Radiation therapy aims to destroy abnormal tissue, notably tumor cells, with minimal damage to surrounding normal tissue. Lars Leksell introduced stereotactic radiosurgery (SRS) in 1951 as an alternative treatment option to conventional whole-brain radiotherapy (WBRT).
SRS uses multiple, convergent beams of high energy x-rays, gamma rays, or protons, delivered to a discrete, radiographically-defined, treatment volume. The delivery of radiation is highly conformal. By using multiple, intersecting beams of radiation, the treatment volume receives a high, therapeutic prescription dose, while surrounding normal brain tissue receives a relatively low dose. This treatment can be tailored precisely, following margins of the treatment volume to allow rapid dissipation of energy beyond the margins, sparing normal tissue. The steep radiation fall-off into surrounding tissues limits toxicity and side effects and maintains safety.
Stereotactic radiosurgery works by radiation-induced DNA damage by ions and free radicals. The vascular endothelium is the primary target with contribution from endothelial-cell apoptosis, microvascular dysfunction, and T-cell response. Histologically, a brisk inflammatory response and severe vasculopathy occur in lesions that respond well to SRS.
Stereotactic radiosurgery is appropriate for patients with brain metastasis and primary tumors, including meningiomas, vestibular schwannomas, pituitary tumors, and those resistant to conventional whole brain radiation therapy (WBRT).
Brain metastases are the most common intracranial tumors in adults, they can occur in up to 30% of patients with cancer, and this incidence is increasing. SRS can be used to treat single or multiple lesions, including deep-seated, surgically inaccessible lesions. SRS can be monotherapy, as an adjunct to surgery for residual disease and in cases of recurrence. It is the treatment of choice for patients with a limited number of cerebral metastases that are not amenable to resection. Multiple, sequential SRS can also be performed, with a median overall survival of 5 to 6 months for patients undergoing 1,2,3 or 4 plus SRS treatments. Uncertainty exists about the use of SRS with WBRT for brain metastasis, and there is no clear consensus. Trials for brain metastasis show advantages in local control with combination therapy but conflicting outcomes for survival and cognition (although most studies show SRS alone results in less cognitive deterioration).
Meningiomas and vestibular schwannomas are extra-axial and have clear, defined margins, lending themselves to conformal SRS techniques. Meningiomas are commonly treated with 12 to 13 Gy in a single fraction, with control rates of 90 to 98% and toxicity less than 10%. SRS provides tumor control equivalent to Simpson grade 1 resection for tumors under 3.5 cm over long-term follow-up. Adjuvant SRS following subtotal resection has a superior 15-year progression-free survival to patients with gross total resection without SRS.
Vestibular schwannomas commonly receive treatment with 12 to 13 Gy in a single fraction. Five-year local control rates for vestibular schwannomas are 92 to 100%, with hearing preservation superior to surgery (32 to 71%), and cranial nerve V and VII preservation to over 95%. Hearing preservation rates of 63 to 94% have been seen with fractionated SRS, although there is a lack of long-term follow-up, and no randomized controlled trials comparing the two modalities.
For pituitary adenomas with invasion of the intrasellar region or cavernous sinus, surgery may only achieve a subtotal resection. In such cases, SRS or fractionated therapy is appropriate. The reported rate of tumor control is 91 to 99%, endocrine disturbance as 1 to 22% and optic neuropathy as 1 to 2% depending on tumor volume. The highest endocrine remission rates are for patients with Cushing disease, and the lowest for those with prolactinomas.
For primary gliomas, studies have looked at the impact of SRS combined with traditional therapy as a means of dose escalation and to shorten treatment time in patients with limited life expectancy. Prospective and retrospective studies reveal a median survival of 6 to 18 months following salvage SRS for recurrent glioblastoma multiforme (GBM) and 6 to 14 months with fractionated therapy. SRS on the previously irradiated brain increases the risk of radionecrosis, so studies have looked at the addition of bevacizumab, with positive results.
Stereotactic radiosurgery can be used to treat vascular pathologies including arteriovenous malformations (AVMs), dural arteriovenous fistulas, and cavernomas. Rates of complete obliteration for AVMs have been quoted as 76% for low-grade Spetzler-Martin I and II, 69% for grade III, and for high-grade IV-V AVMs, obliteration rates range from 0 to 61%. Volume-staged SRS (treating distinct geometrical parts of AVM over time) has higher obliteration rates and similar complication rates compared to dose-staged SRS (fractionated or repeat SRS) for large AVMs that are not amenable to single session SRS. SRS may have a role in patients with dural arteriovenous fistulas not amenable to surgery or endovascular embolization with an acceptable success rate and adverse effect profile.
SRS was originally developed to treat functional disorders, including intractable pain, epilepsy, and movement disorders. The first procedure performed was a thalamotomy for a patient with trigeminal neuralgia. SRS is a treatment option in movement disorders for patients who are not suitable for open neurosurgery and deep brain stimulation (DBS). It has achieved comparable tremor control to DBS and radiofrequency, with 85 to 90% improvement. SRS thalamotomy has focused on the nucleus ventralis intermedius. For trigeminal neuralgia, 50 to 80% of patients achieve complete symptom relief, although a number require repeated SRS treatment, with associated trigeminal dysfunction.
Stereotactic radiosurgery are useful for seizure control for mass lesions, including tumors, AVMs (mean seizure remission rate of 70%) and cavernous malformations (50%). The results of SRS for the treatment of mesial temporal lobe epilepsy show a wide range of efficacies in the literature, ranging from 0 to 86%. Possible mechanisms include neuromodulation and ablation. The recent ROSE trial suggests that open surgery has an advantage over SRS for seizure remission, but that SRS is a safe, appropriate alternative.
Stereotactic radiosurgery is an option for spinal and paraspinal lesions due to its not invasive and targeted approach, including intramedullary and intradural spinal tumors. The most common indication is vertebral metastasis causing cancer-related pain. Other indications include primary treatment for metastases, radioresistant pathologies, failure of radiotherapy, as adjuvant treatment, for residual or recurrent disease. It can yield high rates of pain relief (85 to 92% within a few days to weeks) and tumor control (77 to 94%) and is an indicated therapy option for patients who cannot tolerate surgery, for residual disease, or as a palliative treatment.
Stereotactic body radiosurgery has been in use since the 1990s, including pulmonary and hepatic tumors.
Contraindications include an excessively large target lesion or too many lesions for practical use. Single fraction stereotactic radiosurgery is usually limited to small lesions (typically less than 4 cm) although increasingly fractionated radiosurgery is useful for larger lesions.
For newly diagnosed glioblastoma, a randomized trial comparing SRS followed by external beam radiotherapy and carmustine chemotherapy versus only radiotherapy and carmustine showed no difference in overall survival, improvement in local control, or quality of life. Reports of late toxicity were 4%. This data has support from further studies, trials, and systematic reviews, and currently, there is insufficient evidence to support the use of SRS.
SRS pallidotomy yielded a high complication rate, including visual field defects and is not routinely in use.
There are different devices in operation for stereotactic radiosurgery, which differ in both the type of radiation delivered and the method of focusing the beams to the target.
Ionizing radiation is electromagnetic or particulate radiation, which can produce ions when passing through matter. A photon is a discrete packet of electromagnetic energy and includes radio waves, infrared, visible light, ultraviolet, and X-rays depending on the energy level. X-rays are the only type of photon capable of producing ions, and therefore can be used for SRS. Photon beams can be generated from radioisotope sources (at present, cobalt-60) or from x-ray generating machines (the linear accelerator). Radioactive isotopes are atoms with unstable nuclei that emit ionizing radiation through radioactive decay to stabilize themselves.
Focused gamma beams are the simplest and older stereotactic radiosurgery device, first used on in 1967. It uses a cobalt-60 radioisotope-based device with 192 individual sources of radiation, arranged in a conical tungsten shell. The radioactive decay of cobalt leads to the emission of ionizing radiation in the form of beta particles and two strong gamma radiations – one with 1.17MeV of energy and one with 1.33MeV of energy. This approach means that the effective energy of these focused beams is 1.25 MeV. Treatment energy is measurable in MeV – which is 1 million electron-volts. One electron-volt is the energy gained by an electron that accelerates through a potential difference of 1 volt.
The cobalt sources are arranged in a spherical array via collimator helmets to focus the beams to converge at a single target, which can generate ‘hot spots’ within the treatment volume. The hemispheric configuration limits its use to intracranial pathologies, and it is used mainly as a single-fraction. It currently is in its fifth generation of evolution under a new trade name. This system uses an automated internal collimation system (with sizes of 4, 8, or 16mm) to replace the helmet. Cobalt-60 will decay to nickel, with a half-life of 5.26 years. Practically, this means that the cobalt source needs to be replaced after a period to avoid long treatment times.
Linear accelerator radiosurgery was introduced clinically in the early 1980s. It uses a linear-accelerator-based device to generate high energy X-rays, which is achieved by the use of a magnetron which accelerates electrons against a metal target (usually tungsten). The electrons are produced from an electron gun by thermionic emission. X-rays get emitted as the electrons decelerate in the metal. The photon output is a continuous spectrum of X-rays, with peaks at specific energies depending on the atoms in the target. The number of x-ray particles produced increases as the kinetic energy of the electron increases. A 6 MeV electron is often the choice for SRS. Therefore, the photon output can take any energy from 0 to 6MeV (the energy of the incident electron). For linear accelerator produced energy, energy is denoted as MV (megavolts), not MeV. Notably, this means that photon beams from linear accelerator radiosurgery have a continuous ‘bremsstrahlung’ or ‘deceleration radiation’ spectrum of energy, whereas from radioisotope sources they are fixed. A collimator focuses these X-rays. The accelerator mounts on a gantry, which can rotate with intersecting arcs, focusing the radiation at the isocenter. It can be used for extracranial targets and as fractionated treatments.
Another system is intensity-modulated radiation therapy (IMRT), a linear accelerator-based application which can vary the shape and intensity of the beam; this allows non-uniform dose distribution with steep dose gradients between target volumes and normal brain tissue. It delivers helical tomotherapy plans using a 6 MV unflattened X-ray beam and a binary multileaf collimator. Many small, elongated, and off-axis subfields create the intensity modulation. This method is useful for extracranial and spinal SRS.
Protons, which are positively charged particles found in the nucleus of an atom, are used for particulate radiosurgery. A synchrotron or cyclotron-based device can generate proton beams by ionizing hydrogen. The proton beam can have energy between 20 and 190MeV depending on the device. When charged particles move through the material, they ionize atoms and deposit energy. Protons interact with matter by Coulomb collisions between electrons and nuclei (a binary elastic collision of charged particles interacting through their own electric field), by bremsstrahlung radiation loss and by nuclear reactions. As proton beams travel through tissue, they lose energy, and this energy loss is inversely proportional to the square of the velocity, meaning that the dose distribution pattern shows a slowly rising dose, followed by a sharp increase, called the Bragg peak, near the end of the range. Most of the energy gets deposited at a discrete band of spatial depth, just before the particle stops (unmodulated Bragg peak). Several superimposed, intersecting beams produce a modulated Bragg peak, with sufficient energy for larger treatment volumes. This can provide a moderate entrance dose, uniformly high dose within the target tissue, and zero doses beyond the target. Proton beams can be precisely focused to control the depth of penetration, depositing most of the energy at the target. Due to both the considerable cost and space considerations, proton SRS is a rare option.
To date, no randomized controlled trial exists to compare devices, so physician expertise and machine availability guide practice. Comparative studies are inconclusive, although commonly demonstrate equivalence.
Dosimetry is a vital but difficult component of SRS. With SRS, small fields are used, typically 0.3 x 0.3 cm up to 4 x 4 cm. By definition, a small field is when at least one of three conditions are satisfied: (1) loss of lateral charged particle equilibrium on the beam axis; (2) partial occlusion of the photon source by the collimator; (3) the size of the detector is similar or larger than the beam dimensions. Challenges due to these small fields include lack of charged particle equilibrium, partial blocking of the beam source, changes in stopping power ratios, and the availability of detectors with comparable sizes to the field dimensions. With lateral electronic disequilibrium, there is a lack of lower energy electrons, so the average energy spectrum at the central axis will increase, and the stopping power ratio of water to air will decrease. This results in an overlap between the field penumbra and detector volume. The detector itself produces a perturbation that is hard to quantify, and a correction factor is necessary.
Use of the IAEA/AAPM (International Atomic Energy Agency/American Association of Physicists in Medicine) protocol for reference and relative dosimetry based on Alfonso et al. (2008) is recommended. This uses a correction factor dependent on beam energy, type of detector, type of machine, and focal spot size. Reference dosimetry has its basis on a 10x10 cm field. For SRS machines, where the conventional 10 x 10 cm reference field cannot be established, specific reference conditions related to the machine specific reference fields are used. Calculations are indirect, and, so there are resultant significant deviations in dosimetry. Monte Carlo simulation is extensively used to improve the accuracy of small field dosimetry under the nonequilibrium radiation conditions.
The dose is in gray (Gy), which is the absorption of one joule of radiation energy per kilogram of matter. The SRS dose is biologically equivalent to five to six weeks of daily conventional radiation therapy. The dose is deliverable in either a single session or two to five sessions of fractionated therapy over days - called fractionated stereotactic radiotherapy (FSR or SRT). The advent of non-fixed SRS immobilizations systems, onboard imaging to verify accuracy and patient monitoring systems during radiation allows reproducible, precise patient positions, making fractionation possible.
FSR is usable for eloquent areas, for larger lesions and for lesions close to critical structures (e.g., the optic chiasm, ventral cochlear nucleus, and the brain stem which have lower tolerance). The result of FSR is that the biologically effective dose is increased, with decreased toxicity. By using fractions, the total treatment dose can be kept below the radiation tolerance of critical structures, while still achieving control. For example, an optic apparatus maximum dose associated with a clinically reasonable risk of radiation-induced necrosis of the optic nerve is 10 Gy in 1 fraction, 20 Gy in 3 fractions, and 25 Gy in 5 fractions. The Radiation Therapy Oncology Group Trial, which looked at patients receiving SRS for brain metastases following WBRT or recurrent gliomas post radiation, developed dose limits for SRS of 24 Gy for lesions less than 2 cm, 18 Gy for lesions 2 to 3 cm and 15 Gy for tumors 3 to 4 cm. This meant that the tumors with the larger tumor volume were receiving lower doses, with worse rates of local control. FSR may provide an improved balance of tumor control and toxicity In these instances. Meta-analysis has shown that for large brain metastasis, FSR can reduce the rate of radionecrosis while maintaining or improving rates of one-year local control versus single-fraction treatment.
Deciding on SRS or FSR for brain metastases is multifactorial. Physical factors (tumor size, margins, optimal dose, etc), biological factors (histology of the metastases, use of systemic agents) and clinical factors (life expectancy, co-morbidities, concurrent treatments required) all play a role in decision making. Currently, trials are ongoing looking at the role of FSR for brain metastases, glioblastomas, meningiomas, and vestibular schwannomas, the majority with the primary outcome to determine maximum tolerated dose.
Nurse specialists (oncology nurse)
Stereotactic radiosurgery is a non-invasive, outpatient procedure, which does not require a general anesthetic. The first step is to localize the target. Focused gamma rays involve a specialized helmet surgically fixed to the patient’s skull under local anesthetic. The patient is immobilized with a head frame, secured with screws that pierce the scalp. A frameless version of the technology is also available. A fiducial reference box is placed onto the frame to provide coordinates, and magnetic resonance imaging (MRI), computed tomogram (CT) or angiogram is performed to define the target in three dimensions. With focused gamma ray treatment, the patient and the machine remain stationary throughout the procedure.
With the linear accelerated surgery, either the patient or the gantry can move in space to change the delivery point. In the past, a stereotactic frame was used to restrict movement. However, newer frameless approaches have been developed, with improved patient comfort. One of these technologies uses a small 6 MV linear accelerator mounted on a robotic arm with six degrees of freedom with two orthogonal x-ray cameras to create a dynamically manipulated, real-time, therapy beam. The treatment couch has electronic controls for five degrees of freedom (x, y, z, head tilt, and left-right rotation) with an additional manual clockwise-anticlockwise rotation based on patient position.
Next, an individualized treatment plan is developed to focus the radiation as precisely as possible. A computerized treatment planning system is used and requires depth doses, tissue maximum ratio (the ratio of the dose at a given point in a phantom to the dose at the same point at the reference depth of maximum dose), off-axis factor and collimator output factor for each stereotactic collimator. Individual beams can be adapted to conform to irregular shapes and minimize the damage to normal brain tissue. Dose adjustment is according to the maximum dose, which is deliverable to surrounding structures. Multiple lesions can be delivered sequentially or simultaneously, depending on the device.
Once quality assurance is guaranteed, and an independent output check performed, the patient gets positioned on a treatment couch, and the radiation is delivered. The treatment time varies from thirty minutes to three hours. Intravenous dexamethasone can be given to reduce complications, and this can be tapered post-treatment. Most patients are discharged after an hour and can resume normal activities within one week.
Radiation causes vascular endothelial damage and demyelination of the white matter, leading to necrosis. Acute effects, which occur within weeks of treatment, are likely due to cerebral edema and the disruption of the blood-brain barrier. Symptoms include headache, nausea, and vomiting. Subacute effects are due to diffuse demyelination and resolve within six months. Symptoms include somnolence and fatigability. Late effects, occurring six months post-treatment, are the result of white matter tract damage following an injury to vascular endothelial cells, axonal demyelination, and coagulation necrosis, which can be permanent and includes progressive memory loss.
SRS has a better side effect profile than WBRT. An acute side effect is commonly headache, with less frequent (less than 5%) complications including pin-site infections, seizures, and short term exacerbations of neurological symptoms. Late effects include radiation necrosis, brain edema, and new or worsening neurological deficits. However, this occurs in less than 5% of patients. Systematic reviews suggest that brain edema depends on greater tumor margin, maximum dose, tumor size/ volume, lesion location (particularly parasagittal, parafalcine or convexity), first resection, and pre-existing edema. SRS can cause delayed cranial neuropathies, especially the optic nerve and visual pathways. Factors associated with the injury include the type of nerve, the maximum dose, and length of the irradiated nerve.
Stereotactic radiosurgery is an invaluable treatment option for brain and spine metastasis, primary tumors, vascular and functional conditions. As the techniques develop further, the indications are growing.
Stereotactic radiosurgery is a superior treatment option to WBRT, which is associated with significant neurological complications, including neurocognitive impairment, which limits its use.
The advantage of SRS over surgery is its minimally invasive nature. It is an outpatient procedure, which doesn’t require a general anesthetic, and can treat multiple lesions in the same session with short recovery times. It is useful for deep, surgically inaccessible lesions or those in eloquent areas.
Stereotactic radiosurgery requires the involvement of both the surgical and radiation oncology teams who collaborate effectively to evaluate and treat each patient. Effective implementation of stereotactic radiosurgery involves the use of the interprofessional team, including neurosurgeons, radiation oncologists, neuroradiologists, medical physicists, dosimetrist, radiation therapist, nurse specialists, and the patient.
Radiation oncology nurses are vital for patients receiving stereotactic radiosurgery. These nurses need to work collaboratively with physicians and specialists to coordinate care for optimal patient outcomes. Pre-procedurally, they assess the patient and provide a point of contact and information to the patient and their family. Proper communication and education of the patient, regarding the procedure and risks involved, is of paramount importance. On the day of treatment, the nurse's roles include assisting the clinician with set-up, head ring placement, positioning, maintaining patient immobilization during the treatment session, patient monitoring, maintaining comfort, and discharge planning. Only through an interprofessional team approach will the best outcomes be achieved. [Level V]
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