Hemophilia and other coagulation disorders: neurologic aspects
Jun. 20, 2022
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Stereotactic radiosurgery is the precise delivery of a lethal dose of radiation to a target while minimizing the radiation exposure of the surrounding tissues. This review discusses the 5 techniques of stereotactic radiosurgery: linear accelerator (LINAC)-based stereotactic radiosurgery, Gamma Knife, tomotherapy, robotic mini-linear accelerator (CyberKnife®), and heavy particle or proton beam stereotactic radiosurgery. The major indications for stereotactic radiosurgery for neurosurgical conditions include metastatic brain and spine tumors, primary brain tumors (eg, meningioma, vestibular schwannoma), arteriovenous malformations, and trigeminal neuralgia, and, more rarely, movement disorders, certain types of intractable epilepsy, and psychiatric disorders such as severe depression. The incorporation of real-time patient movement tracking (CyberKnife) allowed for the extension of stereotactic radiosurgery into the treatment of spinal disease as well as non-nervous system conditions, such as lung and prostate cancer. Stereotactic radiosurgery has assumed a significant role, both as the primary modality and in conjunction with surgery or chemotherapy, in treating a wide variety of disorders both within and outside the central nervous system.
• Stereotactic radiosurgery is the precise application of a lethal dose of radiation to a localized lesion while exposing nearby normal tissue to a sublethal dose.
• There are 5 primary techniques for stereotactic radiosurgery delivery: Gamma Knife, LINAC, tomotherapy, CyberKnife®, and heavy particle (proton beam).
• Radiosurgery is used to treat a variety of pathologies, including brain and spine metastases, vestibular schwannomas, pituitary adenomas, primary central nervous system neoplasms, vascular lesions, including arteriovenous malformations, and functional disorders such tremor, epilepsy, and trigeminal neuralgia.
Stereotactic radiosurgery is the precise application of a lethal dose of radiation to a localized lesion while exposing nearby normal tissue to a sublethal dose. If this radiation is fractionated, the same precise deposition of radiation is delivered over several sessions, allowing for a greater total dose to the target tissue and protection of the surrounding normal structures. The principles underlying stereotactic radiosurgery have been understood for decades, but advances in stereotactic techniques, high-resolution imaging, and computer processing have established stereotactic radiosurgery as a standard neurosurgical technique.
The use of radiation to treat disease is based on the Compton effect, where the collision of a photon with an atom creates free radicals that stop cell cycle replication or cause cell death (136). Medical use of radiation for therapy began in 1922 when Coutard and Hautant treated a case of laryngeal carcinoma with radiation therapy (34). In 1934, Coutard described the concept of fractionation: the total dose of radiation is divided into multiple smaller doses allowing for recovery of normal tissue, repopulation of tumor cells, reoxygenation of tumor cells to increase radiosensitivity, and reassortment of tumor cells within the cell cycle (52). Low-energy emission radiation from early machines made tissue penetration inadequate for anything but superficial lesions. High-voltage machines were developed, producing radiation with energy levels of several million electron volts that could be used to treat intracranial neoplasms. These devices were replaced by cobalt 60 units and linear accelerators in the modern era as sources for high-voltage x-rays (23).
In the 1930s, heavy particles were first used by Lawrence and associates at the University of California, Berkeley, to irradiate small volumes of normal and pathologic tissues (79). The Berkeley cyclotron permitted the use of high-energy alpha particles and proton and deuteron beams to treat deeper brain tissue volumes using the "Bragg peak" rotation technique (137).
Leksell created stereotactic radiosurgery in the early 1950s by combining a stereotactic frame with an orthovoltage x-ray tube (84). He later developed the Gamma Knife using 201 cobalt 60 sources. The early Swedish experience with stereotactic radiosurgery for cerebral arteriovenous malformations led to Gamma Knife centers around the world as additional therapeutic applications were developed. The University of Pittsburgh became the site of the first cobalt 60 Gamma Knife unit for clinical use in North America in 1987. The Gamma Knife improved radiation therapy by providing accelerated treatment times and improved conformation of the radiation dose to the shape of the lesion.
Linear accelerator stereotactic radiosurgery offered 4 major advances:
(1) A stereotactic system with a movable isocenter.
By 1987, Winston and Lutz had modified their linear accelerator in Boston to treat neurosurgical patients (146). Available as standard equipment in many radiation therapy departments, only minor modifications were required to convert a standard LINAC to suitability for stereotactic radiosurgery. Ease of fractionation, unlimited field size, and photon delivery flexibility to treat nonspherical lesions were major advantages to this system. Stereotactic radiosurgery requires extensive quality assurance procedures to maintain safety and reliability of radiation dosage and targeting (23).
Commonly used stereotactic radiosurgery systems are the Gamma Knife and the LINAC. Both require rigid fixation of a stereotactic head frame to the patient for optimal spatial accuracy, which is uncomfortable for the patient, is time consuming for the stereotactic radiosurgery team, and makes fractionation difficult. The most current Leksell Gamma Knife systems feature 192 cobalt 60 sources arranged in a cone section configuration with enhanced flexibility in number and diameters of beams intersecting at isocenters compared with previous systems. This allows for treatment of multiple intracranial lesions within a single-session frame placement with submillimeter accuracy (123; 149). The new Leksell Gamma Knife system, approved by the United States Food and Drug Administration in August 2016, uses a cone beam computed tomography scanner and infrared camera to perform Gamma Knife radiosurgery using the thermal plastic mask head immobilization, which is standard for external beam radiation (149; 142). Use of the thermal plastic mask also allows for multiple sessions to be performed without having to apply and reapply a stereotactic frame. One large study of 100 patients who underwent frameless Gamma Knife radiosurgery demonstrated two major improvements: improved workflow and increased number of patients eligible for Gamma Knife due to fractionation. The accuracy of the frameless system is preserved with submillimeter accuracy (142). The use of Gamma Knife has increased rapidly since its inception. A worldwide survey-based study suggested that there appears to be worldwide consensus on its use for meningiomas, metastatic tumors, and arteriovenous malformations; more treatment variation exists for craniopharyngiomas and pituitary tumors (53).
Frameless stereotactic radiosurgery performed on a LINAC system uses optical tracking systems. These systems have a reproducible accuracy of less than 1.0 mm (121). A newer method of LINAC-based radiosurgery known as volumetric arc therapy (VMAT or RapidArc®) delivers radiation in a gantry arc motion, which allows adjustments to both beam dose rate and gantry speed to further customize conformal dose distribution (105). Delivering treatment in this fashion with continuous gantry rotation allows for treatment of multiple intracranial lesions with a few or even a single isocenter set-up and, most importantly, reduces treatment times to 5 to 10 minutes per lesion while maintaining spatial accuracy of less than 1 mm (144; 10).
The CyberKnife® combines a lightweight (130 kg) 6 MeV linear accelerator with a highly maneuverable, articulated robotic arm to position and aim the LINAC. This system improved ease of fractionation, allowed for treatment of young patients without general anesthesia, and had the ability to treat lesions throughout the body. By utilizing real-time image guidance, the need for skeletal fixation for positioning or rigid immobilization of the patient was eliminated. The multiple degrees of freedom afforded by the robotic arm unconstrained the treatment beam and could target nonisocentric beams to any point within the lesion. Maximizing conformation of the treatment beam to the shape of the lesion provided homogenous dosing (23). Treatment with the CyberKnife has proven effective, and with its spatial accuracy and dose homogeneity, it provided the option of stereotactic radiosurgery treatment to patients with lesions in close proximity to critical central nervous system structures.
There are 5 primary techniques for stereotactic radiosurgery delivery: Gamma Knife, LINAC, tomotherapy, CyberKnife®, and heavy particle (proton beam) (46). Gamma Knife radiosurgery requires placing the patient in a stereotactic frame, which is attached to the patient under local anesthesia by pins that penetrate the scalp into the outer table of the skull. The Gamma Knife focuses 192 cobalt 60 radiation sources, mounted in a 18,000 kg shield, through a collimated helmet on to a target 403 mm from the cobalt 60 radiation sources.
Collimation allows for creation of up to 192 16-, 8-, and 4-mm beams that can each be overlaid and blocked to conform to each isocenter. This independently moving sector design allows for significantly enhanced flexibility, which leads to shorter treatment times and the ability to treat multiple intracranial lesions with a single session and frame placement (124). The new Leksell Gamma Knife system, Icon, approved by the FDA in August 2016, uses a cone beam computed tomography scanner and infrared camera to perform Gamma Knife radiosurgery using the thermal plastic mask head immobilization, which is standard for external beam radiation (149; 142). Use of the thermal plastic mask also allows for multiple sessions to be performed without having to apply and reapply a stereotactic frame, which allows for fractionation of the radiation, increasing the number of patients eligible for Gamma Knife.
In VMAT therapy, the LINAC modulates the shape, dose rate, and energy of the exiting beams via a multileaf collimator while rotating continuously around the target. Adjustments can be made to the multileaf collimator, gantry rotation speed, and dose delivery rate, which allows for greater customization of the conformal dose distribution (105). This gives the VMAT the advantage of allowing highly conformal treatments to multiple intracranial lesions with reduced treatment times. New LINAC-based techniques have outputs as high as 1400 monitor units per minute and can complete a high-dose stereotactic treatment in less than 10 minutes. A study of VMAT for the treatment of multiple intracranial metastases has demonstrated effective 1- and 2-year local control rates (86.7% and 71.6% rates, respectively). The intracranial progression-free survival at 6 months and 1 year were 48.5% and 19.4%, respectively (05). In the case of multiple intracranial metastatic lesions, VMAT typically is performed by using multiple isocenters, 1 for each lesion. Alternative approaches for VMAT using multiple noncoplanar treatment arcs have been suggested as a method for reducing overall treatment time (120).
Tomotherapy uses a LINAC mounted within the gantry of a CT scanner, allowing for imaging just prior to treatment delivery (144). The CyberKnife system combines a lightweight LINAC optimized for stereotactic radiosurgery with an articulated highly maneuverable robotic arm.
The system uses image registration techniques from neuroimaging studies prior to treatment and combines them with radiographs of skeletal features associated with the treatment site obtained from 2 fixed diagnostic fluoroscopes mounted on either side of the patient. This information determines the treatment site, coordinates with respect to the CyberKnife LINAC, and actuates the robotic arm to accurately direct the beam to the treatment site. When the target moves (such as with respiration), the process detects the change and realigns the aim of the beam to the new coordinates in near real-time. This system obviates the need for rigid fixation, allows the treatment of lesions throughout the body, and allows for fractionation of treatment without recurrent patient discomfort (02). The flexibility of the CyberKnife has encouraged treatment of extracranial pathology, including spinal lesions and cancers of the liver, lung (36), prostate, and kidney (54). The proton beam system employs the ionization portion of the Bragg peak, which describes deposition of radiation from heavy particle beams such as helium. Charged particles produce a triphasic pattern of radiation with an intermediate dose on entrance of the head and a narrow peak of high-dose radiation (Bragg ionization peak) that can be adjusted to target tissue penetration depth and a minimal exit dose. Although the need for a cyclotron limited proton therapy to only a few centers in the United States for many years, there are now many proton therapy centers. The added cost of refinements for improved accuracy, such as pencil beam scanning, as well as expected reductions in reimbursement for proton therapy, will make the financial viability of many proton therapy centers questionable in the future (41). However, as the cost of this technology lowers with time, there is an important role for proton beam, particularly in the treatment of pediatric patients due to a significantly lower rate of secondary malignancy when compared to photon-based treatments (31). In addition to several solid organ-based tissue cancers, promising results have also been obtained in treating challenging intracranial tumors, such as chordomas (128) and glioblastoma (102), and several trials and investigations are ongoing (101).
Although capable of treating lesions as small as 2 to 3 mm diameter, all 3 techniques require accurate target localization preoperatively, typically with a contrast MRI for primary and metastatic brain tumors, and CT arteriography for arteriovenous malformations. Isodose plots are constructed from the neuroimaging studies to calculate dosimetry. Treatment planning is a team effort including a radiation oncologist, radiation physicist, and neurosurgeon. This effort is aided by advancements in computer programs that help to automate much of the treatment planning and delivery. Stereotactic radiosurgery treatment time varies from under 30 minutes to an hour or more, depending on the number of isocenters treated and the stereotactic radiosurgery technique (system) employed. The patient is usually discharged the same day or within 24 hours. Corticosteroids, antiemetics, or anticonvulsants may be administered.
The goal of stereotactic radiosurgery is the delivery of a lethal radiation dose to the target tissue without damage to the adjacent normal tissue. Most stereotactic radiosurgery devices have total clinical accuracy on the order of 1 to 1.5 mm.
Treatment goals depend on the type and location of the lesion treated. For certain benign tumors, eg, meningiomas and vestibular schwannomas, lesion stabilization may be sufficient; for most malignant tumors, especially symptomatic metastatic tumors, shrinkage or obliteration of the lesion may be necessary. Arteriovenous malformations and other vascular lesions usually require obliteration, which may take 2 years or more after treatment before the risk of bleeding is completely eliminated. For tumors, histological tissue diagnosis and determination of the lesion margins are essential. For functional disorders, notably trigeminal neuralgia and epilepsy, the goal is symptom improvement (117; 140).
Stereotactic radiosurgery was initially used for functional neurosurgery (eg, lesioning the thalamus for cancer pain) (85); functional neurosurgery indications have expanded to include trigeminal neuralgia, movement disorders such as Parkinson disease and essential tremor, epilepsy, and certain affective disorders (107; 73; 13). Current primary indications for stereotactic radiosurgery include malignant tumors (tumors metastatic to the brain or spine, malignant gliomas), benign tumors (meningiomas, vestibular schwannomas, and pituitary adenomas), and arteriovenous malformations.
The terms stereotactic radiosurgery and stereotactic body radiotherapy are often used interchangeably. However, stereotactic radiosurgery, as sanctioned by the American Association of Neurological Surgeons, the Congress of Neurological Surgeons, and the American Society for Radiation Oncology, is strictly defined as the utilization of externally generated ionizing radiation to inactivate or eradicate defined target(s) in the head or spine (12), most typically in one treatment fraction only. Stereotactic body radiotherapy is defined as the delivery of radiation to an extracranial target in multiple fractions, typically 2 to 5 (25). It operates under the same principles as stereotactic radiosurgery, with both practices using external beam radiotherapy with high precision and accuracy to deliver a biologically high radiation dose with locally curative intent (50). Stereotactic body radiotherapy is currently used to manage a wide array of disease sites, including oligometastases and spine, lung, prostate, liver, renal cell, pelvic, and head and neck tumors (93). For the treatment of oligometastases, stereotactic body radiosurgery can lead to high-dose irradiation of tumor sites, delaying the use of toxic systemic therapies and leading to longer survival without disease symptoms (20).
The Congress of Neurological Surgeons has updated its guidelines on the use of stereotactic radiosurgery for the treatment of adults with metastatic brain tumors (48). Although no level 1 evidence exists, stereotactic radiosurgery is recommended on the basis of level 3 evidence as an alternative to surgical resection in cases of solitary brain metastasis when surgery is likely to induce new neurologic deficits (48). If a metastatic brain lesion is treated with surgery, stereotactic radiosurgery is also indicated to reduce local recurrence rates (104). Results from clinical trials continue to support the use of stereotactic radiosurgery for patients with 2 to 4 brain metastases instead of whole-brain radiation therapy as long as their cumulative volume is less than 7 mL (48). Stereotactic radiosurgery alone also has been shown to improve median overall survival for patients with more than 4 metastases as long as the cumulative tumor volume is less than 7 mL (48). There is level 1 evidence, however, to demonstrate that in patients with 2 to 3 brain metastases not amenable to surgery, the addition of stereotactic radiosurgery to whole-brain radiation does not improve survival relative to whole-brain radiation therapy alone (08). Salvage stereotactic radiosurgery is not inferior to whole-brain radiation in patients with 4 or fewer brain metastases (69). Although not well studied in a controlled study, stereotactic radiosurgery for patients with 5 to 15 brain metastases has been shown to be well tolerated without an increase in toxicity, treatment failure, or need for salvage therapy (60). Patients with 10 or more brain metastases treated with LINAC radiosurgery also were able to maintain pretreatment neurocognitive function in the majority of cases (99). There is also interest in using stereotactic radiosurgery preoperatively before surgical resection of intracranial metastases (119). This strategy has the theoretical advantage of preventing dissemination of viable tumor cells that may occur during surgery in order to prevent leptomeningeal disease. It also avoids the common issue with postoperative radiosurgery in defining residual disease and treatment margins in the early postoperative setting when tissue changes may be occurring rapidly complicating imaging interpretation. Although limited data exist, 2 studies involving preoperative radiosurgery in 47 and 66 patients demonstrated 85.6% and 84.1% local control at 1 year after treatment (09; 111). A more recent study demonstrated median overall survival and 2-year overall survival were 17.2 months and 36.7%, respectively, in 117 patients treated with preoperative radiosurgery (115). These findings are similar to conventional postoperative radiosurgery. Leptomeningeal dissemination, however, occurred less frequently at 1 year in patients receiving preoperative radiosurgery compared with post (3.2% vs. 8.3%) (09; 111). No differences in complications attributed to radiosurgery were observed. These limited results demonstrate that preoperative radiosurgery is at least as safe as postoperative treatment and has the potential to be a more effective treatment strategy that requires further investigation.
Postoperative radiosurgery is conventionally used in the treatment of both brain and spinal metastases. The International Stereotactic Radiosurgery Society recommends stereotactic radiosurgery as a first-line treatment for postoperative brain metastases resection cavities, with a meta-analysis of 13 recent studies finding a median local control rate of 80.5% and improved neurocognitive outcomes versus whole-brain radiation therapy (116). Local recurrence rates increase with subtotal resection, larger treatment volume, lower margin dose, and a greater than 3-week delay between surgery and stereotactic radiosurgery (94). Fractionated radiotherapy may be more effective in patients with large tumor cavity volumes or diameters and a preoperative diameter greater than 2.5 cm (116). Postoperative stereotactic body radiotherapy is a safe and efficacious method for increasing local control of resected spinal metastases (04; 16). In a study of 63 patients with spinal metastases, postoperative radiotherapy resulted in a local control rate of 81% at a median follow-up of 12.5 months; local control rate was significantly improved by preoperative embolization and radiotherapy less than 40 days after surgical intervention (16).
Cancer immunotherapy is a rapidly developing and wide-reaching treatment strategy for local and metastatic cancer patients. As this field advances, it will undoubtedly converge with radiotherapy. Timing of immuno- and radiotherapy and indications for each treatment modality will continue to change as further knowledge regarding how these treatments interact emerges. The role of adaptive immunity in immunotherapy raises the possibility that radiotherapy could locally interact with the immune system by triggering the local production of inflammatory cytokines and release of tumor antigens. Radiotherapy may, therefore, have an important role in local treatment as a component of a systemic treatment strategy when combined with immunotherapy. Preclinical and early clinical studies are examining the safety and efficacy of local radiotherapy dosing, fractionation, and timing in combination with systemic immunotherapy (03).
To be considered candidates for radiosurgery, patients should have an established pathological diagnosis with a clearly visible lesion on radiographic imaging to facilitate accurate targeting of the lesion. Lesions with diameters of 4.5 to 5 cm have been treated by CyberKnife in staged procedures. However, most centers consider 2.5 to 3.0 cm to be the upper limit of radiosurgical treatment size. The proximity of the lesion to critical nervous system structures such as the anterior visual pathways, vestibulocochlear nerve, brain stem, and spinal cord must be taken into consideration when evaluating a lesion for treatment with stereotactic radiosurgery, as it may affect the dosage that can be delivered safely. Fractionated stereotactic radiosurgery may be at least as effective as multifractionated focal external beam radiation therapy (89).
The principal contraindication to stereotactic radiosurgery is lesion diameter greater than 2.5 to 3.0 cm because radiation-induced complications increase rapidly with larger volumes treated. Major contraindications to stereotactic radiosurgery include the following:
(1) The tissue diagnosis is uncertain.
Assuming a competent planning team and stereotactic radiosurgery system, a good outcome depends primarily on the lesions sensitivity to radiation, shape, and location (ie, proximity to critical structures).
• Brain metastases. Tumor stabilization or reduction occurs in 75% to 90% of cases (131; 56). A meta-analysis of 32 retrospective studies found that treatment of brainstem metastases with a median of 16 Gy resulted in an 86% local control rate with 2.4% treatment-related grade 3 to 5 toxic effects (27). Using mono-isocentric, non-coplanar, LINAC-based stereotactic technique minimizes the amount of radiation to healthy brain tissue, allowing for the safe and efficacious treatment of multiple brain metastases (57; 05). Hypofractionated radiosurgery was found favorable compared to single-fraction radiosurgery for lesions larger than 3 cm (40). Another analysis found both a reduction in radiation necrosis and an improvement in 1-year local control for hypofractionated versus single-fraction radiosurgery (83). A biologically effective dose of ≥50 Gy was associated with greater rates of local control (118). In the treatment of the resection cavity of brain metastases, adding a 2-mm margin improves local control without increasing toxicity and avoids whole-brain radiation (29). In a secondary analysis of a randomized controlled trial, radiosurgery was noted to have improved early local control relative to surgical resection, but the relative benefit lessened over time (32).
• Spine metastasis. Efficacy has been demonstrated at all levels of the spine, with cervical spine localization referenced to skull base landmarks and thoracic and lumbosacral spine localization referenced to percutaneously placed fiducials (45). Patients with benign spinal tumors, such as meningiomas, neurofibromas, and schwannomas, were found to have comparable control rates relative to their intracranial counterparts (28). Radiosurgery combined with open surgery (vertebroplasty or kyphoplasty) has been utilized to successfully treat spinal cord compression as a result of metastasis (122). Treatment with a single dose of 12 to 24 Gy resulted in adequate control of local progression in spinal metastases with epidural cord compression (72). In an analysis of 54 patients treated with a median of 24 Gy in 3 fractions, local failure occurred in only 8% with a mean follow-up of 14.36 months, and pain improvement was seen in 76% (76). Metastases to the sacral spine had lower rates of local control and pain improvement than metastases to the thoracolumbar spine (77). In long-term follow-up, increased cumulative dose and point dose to the spinal cord or cauda equina was associated with late toxicity. Vertebral compression fractures were the most common and were observed in 17% of patients at both 5 and 10 years after treatment (88). Schaub and colleagues provide a review of literature that defines toxicity endpoints and actionable dosimetric guidelines to limit toxicity secondary to radiosurgery of the spine (127).
• Vestibular schwannoma. Tumor stabilization or reduction occurs in more than 90% of cases (92; 55; 134; 65). In patients who underwent repeat stereotactic radiosurgery for recurrent tumors, tumor control rates at 2, 5, and 10 years were 98.6%, 92.2%, and 92.2%, respectively (64). Radiosurgery is ideal for small- and medium-sized vestibular schwannomas (90; 47). For larger tumors, surgical resection should be performed prior to radiosurgery, with a goal of reducing tumor volume to less than 6 cm3. Tumor control rates of 92%, 91%, and 91% at 5, 10, and 15 years after radiosurgery were observed in a review of 618 patients (43). In the same study, hearing preservation rates of 53%, 34%, and 34% at 5, 10, and 15 years after radiosurgery were observed (43). In a series of 871 patients, hearing preservation rates were 89.8% at 1 year, 76.9% at 3 years, 68.4% at 5 years, 62.5% at 7 years, and 51.4% at 10 years after radiosurgery (65). Hearing preservation is correlated with the protection of the cochlea from radiation (58); tumor margin doses lower than 12 Gy and cochlear doses lower than 4 Gy maximize hearing preservation (138). Decreased rates of hearing preservation were associated with increased tumor size (21; 126) and the diagnosis of neurofibromatosis 2 (126).
• Meningioma. The International Stereotactic Radiosurgery Society recommends stereotactic radiosurgery as an effective treatment for grade 1 meningiomas (95). In a review of studies of large intracranial meningiomas treated with stereotactic radiosurgery, radiographic tumor control ranged from 84% to 100% at follow-up of 2 to 7.5 years (42). However, only 45.1% showed clinical improvement; a two-fold increase in likelihood of improvement was found in non-single-session stereotactic radiosurgery versus single-session stereotactic radiosurgery (OR 2.47) (42). In the treatment of 37 patients with asymptomatic skull base meningiomas with single-session Gamma Knife radiosurgery, tumor size decreased, and there was no mortality caused by either the tumor or the procedure for a mean follow-up of 58.5 months (112). Radiosurgery may also be an effective treatment option for radiation-induced meningiomas (62).
• Arteriovenous malformation. The International Stereotactic Radiosurgery Society cautiously recommends stereotactic radiosurgery as a safe and effective treatment for grade 1 to 2 arteriovenous malformations, particularly in deep or eloquent regions, based on analysis of 1102 arteriovenous malformations in which total obliteration without hemorrhage was achieved in 78% (49). Overall, radiosurgery reduces the risk of arteriovenous malformation hemorrhage, although the benefit is strongly driven by obliteration (39). Success is inversely proportional to the volume and flow of the arteriovenous malformation, with nearly complete success for arteriovenous malformations less than 1 cm in diameter, 75% to 90% success for lesions 1 to 3 cm in diameter, and 35% to 65% success for larger lesions (130). For very large arteriovenous malformations (larger than 10 cm3), a second radiosurgery or surgical intervention treatment within 3 years from the first may be necessary (150; 152). For patients with similar arteriovenous malformations, surgical resection and radiosurgery demonstrate similar rates of deficit-free obliteration. Obliteration of the arteriovenous malformation nidus was more frequently achieved with surgery but at the risk of increased new permanent neurologic deficit (26). In a review of 8 studies of spinal arteriovenous malformations treated with 18 to 21 Gy over 2 to 4 fractions, good outcomes were seen in 92.2% with no post-treatment hemorrhage over an average follow-up period of 46.8 months (153). Most centers consider radiosurgery to be ineffective in the treatment of cavernous malformations (07; 24; 80; 103; 114).
• Dural arteriovenous fistulas. In the treatment of 124 low-risk and 73 high-risk cases of dural arteriovenous fistulas, stereotactic radiosurgery was found to be a safe option with few complications (139). A cohort of 114 patients was treated with a mean margin dose of 21.8 Gy, resulting in obliteration rates of 41.3%, 61.1%, 70.1%, and 82.0% at 3, 5, 7, and 10 years, respectively (133). In a study of 131 patients, cavernous sinus arteriovenous fistulas were more likely to be obliterated than noncavernous sinus fistulas (OR = 4.189) (61).
• Hemangioblastomas. A quantitative meta-analysis of 14 studies of stereotactic radiosurgery use for CNS hemangioblastomas showed an 88.4% 5-year progression-free survival (110). In a large international study of 517 participants with a mean target volume of 0.2 to 0.7 cm3, local tumor control rate after stereotactic radiosurgery was 92% at 3 years, 89% at 5 years, and 79% at 10 years (151). A cohort of 15 patients with 101 lesions was treated with Gamma Knife stereotactic radiosurgery with a median pretreatment volume of 28 mm3 and a median marginal dose of 17.8 Gy. Ninety-seven percent of patients were free from new hemangioblastoma formation at 1 year, 80% at 3 years, and 46% at 5 years. Local failure occurred in only 4% of the treated lesions (87).
• Pituitary adenomas. The International Stereotactic Radiosurgery Society recommends stereotactic radiosurgery as an effective and safe treatment for nonfunctional pituitary adenomas based on a meta-analysis of 27 studies that found 5- and 10-year random effects local control estimates after stereotactic radiosurgery (average 15.0 Gy) of 94% and 83%, respectively (75). Post-stereotactic radiosurgery panhypopituitarism occurred in 21% (75). Stereotactic radiosurgery has also been used to treat patients with acromegaly, with low-dose radiosurgery to 15.8 Gy leading to remission in 43.4% of 76 patients treated (109). Another study found similar endocrine remission in acromegaly with 83.3% local tumor control in 21 patients treated (06). In a separate meta-analysis of residual or recurrent tumor control, stereotactic radiosurgery with a mean radiation marginal dose of 19.6 Gy resulted in 95% overall tumor control and 67% hormonal control in secreting tumors, with few side effects (59).
• Chordoma and chondrosarcoma. Stereotactic radiosurgery is currently used in both primary tumor management of small tumors and restricting local progression following surgery (141; 68). A review of the National Cancer Database of 1478 patients with skull base, sacral, or mobile spine chordoma showed a 5-year survival rate of 82.3% with surgical resection and adjuvant radiotherapy versus 70.6% for surgical resection alone in patients with positive tumor margins; stereotactic radiosurgery resulted in higher survival rates than traditional external beam radiation therapy. There was no survival benefit in patients with negative margins (38).
• High-grade glioma. The use of stereotactic radiosurgery in glioma is controversial. The standard treatment of high-grade gliomas includes surgical resection, external beam radiation, and adjuvant temozolomide. Most patients experience tumor progression within the initial tumor margin, and there is no standard treatment for this recurrence. For those who cannot undergo redo resection, stereotactic radiosurgery has been used for the treatment of small volume recurrence or poor surgical candidacy. Results are varied, presumably because of the infiltrative nature of gliomas; however, with refinements in targeted molecular agents, there may be a role for radiosurgery in the treatment of recurrent high-grade gliomas (14; 98). A completed randomized, controlled trial of the addition of stereotactic radiosurgery to conventional radiation and chemotherapy versus conventional radiation and chemotherapy alone did not improve outcome, quality of life, or cognitive function (132). A major cause of disease progression was beyond local failure outside of the stereotactic radiosurgery target in one single-center retrospective study (30). On the other hand, a phase 1 trial of stereotactic radiosurgery with bevacizumab in patients with recurrent glioblastoma using higher doses of stereotactic radiosurgery than the prior study, including only 9 patients, demonstrated a median progression-free survival of 7.5 months and overall survival of 13 months, consistent with prior retrospective and prospective studies stating that stereotactic radiosurgery benefits treatment of high-grade gliomas (15; 01; 125). The use of stereotactic radiosurgery and hyperfractionated radiosurgery for the treatment of newly diagnosed and recurrent glioblastoma has generated interest in the field despite the lack of prospective data (129). Overall, the use of stereotactic radiosurgery has been controversial in the treatment of primary or recurrent glioma because data on outcome improvement have been mixed.
• Low-grade glioma. In regards to low-grade gliomas, safe surgical resection is the first choice of treatment, but stereotactic radiosurgery has been used for lesions that are too deep to access, particularly pilocytic astrocytomas and grade 2 astrocytomas. For pilocytic astrocytomas, stereotactic radiosurgery was used in both adults and children as postoperative adjuvant and in recurrent or unresectable lesions. Progression-free survival at 1, 3, and 5 years was 84%, 32%, and 32%, respectively, for adult patients with stereotactic radiosurgery, and those who underwent surgical resection had better outcomes (66). In pediatric patients, the progression-free survival was 92%, 83%, and 71% at 1, 3, and 5 years, respectively, with better outcomes in those with small residual solid tumors (67). In grade 2 astrocytomas, tumor control rates were 67% to 92% with stereotactic radiosurgery in single-center retrospective studies, with up to 41% noted to have radiation-related edema (70; 51; 145). Stereotactic radiosurgery may be an alternative or supplement to surgery in deep or difficult to access locations for these low-grade gliomas.
• Other indications. Indications for stereotactic radiosurgery have continued to expand. Studies have demonstrated the utility of stereotactic radiosurgery for a variety of conditions. In a retrospective study consisting of 73 patients with medically refractory essential tremor, Gamma Knife thalamotomy was performed with a median central dose of 140 Gy (range, 130-150) (106). Overall, 93.2% of patients showed improvement in tremor with 60.3% reporting tremor cessation or barely perceptible tremor. Martinez Moreno and colleagues retrospectively analyzed the use of Gamma Knife radiosurgery (86.5 Gy [range: 80-90 Gy]; median: 90 Gy) in 117 patients with medically refractory trigeminal neuralgia (96). The pain-free rate without medications at 3, 5, and 7 years was 85%, 81%, and 76% of patients. Compared to microvascular decompression surgery, stereotactic radiosurgery was found to be less effective than surgery for increasing pain-free intervals (143; 86). Although the use of stereotactic radiosurgery for the treatment of glossopharyngeal neuralgia has not been extensively investigated, some studies suggest that it may be a safe and effective option (113; 17). A meta-analysis found that it had a lower incidence of pain relief but also a lower rate of complications than nerve section (91). Radiosurgery has also been compared to open surgical resection of the anterior temporal lobe for the treatment of mesial temporal sclerosis. Although surgery demonstrated an advantage in terms of proportion of seizure remission (78% vs. 52%), radiosurgery also appears to be safe and effective as an alternative for patients who are unable to undergo open surgery (11). In the treatment of epilepsy-causing hypothalamic hamartomas, radiosurgery is a safe and efficacious alternative to open microsurgery (18).
Adverse reactions to stereotactic radiosurgery can be defined as acute (days), early (weeks to months), or late (> 3 months). Both acute and early reactions are usually self-limiting with no permanent neurologic injury.
Nausea and vomiting are common acute reactions after treatment of posterior fossa lesions, with symptoms occurring in 10% to 16% of patients within 6 hours of treatment. Pretreatment with antiemetics and steroids is useful in minimizing or preventing these symptoms.
Much of the pathology treated with stereotactic radiosurgery has an inherent seizure association. After stereotactic radiosurgery, the risk for seizure is probably elevated for the first 48 hours. Maintenance of therapeutic levels of appropriate antiepileptic drugs is recommended to prevent seizures during the immediate post-treatment period. Further complications that may occur include vertigo, paresthesias, and trigeminal neuralgia (22).
Late reactions to radiosurgery are associated with variable degrees of transient and permanent neurologic sequelae that occur 6 to 9 months after treatment and may have visible changes on CT or MRI (81). In normal tissue near the lesion or in the treatment area, the high dose of radiation may cause blood-brain barrier alterations, cytotoxic edema, myelin lesions, atrophy, calcification, cyst formations, thrombosis of regional vessels (generally in the case of tortuous veins, varices, or venous anomalies), and vasculopathy. Tumoral cytotoxic edema in combination with post-treatment edema may create problems with increased intracranial pressure. These often present several months after stereotactic radiosurgery, with evidence of headaches and perilesional edema on neuroimaging studies. Treatment consists of corticosteroids and diuretics. The condition is usually self-limiting but particularly on occasion when large volumes have been treated with stereotactic radiosurgery, these areas may require surgical decompression. Treatment consists of steroids, often requiring a protracted course of 12 months or longer for resolution. Severe cases may require surgical resection of necrotic tissue to reduce mass effect (135). Data from the treatment of arteriovenous malformations suggest that repeat radiosurgery treatments and deep location of a lesion are risk factors for symptomatic radiation-induced changes (63). Finally, pituitary insufficiency is a potential complication of stereotactic radiosurgery for lesions adjacent to the pituitary gland or hypothalamus.
Though rare, radiation-induced vasculopathy may perforate key branches of cerebral vasculature surrounding targets of radiosurgery, such as the middle cerebral artery (71). Visual deficits can be encountered with targeting areas surrounding the post-geniculate visual pathway, but they are relatively rare, with the risk of sustaining a deficit being 3% at 3 years, 5% at 5 years, and 8% at 10 years (19). Radiation necrosis is a severe complication that may occur in up to 10% of brain radiotherapy cases and can be treated with bevacizumab (35). In the treatment of brain metastasis, radiation necrosis may occur up to 5.3 years after treatment (44).
Treatment of lesions of the skull base may result in cranial neuropathies. Sensitivity to radiation injury varies among cranial nerves, with the optic nerve being the most sensitive (single-fraction threshold for injury of approximately 800 cGy) (74). However, specific contouring and targeting strategies that avoid the optic nerve and pathways are successful at avoiding this complication. The cochlear and trigeminal nerves are the next most frequently injured nerves.
Malignant transformation or secondary malignancy following stereotactic radiosurgery is rare (97). Transformation of grade 1 meningiomas to high-grade meningioma and new diagnoses of post-radiation glioblastoma, osteosarcoma, and chondrosarcoma following stereotactic radiosurgery have been reported (108; 82; 78). The time from initial radiosurgery to detection of the secondary malignancy ranged from 58 months (glioblastoma) to 14 years (chondrosarcoma). Of 14,168 patients treated with stereotactic radiosurgery for a variety of intracranial pathologies, the cumulative incidence of radiation-associated malignancy was 0.045% over 10 years, which is similar to the risk of independently developing a malignant CNS tumor (147).
Prognosis varies with the pathological diagnosis and neuroanatomical location of the lesion, as discussed above.
Using stereotactic radiosurgery to treat a woman harboring a brain lesion during pregnancy is feasible because, with abdominal protection, the fetal radiation exposure can be limited to less than 1 rad. Thoracolumbar spinal lesions, however, represent a situation where extremely careful stereotactic radiosurgery treatment planning is essential to minimize fetal radiation exposure. Elderly patients harboring brain lesions or cranial neuralgias may be candidates for stereotactic radiosurgery because it carries lower risks compared to surgical alternatives (33; 100; 113). Special considerations should be given in this patient population, however, due to increased risks of neurologic toxicity (100). Discussions on the goals of care and a neurologic assessment should be performed (100).
Case 1. A 59-year-old female presented to the neurosurgery clinic with a known diagnosis of invasive lung adenocarcinoma. She developed a severe headache and difficulty with balance 1 month prior to presentation, and work-up demonstrated two new intracranial metastases. She was found to have a dominant 2.6 x 1.8 x 2.2 cm left lateral cerebellar hemisphere lesion with surrounding perilesional edema as well as a much smaller right cerebellar lesion.
Axial post-contrast MRI prior to treatment, demonstrating left lateral cerebellar enhancing lesion. (Contributed by Dr. Jason A Heth.)
She was started on dexamethasone, and her symptoms improved. She underwent stereotactic radiosurgery to both lesions, 19 to 22 Gy in a single fraction. Later that same day she underwent craniotomy for tumor resection of the left lateral cerebellar lesion.
Immediate postoperative axial post-contrast MRI. (Contributed by Dr. Jason A Heth.)
She tolerated surgery well and was discharged to home on postoperative day 2. Postoperatively, she remained neurologically intact. At her 3-month follow-up, her right cerebellar lesion was no longer present, and a new area of contrast enhancement was seen within the resection cavity.
Coronal post-contrast MRI about 3 months after stereotactic radiosurgery and craniotomy, which demonstrates resolution of the tiny right cerebellar lesion and a new left cerebellar nodular enhancement within the resection cavit...
This was favored to represent radiation effects over tumor progression due to imaging characteristics. She continues to be followed by neurosurgery, radiation oncology, and medical oncology as an outpatient.
Case 2. A 41-year-old female developed progressive and disabling spastic quadriparesis over 15 years--Brown-Sequard syndrome with significant loss of right-hand function in particular. Spinal arteriogram demonstrated a C2-C3 spinal cord arteriovenous malformation, which had hemorrhaged on 3 occasions.
Due to the intramedullary location of the arteriovenous malformation, the patient was not a good candidate for microsurgical resection or embolization. Initial stereotactic radiosurgery was with the CyberKnife (10 mm collimator, 3 fractions, total peripheral dose 21 Gy). Clinically, the patient steadily improved, in particular her gait and right-hand function. Spinal arteriogram at 3 years post-stereotactic radiosurgery showed 70% obliteration of the arteriovenous malformation.
She, therefore, underwent a second CyberKnife stereotactic radiosurgery (7.5 mm collimator, 2 fractions, 85% isodose line total 15 Gy). MRI at 4 years following initial stereotactic radiosurgery showed continued improvement, which paralleled her clinical course.
Case 3. A 76-year-old man presented with a 5-year history of progressive hearing loss in the left ear. An MRI revealed a 12 x 15 x 9 mm contrast-enhancing lesion in the cerebellopontine angle that, on close inspection, followed the course of the facial nerve. The lesion did not compress the brainstem and he demonstrated intact facial function. The patient had no history of neurofibromatosis. Over time, the lesion continued to demonstrate a slow, linear growth pattern. The patient was referred for stereotactic radiosurgery and received a total dose of 12 Gy to the 80% isodose surface with a total treatment tumor volume of 1.77 cm3. The patient tolerated the procedure well and the tumor decreased in size on 1-year interval follow-up imaging. He continues to have intact facial function. Central to this case is the recognition that the cerebellopontine angle lesion was likely a facial nerve schwannoma and not a vestibular schwannoma. Open surgical resection would expose the patient to a high risk of facial nerve dysfunction. Although this is also a risk with stereotactic radiosurgery, the patient has not experienced this complication and continues to do well clinically.
Case 4. A 77-year-old woman presented to the emergency room with confusion, difficulty concentrating, and short-term memory loss. An MRI was ordered, which demonstrated a large left frontal parafalcine contrast-enhancing mass with surrounding vasogenic edema most concerning for a meningioma.
Contrasted axial MRI obtained for confusion and memory loss demonstrates a large left frontal parafalcine homogenously enhancing lesion concerning for a meningioma. (Contributed by Dr. Jason A Heth.)
She underwent a bifrontal craniotomy for tumor resection, which was complicated by significant cerebral edema, necessitating early closure and subtotal resection.
Axial post-contrast MRI immediately after subtotal resection demonstrates debulking of the lesion. (Contributed by Dr. Jason A Heth.)
Pathology confirmed a grade 1 meningioma. Initially, she did quite well after this surgery and returned to her neurologic baseline. She was observed on an outpatient basis with slow growth of the tumor. About 1 year after surgery, she developed confusion again and was noted to have rapid growth of her meningioma.
Outpatient contrasted MRI demonstrates growth of the left frontal parafalcine meningioma prompting a return to the operating room for redo resection. (Contributed by Dr. Jason A Heth.)
She returned to the operating room for another gross total resection of her meningioma, which resulted in memory improvement yet again.
Axial post-contrast MRI after second resection of meningioma. (Contributed by Dr. Jason A Heth.)
She was followed on an outpatient basis, and 5 years after her second surgery was noted to have progression of a new enhancing small lesion within the resection cavity.
Five-year postoperative follow-up contrasted MRI demonstrating regrowth of contrast-enhancing tumor within the operative cavity, indicating recurrence of the meningioma. (Contributed by Dr. Jason A Heth.)
Stereotactic radiosurgery, 12 Gy in 1 fraction, was recommended given her advanced age. Three years after stereotactic radiosurgery, the size of her meningioma remained stable and she remained neurologically intact.
Contrasted MRI 3 years after stereotactic radiosurgery demonstrating stability of the left frontal meningioma recurrence. (Contributed by Dr. Jason A Heth.)
The goal of radiation therapy is to destroy target cells through the delivery of lethal doses of high-power energy. Radiation beams impart energy to all tissues traversed, invariably damaging surrounding nontarget (normal) tissue, resulting in complications such as impaired wound healing, injury to skin, arteries, and the central or peripheral nervous system, and the induction of secondary malignancies.
Stereotactic radiosurgery seeks to deliver a high dose of radiation to the target while minimizing radiation to surrounding normal tissues. A heavy particle beam accurately delivers much of its energy at a depth predictable by Bragg-peak calculations. Gamma Knife stereotactic radiosurgery relies on multiple sources of cobalt 60 high-energy photons, collimated to limit beam divergence, to focus the radiation on a target. In addition to movement of the gantry and the patient, LINAC employs collimated high-energy photons in a series of converging arcs to focus the radiation on a target. Other LINAC techniques include the use of multiple converging shaped beams (shaped-beam radiosurgery), intensity-modulated fixed beams (IMRS), and intensity-modulated arc therapy (IMAT).
The frame-based stereotactic radiosurgery techniques generate an isocentric spherical region of high-dose volume (148). Nonspherical or irregularly shaped targets are treated with multiple isocenters. Multiple isocenters create central necrosis of the target, surrounded by a thin intermediate area of less severely damaged tissue (penumbra); the thinner the penumbra, the more accurate the targeting. A sublethal radiation dose causes vascular intima hyperplasia leading to capillary occlusion, allowing for obliteration of arteriovenous malformations and tumor neovascularity (37).
The CyberKnife delivers non-isocentric spherical radiation beams to lesions that are nonspherical in shape. Mounting the LINAC on a robotic arm created an unconstrained delivery system, making the CyberKnife free to generate beams that originate at arbitrary points within the workspace and target arbitrary points within the lesion.
There is no qualitative difference between cobalt 60 gamma radiation and high-energy x-rays, as relative radiobiological efficiency is equivalent in both. Accelerators derive a theoretical advantage from deeper tissue penetration, especially in 10 to 18 MeV. This limits adherence problems of superficial planes, which are characteristic after cobalt 60 therapies. At present, there is no clinical difference between results obtained with either method.
Jason A Heth MD
Dr. Heth of the University of Michigan has no relevant financial relationships to disclose.See Profile
Clare M Wieland
Ms. Wieland of University of Michigan has no relevant financial relationships to disclose.See Profile
Katherine Holste MD
Dr. Holste of the University of Michigan has no relevant financial relationships to disclose.See Profile
Matthew Lorincz MD PhD
Dr. Lorincz of the University of Michigan received honorariums from Alexion and Xenith for advisory board service.See Profile
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