial swelling, treating the symptoms rather than the underlying cause. There is a difference between normal tissue injuries and those caused by radiation. In radiation, the injury is concentrated in the center of the wound, and “fades” into the surrounding tissue, becoming gradually less pronounced. Because there is no abrupt difference in oxygen levels, the body does not recognize the need to grow new blood vessels (revascularization) into the injured area and bring the necessary oxygen and nutrients to promote healing.
Although the direct bacteriocidal effects of HBOT fight infection, HBOT is by no means a cure for tumors, but can be recommended as part of an integrated, personally tailored treatment for a difficult condition. What is interesting is that HBOT does not only treat the underlying cause of post-radiation symptoms; it is the only known treatment potentially capable of reversing brain radiation necrosis. When tissues have received dosage totaling more than 5000 cGy (SI unit of absorbed dose I Rad = 0.01 Gy), the response to HBOT is the regeneration of blood capillaries in the affected region, tissue healing, and increased tissue oxygenation. Most patients with chronic radiation injuries and no underlying tumor activity can be cured. ©2007 Florida Oxygen
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