Stereotactic Irradiation: Linear Accelerator and Gamma Knife

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Chapter 17 Stereotactic Irradiation

Linear Accelerator and Gamma Knife

Derek R. McHaffie, Deepak Khuntia, John H. Suh, Wolfgang Tomé, Minesh P. Mehta

Radiosurgery was first described in 1951 by Lars Leksell,¹ a neurosurgeon at the Karolinska Institute in Stockholm, Sweden. The term radiosurgery was selected because of the similarity of this technique to stereotactic neurosurgery. The initial work by Leksell first involved the treatment of patients with functional disorders and benign conditions such as chronic pain and arteriovenous malformations but later included benign and malignant tumors. The first patient was treated with the Gamma Knife in 1968.² The limited availability, skepticism regarding the technology, and prohibitive costs initially limited the spread of Gamma Knife technology. By the 1980s, linear accelerator-based radiosurgery had evolved and further renewed the interest in stereotactic radiosurgery.

Because of hardware and software improvements, the use of radiosurgery has proliferated and several hundreds of thousands of patients have now been treated. In this chapter, we discuss the physics and radiobiologic principles of radiosurgery, as well as the clinical application of this technology. Particle beam therapy is not the focus of this chapter.

Basic Principles Of Radiosurgery

Radiosurgery differs significantly from conventional fractionated radiotherapy. By definition, radiosurgery implies a single treatment. With conventional fractionation regimens, some normal brain tissue adjacent to a target receives a nearly full dose of radiation. Normal brain parenchyma is relatively unforgiving in regard to late toxicity and, therefore, the fact that radiosurgery can treat with high-dose gradients adjacent to a nonmobile target makes the use of radiosurgery in the brain attractive. The use of a very large number of beams ensures that no individual beam contributes significantly to the cumulative dose, so that the amount of radiation delivered to normal tissues in the beams’ paths is minimized. This geometry provides physical dose distribution advantages for relatively small targets, usually less than 4 cm in diameter. Targets larger than 4 cm result in an unacceptable increase in dose to adjacent normal brain tissue.

Radiosurgery can be performed using various devices, including the multicobalt unit known commercially as the Gamma Knife (GK), particle beam devices, or modified linear accelerators. With technologic advances in software and hardware, a clear superiority of one technology over another has disappeared and mature clinical results demonstrate no outcome differences based on technology.³ A comparison of some of the features of the Gamma Knife and linear accelerator techniques is presented in Table 17-1. Because the linear accelerator-based units can also treat non-radiosurgery patients during “downtimes,” cost and volume considerations are key features that determine equipment selection.³

TABLE 17-1 Comparing Gamma Knife and Linear Accelerator Radiosurgery Characteristics

	Gamma Knife	Linac Radiosurgery
Clinical experience	Over three decades	Over two decades
Accuracy	Submillimeter	Submillimeter
QA	Fewer QA checks	More QA checks
Machine use	Dedicated machine	Usually not a dedicated machine
Functional disorders	Longer experience	Shorter experience
Can be used for extracranial radiosurgery	No	Yes
Price	High; must replace source every 5-7 years	Less expensive; no source replacement
Tumor location	Difficult to radiate peripheral lesions	Can treat peripheral lesions
Fractionated treatments	Not practical	Can treat with fractionated regimens
Treatment time	About equal	About equal

QA, quality assurance.

Radiosurgical and neurosurgical approaches are often complementary, but there are key differences. Radiosurgery does not require a craniotomy or general anesthesia and is performed on an outpatient basis. In a cost-effectiveness/cost-utility analysis by Mehta and colleagues ⁴ in the 1990s, the authors showed that the average cost per week of survival for a single brain metastasis was $310 for radiotherapy, $524 for resection plus irradiation, and only $270 for radiosurgery plus whole-brain irradiation. With the advent of shorter hospital stays following neurosurgical procedures, these numbers have probably changed somewhat. Other advantages include lower postoperative risks for bleeding or infection and rapid recovery times. Patients who are working before treatment often can return to work within 1 or 2 days. More importantly, neurosurgically inaccessible lesions and patients deemed unfit for surgery or anesthesia can often be treated with radiosurgery.

The clinical applications of radiosurgery have grown substantially over the past decade. There are multiple disease processes where the use of stereotactic radiosurgery has a well-established and defined role. Current indications, discussed later in greater detail, include arteriovenous malformations, benign brain tumors, malignant brain tumors, and functional disorders (Table 17-2). With improved ability to localize targets throughout the body, the principles of radiosurgery have expanded to include extracranial applications, with emerging roles in the management of lung, hepatic, and spinal tumors, among others. Some concepts of the radiosurgery paradigm have been incorporated into a strategy employing fractionated treatments; this approach, referred to as fractionated stereotactic radiotherapy (FSRT), is applied to both intracranial and extracranial lesions.

TABLE 17-2 Clinical Applications of Radiosurgery

Radiosurgery is an important tool available to the neurosurgeon and radiation oncologist. Proper implementation of the treatment requires collaboration among neurosurgeons, radiation oncologists, and medical physicists. This allows for thoughtful coordination of care, improved quality assurance, reduction in practice variation, a strategic marketing advantage, and improved patient satisfaction. Each specialty brings unique skills that are required for a successful radiosurgery program.⁵

Physics Of Radiosurgery

Stereotactic radiosurgery (SRS) involves the use of numerous beamlets of radiation aimed precisely at an immobilized target to deliver a single session of high-dose radiation. Though no single beamlet carries significant weight, a large dose is deposited at the intersection of these beamlets with a steep dose fall-off outside the target. As tumor size increases, this fall-off becomes shallower ⁶; typically, radiosurgery becomes prohibitive at sizes in excess of 4 to 5 cm.

Physics Fundamentals

Multicobalt units containing cobalt-60 (⁶⁰Co) sources include devices such as the Gamma Knife and the Rotating Gamma System (developed in China) (Figs. 17-1 and 17-2). ⁶⁰Co decays with a half-life of 5.26 years, requiring that sources be replaced every 5 to 7 years. For new sources, total activity is approximately 6000 Ci with a dose rate of 400 cGy/minute. Radioactive decay releases two gamma rays with an average energy of approximately 1.25 MeV. A gamma ray and an x ray cannot be discriminated and differ only in source of origin. Gamma rays result from radioactive decay, whereas x rays are generated by accelerating electrons (in a linear accelerator) and colliding them into a tungsten target.

Figure 17-1 A, Gamma Knife model C unit. The Gamma Knife unit is the most common gamma ray–based radiosurgery unit used in the world. B, The model C unit is equipped with an automatic positioning system (APS) that reduces the need for manual position adjustments during treatment. Pictured is the 14-mm collimator helmet. C, Perfexion, the newest Gamma Knife system, incorporates automated collimator changes and expands the treatment volume to include the cervical spine and head and neck regions.

Figure 17-2 Rotating Gamma System. This system was developed in China, but the device is commercially used in a few centers in the United States.

Courtesy Tomasz Helenowski, M.D., Rotating Gamma System Institute, Gurnee, Illinois.

Protons are charged particles that have been adopted in a few centers for use in radiosurgery. One of the advantages of protons is that they deposit most of their energy over a finite distance, with very little exit dose. This narrow region of energy deposition is known as the Bragg peak and it may allow for a reduction in integral dose (total dose to the patient).

Components of a Radiosurgery Unit

Both multicobalt and linear accelerator units have at their heart a source of radiation (cobalt for the Gamma Knife [GK] and the linear accelerator for linac-based units), a couch, a stereotactic helmet or frame system to ensure precise localization and immobilization, and sophisticated treatment planning software. When properly calibrated, an isocenter alignment to better than 1 mm can be achieved with either the GK or the linac radiosurgery system, although it is important to recognize that image resolution, which depends on the slice thickness, is usually of a cruder magnitude.⁷

The use of the stereotactic frame ensures reproducible patient position and serves as the platform to which various coordinate localization devices can be attached. Generally, the frames are applied under a local anesthetic and sedation with multiple pins that penetrate the skin and fix to the outer table of the skull. Coordinate systems used for radiosurgery are based on Cartesian coordinates and allow for the precise definition of the target relative to the origin of the stereotactic localization system one is using. This permits precise geometric definition for the placement of various isocenters (or “shots”) and the correct beam geometry. The coordinate system is established in the treatment planning system and is used during treatment planning to define each of the shots or groups of arcs used to deliver focused radiation to the target.

Pretreatment Quality Assurance

Because GK radiosurgery uses live sources, radiation exposure and safety are important issues. Exposure maps of the entire room and surrounding environment are therefore necessary. The central dogmas of radiation safety—namely, time, distance, and shielding—are paramount, especially when live sources are used. Principles of ALARA (as low as reasonably achievable) need to be implemented. Typical “action levels” include level I with 10% exposure (125 mR/quarter) and level II with 30% exposure (375 mR/quarter) of the maximum allowable. Obtaining these action levels will result in consequences, which vary depending on the rules set by the specific institution’s radiation safety department.

In regard to actual operation, only trained oncologists or therapists can operate radiosurgery units. All operators must be in the vicinity of the control area during the treatment. The operator will ensure that all required safety checks have been performed and that the written directive has been completed. In addition to their involvement in calibration and treatment planning, physicists play a major role in ensuring that radiation safety measures are in concordance with regulatory guidelines.

An in-depth description of the various linac radiosurgery systems is beyond the scope of this chapter, and the interested reader is referred to Task Group Report 54 of the American Association of Physicists in Medicine.⁷ In general, linac radiosurgery systems can be classified into three groups. First, there are couch-mounted systems that use the treatment lasers or implanted fiducial markers as their target verification system; these systems are probably the least accurate because they have an isocenter stability of at best ±2 mm for any couch and gantry angle. Next, there are the so-called floor stand–mounted systems that connect to the treatment couch and allow the user to correct for inaccuracies in the rotation of the couch during treatment. However, these systems do not allow for corrections of inaccuracies in gantry rotation and, therefore, such systems have at best an isocenter stability of ±1 mm for any couch and gantry angle. The most accurate linac radiosurgery system uses a floor stand with a high-precision bearing that is indexed to the linac but does not connect to the treatment couch. In this system, the floor stand is decoupled from the linac treatment couch; this allows for a high accuracy of couch rotation, on the order of a few hundredths of a millimeter. Furthermore, this system has a separate arm rotating around a high-precision bearing that holds the collimator, which is coupled to the linac gantry using a gimbal bearing. Because all translational and rotational degrees of freedom are decoupled from the linac, this system can be calibrated to have an isocenter stability that is equal to that of a GK of ±0.25 mm for any gantry and couch angle.⁸

Regardless of which radiosurgery system used, a comprehensive pretreatment quality assurance (QA) program should be implemented. A typical program consists of three parts. First, verification that the frame has not slipped by using a depth helmet to measure the distance from the patient’s skull to the helmet by means of various predefined access points. A measurement is taken before the patient is imaged, after the patient is imaged, and before the patient is set up on the floor stand. Only if all measurements are within 1 mm does one proceed with the treatment. Second, a pretreatment isocenter verification film is obtained. In this test, the coordinates of the first isocenter are set up on the floor stand and a QA phantom independently. This test film serves two purposes: it checks that the isocenter has been correctly set up on the floor stand, and it allows confirmation of the integrity of the radiosurgery system. Third, a thorough, independent pretreatment check is carried out by the attending physician, including verification of the isocenter coordinates, the collimator setting, the collimator angle, the cone size, the system interlocks, and a final check verifying patient positioning.

Radiobiologic Considerations

Radiobiologically, the use of a single fraction to treat a small volume differs significantly from conventional fractionated external beam irradiation (EBRT) procedures. This poses unique challenges in that the increased biologic effect on normal tissues is more pronounced than it is on tumors ⁹ (Fig. 17-3). The most important factor influencing the risk of developing late side effects is fraction size. Therefore single-fraction radiosurgery needs to be exquisitely accurate and must minimize the dose to normal tissue.

Figure 17-3 Representation of radiosurgery versus radiotherapy dose for both early- and late-responding tissues.

From Mehta MP: The physical, biologic, and clinical basis of radiosurgery, Curr Probl Cancer 19(5):265-329, 1995.

Another potential disadvantage of using single-fraction treatment is the inability to exploit the temporal effects of cell cycle distribution. Because cells are thought to be most sensitive in the G2 and M phases of the cell cycle, fractionating radiation treatment allows redistribution of cells into the radiosensitive phases, which may improve cell kill. Hypoxia is another important variable to recognize. Malignant tumors are usually partially hypoxic, and fractionated treatments take advantage of the reoxygenation of the tumor that occurs between fractions. The use of single-fraction SRS does not exploit cell redistribution and reoxygenation for therapeutic gain.

Despite these theoretical disadvantages of single-fraction radiation, efficacy with minimal toxicity has been shown in clinical trials in a multitude of disease sites. Radiosurgery, by treating in a single-fraction regimen, minimizes the deleterious effects of repopulation (tumor regrowth between fractions). Further, the high doses of radiation could potentially overcome the disadvantages of single-fraction delivery. Recent observations suggest the DNA-centric model of classical radiobiology is more complex than initial experiments appreciated, including effects on membrane-bound signaling pathways.¹⁰ It appears that radiation effects on the tumor microvasculature are also an important component of tumor response and control.¹¹ Higher ablative doses of radiation have been shown to induce marked endothelial apoptosis with substantial downstream effects on the competency of tumor microvasculature.¹¹ At doses of more than 8 Gy per fraction, the linear quadratic (LQ) model does not accurately predict cell kill or toxicity.¹² This poses significant clinical challenges in developing dose-volume normal tissue constraints for SRS and stereotactic body radiotherapy (SBRT), as the LQ model is often used to account for differences in dose per fraction when extrapolating from toxicity analyses obtained using conventional regimens.

Treatment Planning

Treatment planning methods vary based on the software, but ultimately the treatment plans are similar. The GK system contains 201 ⁶⁰Co sources that are channeled through a tungsten collimator helmet generating narrow radiation pencil-beams to coincide within 0.1 mm of each other at the geometric center of the helmet. Multiple circular collimators are used to generate “shots” to fill a particular volume using one or multiple isocenters. Doses are typically prescribed to the 50% isodose line. There are four helmets with varying collimator sizes of 4, 8, 14, and 18 mm used in the GK system. The latest GK unit, Perfexion, provides automated change of collimator helmets, reducing treatment times when multiple collimator sizes are employed.

Multiple linac-based radiosurgical systems are commercially available, including Novalis BrainLAB (BrainLAB AG, Feldkirchen, Germany), Radionics XKnife (Integra, Plainsboro, New Jersey), TomoTherapy (TomoTherapy, Inc., Madison, Wisconsin), CyberKnife (Accuray, Inc., Sunnyvale, California), and others. With linac-based radiosurgery, optimal distributions can be obtained by using a micro-multileaf collimator or circular collimators that “shape” the beam. These devices allow for fractionation, more flexibility with beam shaping, and also modulation of beam intensity. Linac-based devices are also more readily adaptable for extracranial radiosurgery or fractionated delivery.

Both GK and conventional linac-based SRS treatment planning procedures begin with the placement of the stereotactic head frame on the patient. The head frame is used for precise localization and rigid immobilization to guarantee that the patient’s position from the time of imaging to the time of treatment does not change. Before the stereotactic CT is acquired, a stereotactic localizer ring is attached to the head frame. For linac radiosurgery, the most commonly used independent stereotactic localization system is the Brown-Roberts-Wells (BRW) system (Fig. 17-4). The BRW localizer has an inner diameter of 29 cm and a height of 16 cm and consists of nine carbon fiber rods that are arranged into three N-shaped structures between two aluminum rings, which are placed at 120-degree angles around the rings. Because three N-shaped fiducials are used, one obtains a system of linear equations that allow for definition of an independent, absolute coordinate system. Therefore one does not have to QA the table indexing of the CT scanner, because the slice position of each scan can be uniquely determined.

Figure 17-4 Phantom with head ring as well as the Brown-Roberts-Wells (BRW) coordinate system in place.

The origin of the BRW system lies within the localizer and therefore divides the brain into eight distinct quadrants. Any point within this geometric configuration can be uniquely defined by specifying anterior-posterior, lateral, and axial coordinates. During the stereotactic CT scan, portions of these N-shaped structures are included in each image, which allows for their identification during treatment planning. To reduce the error in localization, the slice thickness of the CT scan should be the smallest attainable on the scanner. Once the stereotactic CT scan has been acquired, it is transferred to the treatment planning system and the BRW coordinate system is defined by localizing each of the nine rods in each of the CT slices (Fig. 17-5).

Figure 17-5 Four-panel view of acquired stereotactic CT illustrating how the BRW localizer rods are embedded into the CT images.

Next, the target volume, or gross tumor volume (GTV), is outlined. Because magnetic resonance imaging (MRI) often provides better tumor visualization than CT scanning, the GTV is often delineated directly from MRI studies. MRI alone does not provide a sufficient database for stereotactic treatment planning, because magnetic field nonuniformity, gradient field nonlinearity, eddy current effects, and susceptibility artifacts at air/tissue interfaces can introduce significant geometric image distortions that affect the accuracy of treatment plans generated using MRI alone. A three-dimensional volumetric MRI is acquired either before or after head ring placement. After acquiring the stereotactic CT scan, the MRI dataset (which may or may not be stereotactically generated) is fused onto the CT image space through correlation of anatomic landmarks in both image sets. During treatment planning, the regions of interest and dose distribution may be displayed on either the CT image or the fused MRI images, but dosimetric calculations are ideally performed on the underlying CT database (Fig. 17-6). If the MRI is to be obtained after head frame placement, magnetic resonance–compatible head rings need to be used.

Figure 17-6 Image fusion of a stereotactic CT with a T1-3D-SPGR MRI image set with gadolinium contrast. The MRI has been pixilated to show the underlying CT. The difference in tumor visualization between the two imaging modalities is visible.

Some investigators use a “noninvasive” fiducial system in which several fiducials are either implanted subcutaneously or taped on the patient. The fiducials then provide the frame of reference for obtaining stereotactic coordinates. The noninvasive nature of this approach is appealing, but there are concerns regarding perceived problems with patient immobilization during treatment. One such frameless system is the CyberKnife, which is particularly suited for both central nervous system and extracranial applications. The CyberKnife combines a compact 6-MV linear accelerator waveguide with a robotic arm with 6 degrees of freedom. It contains adjustable collimator cones ranging from 5 to 60 mm to deliver highly conformal treatment through several hundred narrow radiation beams from many different angles. For brain radiosurgery, immobilization uses only a thermoplastic facemask. Two orthogonal x-ray cameras mounted to the ceiling allow for real-time tracking based upon bony landmarks or implanted fiducials.

Conventional linac radiosurgery uses multiple non-coplanar arc sets to treat the target volume through a variety of collimator diameters ranging in size from 4 mm to 50 mm, depending on the system (Fig. 17-7). For irregularly shaped lesions such as vestibular schwannomas and arteriovenous malformations (AVMs), arcs delivered through a single circular collimator would lead to the inclusion of a large amount of normal brain tissue, which would yield inferior conformality. In these cases, it is advantageous to use multiple isocenters to conform the prescription isodose shell to the GTV (Fig. 17-8). The dose is typically prescribed to the 70% to 90% isodose line. Whenever multiple isocenters are used, homogeneity is sacrificed for conformality. Ideally, a desirable conformality index (prescribed isodose volume divided by target volume) should be 2 or less and the heterogeneity index (maximum dose divided by prescribed dose) should also be 2 or less.

Figure 17-7 Typical five nonopposing arrangements used in multi-isocenter treatment planning for linac-based radiosurgery.

Figure 17-8 Three selected axial cuts through a vestibular schwannoma showing the resulting conformal treatment plan using four different isocenters. The gadolinium contrast-enhanced thin-slice T1-3D-SPGR MRI data set has been fused to the underlying stereotactic CT to visualize the vestibular schwannoma. The 12.5-Gy treatment isodose line and the 10-Gy isodose line are shown.

Clinical Applications

Both the GK and linac-based forms of radiosurgery have been used in a variety of benign and malignant diseases. Table 17-2 summarizes the most common clinical applications for radiosurgery. In this section we outline some of the basic applications of radiosurgery and results of therapy. Specifics pertaining to each disease are discussed in greater detail in its respective chapter.

Benign Tumors

Meningiomas

Benign diseases make up a considerable proportion of the applications for radiosurgery, with meningioma being one of the most common indications. Up to one-third of meningiomas, however, present in locations not amenable to complete removal. Radiosurgery plays an important role in the treatment of small lesions (<3 to 4 cm) that are surgically inaccessible, such as those in cavernous sinus or posterior parasagittal locations, or those that have been subtotally resected but consistently have been shown to result in high recurrence rates.

Two of the largest series that have examined results of SRS are from the Mayo Clinic and the University of Pittsburgh, both of which have shown local control in more than 90% for benign meningiomas at 5 years.^13,^14,¹⁵ The Mayo Clinic series had a significant complication rate of 13% versus 7% for the University of Pittsburgh series.

Based on published reports, the optimal dose to the margin of the tumor appears to be 12 to 16 Gy. A recent report by Kollova and colleagues ¹⁶ showed that doses above 16 Gy increased the risk of treatment-related edema without a corresponding improvement in tumor control. Inclusion of the dural tail within the treatment volume remains a topic of controversy. Limited histopathologic analysis has shown that microscopic tumor extension into the dural tail is limited to 2 mm.¹⁷ The most common toxicities include cranial nerve deficits for basal tumors and peritumoral edema for nonbasal tumors. The risk of optic neuropathy is very low, with maximum dose constraints to the optic nerves and chiasm of between 8 and 10 Gy.^13,¹⁸ In addition to the dose, a treatment volume of more than 5 cm³, a tumor-brain contact interface of 1 cm² or more, the presence of pretreatment edema, and parasagittal location each increase the risk of peritumoral edema.^16,19,20,21 These factors should be considered when deciding whether or not to include none of the dural tail or only a portion of it within the clinical target volume (CTV), which for all practical purposes is the same as the GTV. With SRS, radiologic response is seen in 50% to 60% of patients, and the remainder of those without progression demonstrated tumor stability.^16,22

Based on these data, it is reasonable to conclude that small meningiomas can be controlled with radiosurgery in the majority of patients, with initial results comparable to those of complete resection (Fig. 17-9). It must, however, be borne in mind that most cases in which this approach has been used have had relatively short follow-up studies and that long-term results (more than 10 years of follow-up studies for each patient) are indeed very sparse. The University of Pittsburgh recently updated their 18-year experience in a cohort of 972 patients. Local control rates in grade 1 meningioma or lesions without histology were 91% and 95%, respectively, in 75 patients with a minimum follow up of 10 years.

Figure 17-9 A, Radiosurgery plan showing tumor volume and 18-Gy isodose line covering entire tumor. B, Posttreatment MRI with complete resolution of the lesion.

Vestibular Schwannomas

Vestibular schwannomas make up between 6% and 8% of all primary intracranial tumors. There are approximately 1200 cases per year. Vestibular schwannomas are thought to arise at the point where nerve sheaths are replaced by fibroblasts. This transition point is referred to as the Obersteiner-Redlich zone and is usually located with the internal auditory canal. Though benign, the lesions can cause severe local symptoms. Typical growth rates are less than 2 mm per year. Common symptoms include unilateral sensorineural hearing loss (>90%), tinnitus, unsteady gait, facial numbness or weakness, mastoid pain, and headaches. Late presentations can include brain stem compression. The typical appearance on T1-weighted MRI with contrast shows a homogenously enhancing mass within the cerebellopontine angle with a variable tail extending into the internal auditory meatus.

Treatment options include observation for appropriately selected patients, microsurgical resection, SRS, or fractionated radiotherapy. Based on single-institution experiences, all three approaches appear to result in a tumor control probability of more than 90%. Microsurgery is preferred for lesions larger than 3 cm.²⁴ There are no randomized trials directly comparing different methods. The goals of treatment include maximizing tumor control while preserving hearing and facial nerve and trigeminal nerve function. Treatment recommendations are influenced by age, comorbidities, tumor size, presenting symptoms, proximity to the brainstem or cochlea, and patient preference.

When SRS is chosen as the treatment option, the recommended dose is 12 to 13 Gy in a single fraction.25,26,27 Initial experiences with doses in the range of 16 to 20 Gy resulted in a higher rate of treatment-related toxicity. A recent review of the literature reveals that with modern SRS techniques and doses, hearing preservation is achieved in 50% to 89% of patients, with a risk of less than 5% for facial or trigeminal neuropathy.^28,²⁹ The risk of sensorineural hearing loss is related to the dose of radiation delivered to cranial nerve VIII, the cochlea, and the ventral cochlear nucleus.^30,31

There are three prospective nonrandomized studies in the literature comparing SRS and microsurgery, all of which showed improved serviceable hearing preservation and reduced facial nerve toxicity in patients treated with SRS.³²^–³⁴ Two retrospective, single-institution, matched-pair analyses have reported similar findings.^35,³⁶ The prospective series by Regis and associates³³ reported a statistically lower incidence of trigeminal nerve deficits with SRS. The risk of cranial nerve injury with microsurgical resection is highly dependent on tumor size, operative approach (retrosigmoid, middle cranial fossa, or translabyrinthine), and the surgeon’s skill and experience. Nonetheless, SRS may be the preferred treatment in properly selected patients with vestibular schwannomas less than 3 cm in size.

Published nonrandomized data support comparable efficacy between SRS and fractionated stereotactic radiotherapy (FSRT). Common regimens include conventionally fractionated doses of 45 to 50 Gy at 1.8 Gy/fraction or abbreviated-course, hypofractionated regimens, such as 20 to 25 Gy at 4 to 5 Gy/fraction. The best series to date is a trial done by Meijer and colleagues ³⁷ in the Netherlands. Their group prospectively evaluated 129 patients with vestibular schwannomas. Patients were assigned to receive either 20 to 25 Gy in four to five fractions (80 dentate patients) or 10 to 12.5 Gy in a single fraction (49 edentate patients). Local control rates, hearing preservation, and cranial nerve VII complications were not statistically different. There was an increase in cranial nerve V complications with single-fraction radiosurgery (8% vs. 2%).

A retrospective series from Thomas Jefferson University reported high rates of hearing preservation in the range of 80% to 85% using conventional FSRT, a rate that was 2.5-fold higher than rates for SRS.³⁸ A more recent analysis showed no difference in tumor control or cranial nerve deficits between SRS at 13 Gy or less and conventional FSRT.³⁹ Neither SRS nor fractionated approaches have been tested in prospective, controlled clinical trials for this disease.

Pituitary Adenomas

Ten to fifteen percent of intracranial neoplasms are pituitary adenomas. Irradiation is generally reserved for patients who have incompletely resected tumors or recurrent disease. Based on the size and location, either SRS or conformal EBRT may be considered. SRS is typically contraindicated for tumors within 3 to 5 mm of the optic chiasm, respecting a maximum dose constant of 10 Gy or less to the optic nerves and chiasm.⁴⁰ Typical single-fraction SRS doses to the pituitary have ranged from 10 to 30 Gy, but doses in the range of 13 to 14 Gy have been found to be equivalent to higher doses.⁴¹ Local control using SRS is generally in excess of 90% for nonsecretory tumors. Radiation-induced hypopituitarism occurs in more than 50% of patients and is the most common late toxicity.⁴²

For secretory tumors, SRS appears to result in a shorter time to hormone normalization than fractionated radiotherapy.43,44 Though tumor control remains high, hormonal remission is seen in 25% to 75% of patients and depends on the tumor subtype (i.e., prolactinoma, Cushing’s disease, Nelson’s syndrome, or acromegaly). Cytostatic medical management of secreting pituitary adenomas is often employed. Patients receiving octreotide or dopamine agonists have had markedly inferior control rates with radiotherapy in several series.^45,46 If symptoms allow, these medications should be discontinued in advance of treatment.

Malignant Tumors

Brain Metastasis

Brain metastasis affects over 150,000 patients in the United States annually and is the most common setting in which radiosurgery is employed. We will briefly describe the rationale for radiosurgery for brain metastasis.

Dose selection parameters for treating brain metastases with SRS were defined by a phase I Radiation Therapy Oncology Group (RTOG) trial. Properly selected parameters result in a rate of less than 20% of grade 3 or higher neurotoxicity when they are combined with whole-brain radiotherapy (WBRT).⁴⁷ Recommended doses for brain metastasis are based on a maximal diameter of 21 to 24 Gy for lesions of 2 cm or less, 18 Gy for lesions of 2 to less than 3 cm, and 15 Gy for lesions of 3 to 4 cm. RTOG 95-08 investigated WBRT (37.5 Gy/15 fractions) with or without SRS in a randomized design. The trial showed a survival benefit for patients with a single brain metastasis. Additionally, post-hoc subgroup analysis suggests an improved median survival with up to three brain metastases in patients younger than 50 years, those who have non–small cell lung cancer, or those with recursive partitioning analysis (RPA) class I disease.⁴⁸

Both surgery and SRS have a proven survival benefit in the management of a single brain metastasis.^48,⁴⁹ Typically, surgery is preferred in patients with good performance status, large lesions (>3 cm), or symptomatic tumors with substantial vasogenic edema.⁵⁰ In patients who are good candidates for either surgery or SRS, there are no randomized data currently available to indicate which is the preferred treatment modality. Multiple phase III trials are currently ongoing. Rades and colleagues⁵¹ recently reported a matched-pair analysis of WBRT plus surgery or SRS in 104 patients with one to three brain metastases. At 1 year, this study found improved rates of overall survival, intracerebral control, and local control with SRS.⁵¹ However, the value of surgery for multiple brain metastases has not been established.

Currently, eliminating WBRT in SRS patients is controversial. Initial retrospective series have suggested that eliminating WBRT increases the likelihood of central nervous system relapse but does not necessarily affect survival rates.52,53,54 This was confirmed in a randomized trial by the Japanese Radiation Oncology Study Group (JROSG 99-11).⁵⁵ The preservation of neurologic function is a fine balance between the toxicity of brain irradiation and the negative consequences of tumor relapse.⁵⁶ A recent randomized trial from the M. D. Anderson Cancer Center showed that the addition of WBRT to SRS is associated with a significant decline in learning and memory at 4 months.⁵⁷ However, this trial and others have consistently shown higher rates of intracranial relapse when WBRT is excluded and the preservation of neurocognitive function is strongly correlated with tumor control with more extended follow-up.⁵⁸

Gliomas

Because at least 80% of gliomas fail within 2 cm of the primary tumor, high-dose local irradiation has been hypothesized as a means of improving tumor control rates. In an effort to delineate the role of SRS, the RTOG conducted a randomized trial of 203 patients with glioblastoma multiforme who received either 60 Gy of EBRT at 2 Gy/fraction with BCNU or SRS prior to EBRT and BCNU.⁵⁹ Radiosurgery did not add to the overall survival rates, quality of life, or neurologic function as performed in this trial. Malignant gliomas are most commonly large, diffusively infiltrative tumors with substantial surrounding edema known to harbor microscopic disease, reducing the likelihood of success of SRS. Based upon this trial, there is currently no well-defined role for SRS in the adjuvant setting for glioblastoma multiforme and potentially for all gliomas.

Despite a lack of proven benefit for primary gliomas, there is considerable interest in SRS for treatment of recurrent malignant gliomas. Multiple institutional series have been reported, some of which suggest a survival benefit in comparison with historical controls.⁶⁰ However, such reports are particularly susceptible to patient selection bias, and no prospective studies have adequately defined a role for SRS at present. Patients with small-volume, focal, or nodular recurrent disease may be candidates for this modality. Current limitations of this strategy include adequately defining target volumes and a high risk of radiation-related complications. SRS dose selection is based upon volume and was defined by RTOG 90-05 (see the previous section on brain metastases) because approximately 40% of patients included in this phase I trial had had previously irradiated primary brain tumors. Several analyses have suggested that younger patient age, higher performance status, smaller tumor volume, unifocal recurrence, and hemispheric location are factors that affect the outcome following SRS for recurrent disease.^61,62

Vascular Lesions

Arteriovenous Malformations

Arteriovenous malformations (AVMs) represent abnormal clusters of arteries and veins that shunt blood from the arterial system to the venous system without an intervening capillary network. If left untreated, there is a risk of hemorrhage of about 1% to 4% per year with high rates of associated morbidity and mortality. Therefore, treatment is often considered in an asymptomatic patient. Treatment options include observation, embolization, surgery, or SRS. Surgery is the treatment of choice, when feasible, as it immediately removes the risk of hemorrhage. However, if the volume of the nidus is small and inoperable, SRS is a safe and effective alternative.

The high dose of radiation presumably unleashes a cytokine cascade that induces fibrointimal reaction, thrombosis, and eventual obliteration of the AVM nidus over 1 to 3 years. Typical doses used are in the range of 15 to 30 Gy. Target volume definition is a multidisciplinary process using a combination of angiography, CT angiography, and MRI/MRA of the brain. Large or diffuse AVMs can be approached with initial embolization to reduce the volume of nidus before SRS. Sequential SRS to larger volumes has also been reported.⁶³

Complete obliteration of the nidus is observed in 75% to 90% of AVMs treated with radiosurgery. Both smaller nidus volume and radiation dose are predictors of successful obliteration.64,65,66 However, it may take up to 3 years for complete obliteration. During the latency period, there is evidence for a reduced risk of hemorrhage despite radiologic persistence.^67,⁶⁸ Following obliteration, the risk of hemorrhage is reduced by approximately 90%, but it is not eliminated.⁶⁸

Functional Disorders

Trigeminal Neuralgia

Trigeminal neuralgia (also known as tic douloureux) is a syndrome characterized by paroxysmal facial pain. It affects about 150,000 people worldwide each year. This disorder is characterized by brief attacks of severe pain in the face, mouth, and teeth that tends to radiate into the face on the affected side. It is not known what causes trigeminal neuralgia, although most authorities believe that vascular compression on the trigeminal nerve near the pons causes most cases. It is to this region of the brain that local treatments are directed.

Initially, trigeminal neuralgia is managed medically with agents such as carbamazepine, which is the treatment of choice. Other medications include oxcarbazepine, lamotrigine, gabapentin, phenytoin, benzodiazepines, and baclofen, which are often used in combination if tolerated. Procedural intervention is considered for symptoms refractory to medical management. Treatment options include microvascular decompression, balloon compression, glycerol rhizotomy, radiofrequency rhizotomy, and SRS, all of which have been proven to produce pain relief in most patients.

For patients refractory to medications, SRS is the least invasive procedure. Typical doses are 70 to 90 Gy in a single fraction directed at the dorsal root entry zone of cranial nerve V into the pons (Fig. 17-10). Initial SRS directed at the gasserian ganglion produced inferior results. It is thought that delivering high doses of radiation to this region will induce a block of the emphatic transmission through the pain fibers only. Pain relief is experienced with a latency of approximately 1 month. Paresthesia is the most common side effect.

Figure 17-10 A, Typical Gamma Knife radiosurgery dose distribution targeted at the root entry zone of cranial nerve V. The prescription dose is typically 70 to 90 Gy prescribed to the 100% isodose line. B, MRI taken 6 months after radiosurgery demonstrating radiographic changes in cranial nerve V.

Results from the University of Pittsburgh series indicate that approximately 70% of patients have some pain relief, with about 40% experiencing complete pain relief and no longer needing any medications.⁶⁹ Patients with typical symptoms (i.e., sharp, electric shock–like pain as opposed to dull aching or burning pain) have superior results compared with those with atypical symptoms. Also, patients with no previous surgical manipulations have a higher likelihood of obtaining complete pain relief. Similar results using linac-based SRS have been reported by Bradley and colleagues⁷⁰ from the University of Wisconsin. The response rate is durable for approximately 50% of patients.^71,72

Flickinger and associates ⁷³ randomized 87 patients with trigeminal neuralgia to receive either a single isocenter (sphere) or two isocenters (elliptical treatment volume) set up using the GK. A maximal dose of 75 Gy was delivered with 4-mm–diameter collimators. The actuarial rate of obtaining complete pain relief was 67.7% ±5.1%, with pain relief similar for one- and two-isocenter SRS. Pain recurred in 30 of 72 responding patients. Numbness and paresthesias correlated with the length of nerve irradiated. Therefore the authors concluded that calibrating the treatment volume to include a longer nerve length for trigeminal neuralgia SRS does not significantly improve pain relief but may increase complications.

Attempts for retreatment with SRS have also been reported. The University of Pittsburgh series reports rates of approximately 50% for complete pain relief and 13% for numbness following retreatment, whereas the Mayo Clinic series reports rates of 90% for pain relief and minor numbness in all patients with retreatment.74,75 Similar results have been reported by others.⁷⁶

Other Functional Disorders

Other functional disorders treated with radiosurgery include cluster headaches, obsessive compulsive disorder (OCD), Parkinson’s disease, chronic pain syndromes, and epilepsy. Currently, standard radiation recommendations for these disorders have not been developed and conclusive evidence of efficacy has not been established.

Medical management is generally the first line of treatment for cluster headaches. If patients are refractory to medical or surgical techniques, SRS can be considered. The target, as in trigeminal neuralgia, is the root entry zone of cranial nerve V. Typical doses are 70 to 80 Gy to the 100% isodose line. Initial results from small series are conflicting on the efficacy of radiosurgery in the management of intractable cluster headaches.77,78

For Parkinson’s disease, medical treatment, surgical treatment, and electrotherapy are first considered. If symptoms are refractory to this management, SRS can be considered. The target for this disease is the globus pallidus (posterior-ventral region) for patients with dyskinesia or akinesia. If patients have tremors, the ventrolateral thalamus region is targeted. Typical doses are in the range of 130 to 140 Gy, prescribed to the 100% isodose line.

Patients who have OCD that is refractory to treatment with medications, surgery, or radiofrequency capsulotomy may be considered for SRS. The target is the anterior capsule, bilaterally. Typical doses are 120 Gy to the 100% isodose line. Patients with epilepsy can also be treated with SRS if their symptoms are refractory to other modalities. Doses are typically 18 Gy to the 50% isodose line centered on the hippocampus.

Stereotactic Body Radiotherapy

With improvements in hardware, image guidance, and immobilization, the principles of radiosurgery are now being applied outside of the brain. As with SRS, stereotactic body radiotherapy (SBRT) was developed at the Karolinska Institute in Sweden in the 1990s, using a body frame for immobilization and the principles of stereotaxis for target localization.⁷⁹ It involves the precise delivery of high doses of radiation over one to five fractions using sophisticated treatment planning to generate steep dose gradients for maximal normal tissue sparing, often aided by various methods of image guidance and motion management. Over the last decade, these techniques have been refined and more widely implemented in the treatment of many cancers. Broadly, SBRT is useful as aggressive local therapy for oligometastatic disease and ablation of clinically localized, early-stage malignant tumors. It is currently being investigated for early-stage non–small cell lung cancer and lung metastases, prostate cancer, bone and spinal metastases, liver metastases, hepatocellular carcinoma, pancreatic cancer, renal cell carcinoma, and other abdominal tumors. Here we briefly introduce some of the concepts of SBRT.

Because of the high radiation doses delivered, SBRT requires very high confidence in target localization to limit the amount of damage to surrounding normal tissues. Because of the complex target motion of extracranial structures, however, the treating physician must be able to take into account and manage daily setup variability and intrafraction motion in a way that allows for highly targeted therapy. This also requires modern delivery systems with the ability to shape the prescription isodose with a high degree of conformality.

During the CT simulation process, immobilization is necessary; a whole body vacuum mold, which also serves to reduce internal motion, may be needed (see Fig. 17-11A). There are multiple reproducible systems that provide the necessary immobilization—many of which are institution specific—such as body frames, vacuum molds, abdominal compression techniques, and thermoplastic devices. Such immobilization strategies limit the effects of respiratory motion by restricting chest wall rise and diaphragmatic excursion. At the University of Wisconsin, chest wall motion can be reduced to 2 mm by using a vacuum system with an abdominal pressure pillow (Fig. 17-11B). Patients with poor pulmonary reserve, however, must be monitored closely. Alternatively, respiratory gating can be used to track the patient’s range of motion throughout respiration and deliver treatment only during the chosen phase of the respiratory cycle. In the management of lung and liver tumors, four-dimensional CT scans or fluoroscopic motion studies are conducted to provide accurate planning target volume (PTV) measurements. For tumors with avidity for positron emission tomography (PET), FDG-PET imaging is often performed with the patient in a body mold to improve the accuracy of delineating the tumor. Because the PET image is acquired over an extended period, motion is already accounted for in the fusion of the PET image to the four-dimensional CT image.

Figure 17-11 A, CT simulation is conducted with the patient in an immobilization device. Shown here is the Vac-Loc bag, which is immobilized using −80 mbar of pressure in the vacuum. B, Abdominal pressure pillow.

Daily treatment image guidance is essential to ensure proper localization, reduce setup variability, and ensure that there is not a geographic miss for each fraction. Most commonly, this involves kilovoltage or megavoltage CT guidance for the delivery of each fraction. Cone beam CT refers to the incorporation of the imaging system into the linear accelerator. A CT machine on rails takes advantage of a shared tabletop for both CT imaging and a linear accelerator. All major manufacturers of linear accelerators currently produce delivery systems incorporating CT guidance. A variety of other systems with shared principles but different methods and technologies are in use for SBRT as well, including the Novalis BrainLAB system, TomoTherapy system, and Accuracy, Inc., CyberKnife system.

The goal of dependable and reproducible immobilization, motion management, and image guidance is to restrict necessary PTV margins yet ensure the desired coverage of the CTV. There is no consensus on required PTV margins, which are typically institution specific and depend on an understanding of interfractional and intrafractional variability for a given delivery system and disease site. Treatment planning usually involves three-dimensional conformal radiotherapy (3DCRT) with multiple beam arrangement, often non-coplanar, or intensity-modulated radiotherapy (IMRT) to produce distributions with a very rapid fall-off (Fig. 17-12). Typically, when using 3DCRT, dosimetric margins around the PTV are selected so that the 80% isodose line encompasses 100% of the PTV. When inverse planning is employed, dose homogeneity within the PTV is important, given the high dose per fraction. For all techniques, the goal is to limit the volume of normal tissue receiving the prescription dose.

Figure 17-12 Beam arrangements are shown for a T1 non–small cell lung cancer. Ideally, all beams are selected to minimize exit to the contralateral lung. Dosimetric margins are selected to ensure that the PTV is enclosed by the 80% of maximum isodose shell.

Early-Stage Lung Cancer

Most of the experience with SBRT to date is in the treatment of early-stage non–small cell lung cancer (NSCLC). The standard of care for medically operable, stage I NSCLC is lobar resection. Traditional EBRT produced inferior results.^80,⁸¹ With modern techniques, however, dose-per-fraction escalation using SBRT is possible and offers the potential for improved results.

Single-institution experiences have reported improved outcomes with SBRT in comparison with historical controls.82,83,84,85–87 The initial phase I dose escalation protocol from Timmerman and colleagues⁸⁸ failed to reach the maximum tolerated dose for a three-fraction regimen for peripheral lesions, reaching 20 Gy per fraction for medically inoperable patients. Multiple fractionation schemes have been employed, ranging from 24 to 60 Gy in one to five fractions. A Japanese multi-institutional analysis showed that, regardless of the chosen hypofractionated regimen, a biologically effective dose (BED) of more than 100 Gy was associated with a statistically significant improvement in local control.⁸⁴

The first North American multicenter phase II trial (RTOG 0236) in medically inoperable, peripherally located, early-stage NSCLC patients with tumors of less than 5 cm was recently completed. It accrued 59 patients treated to 60 Gy in three fractions of 20 Gy per fraction separated by at least 40 hours. The 3-year primary tumor and lobar control rates were 97.6% and 90.6%, respectively.⁸⁹

Future directions include evaluating the role of SBRT in the definitive management of operable patients. RTOG 0618, a single-arm phase II trial with the same fractionation, is currently enrolling operable early stage patients. A recent case-matched analysis comparing SBRT with sublobar resection for borderline resectable T1-2N0 NSCLC suggested similar disease control rates.⁹⁰ A randomized trial is currently ongoing in the Netherlands comparing SBRT with definitive resection.

At present, SBRT for NSCLC is limited to peripheral lesions, based on excessive rates of grade 3 to 5 toxicity when treating lesions within 2 cm of the proximal bronchial tree with doses of 60 Gy in three fractions.⁹¹ A report from the M. D. Anderson Cancer Center showed acceptable toxicity when treating central lesions using image-guided IMRT to a dose of 50 Gy in four fractions.⁹² The RTOG is currently conducting a phase I/II dose escalation study to evaluate the optimal fractionation schedule and associated toxicity and disease control rates when treating centrally located early-stage tumors.