Gamma Knife Surgery for Cerebral Vascular Malformations and Tumors

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Chapter 5 Gamma Knife Surgery for Cerebral Vascular Malformations and Tumors

The gamma knife is a neurosurgical tool used either as a primary or adjuvant procedure for intracranial pathologies. It was developed in the late 1960s as an alternative to open stereotactic lesioning for functional disorders. Variations in anatomy and needs for physiologic confirmation of the target limited its usefulness for these indications at that time. However, the technology was found to be efficacious in the management of structural disorders later on. The limited scope of the pathologies treated with the gamma knife (intracranial) and unique technology make the gamma knife an extension of the neurosurgeons’ therapeutic armamentarium and not a separate specialty. It should not be mistaken for a form of radiation therapy, for it differs in concept from the radiation oncologists’ idea of tumor treatment that is based on variable tissue response to fractionated radiation. It is a single session, stereotactically guided procedure for various neurosurgical pathologic processes limiting exposure to radiation as much as possible to the lesion only.

Recently it has been shown that the gamma knife can palliate some ocular tumors. In a more limited application of the concept, the treatment of extracranial tumors in abdominal and thoracic locations has evolved with the use of the various stereotactic body radiation therapy machines.¹^–⁴ Obviously, lesions that lie outside the central nervous system will not be treated by a neurosurgeon. However, when it is used for neurosurgical pathology, no one is more qualified to apply it. It is the operator and the pathology that define the use of a technology. When Walter Dandy placed a cystoscope in a ventricle for the first time, he was not performing a urologic procedure.⁵ The microscope when used by the neurosurgeon, ophthalmologist, or otolaryngologist is a neurosurgical, ophthalmologic, or otolaryngologic instrument, respectively.

It is remarkable how difficult it was, and still is for some neurosurgeons, to accept the use of gamma knife as a neurosurgical tool. Some of the causes of this reticence can be identified:

1. Lack of historic perspective makes it difficult for some neurosurgeons to realize that Leksell’s concept was rooted in the philosophy of the founders of neurosurgery, that is, recognition of technological advances and their application to neurosurgical practice. The early adoption by Cushing of the x-ray machine, his use of the “radium bomb” in glioma treatment,⁶ and the introduction, also by Cushing, of radiofrequency treatment of lesions are just a few examples of “technology transfer.”

2. The difficulty of accepting a neurosurgical procedure without opening the skull, despite the fact that every neurosurgeon knows that trephination is itself a minor part of the neurosurgical act. The laser beam, the bipolar coagulator, and the ultrasound probe are accepted without resistance because they are used after trephining the skull. The recently introduced “photon radiosurgery” with its limited scope compared to gamma surgery is accepted widely as “neurosurgery” because it reaches the target through a small burr hole.

3. The loss of the thrill and glamor provided by open surgery.

4. The deeply rooted acceptance of the dogma that where ionizing beams are involved a radiotherapist is needed. The last 40 years have demonstrated that a neurosurgeon can acquire the necessary knowledge of radiophysics and radiobiology to handle ionizing beams. This is much easier than for a radiation oncologist to master neuroanatomy and management of neurosurgical lesions, and thus to exclude bias when deciding whether to use the microscope or the gamma knife in each particular case.

The trend in cranial as well as spinal neurosurgery has been minimally invasive approaches. These may be achieved with the increasing skill of the operators and by new technology. If the result of these changes in the procedure, aspects are modified or even eliminated, the procedure is still neurosurgical. To relegate less-invasive procedures to non-surgeons is to argue that the only aspect of a patient’s care that is unique to a surgeon is purely technical. This is patently untrue; it is the surgeon’s responsibility to maintain surgical care standards by adapting to new technologies.

There is no substitute at this time for the physical extirpation of a mass lesion in terms of cure or control of either vascular or oncologic pathologies. The attractiveness of radiosurgery is not that it supplants open neurosurgical procedures, but that it allows treatment of pathologies only treated earlier with unacceptable morbidity or mortality. There is, and likely always will be a gray area where the benefits of various modalities are debated. It will only be through evaluation of long-term results of these various therapies as well as their availability, cost, experience of the operators and individual patient preferences that the “best” therapy in any given case is decided.

In this chapter we describe the results of our experience with the gamma knife as well as published results of other centers where required.

Table 5-1 lists all the cases treated with the gamma knife worldwide through 2006. It should be kept in mind that many of the indications listed are not universally accepted as appropriate for gamma surgery. In this chapter we will give our version of the facts for each indication.

TABLE 5-1 Cases Treated with Gamma Knife Worldwide through December 2008

Diagnosis	n	Percentage
Vascular	65,084	12.95
Arteriovenous malformation	57,136	11.37
Cavernous angioma	3,258	0.65
Other vascular	4690	0.93
Tumor	397,215	79.01
Benign	176,319	35.07
Vestibular schwannoma	46,835	9.32
Trigeminal schwannoma	2,822	0.56
Other schwannoma	1,590	0.32
Meningioma	64,115	12.75
Pituitary tumor	38,553	7.67
Pineal tumor	3,540	0.70
Craniopharyngioma	4,053	0.81
Hemangioblastoma	2,056	0.41
Chordoma	1,911	0.38
Hemaniopericytoma	1,151	0.23
Benign glial tumors	3,594	0.71
Other benign tumors	6,099	1.21
Malignant	220,896	43.94
Metastasis	185,070	36.81
Malignant glial tumors	26,437	5.26
Chondrosarcoma	775	0.15
Nasopharyngeal carcinoma	1,454	0.29
Other malignant tumors	7,160	1.42
Ocular Disorder	1,966	0.39
Functional	38,461	7.65
Intractable pain targets	622	0.12
Trigeminal neuralgia	32,798	6.52
Parkinson’s disease	1,473	0.29
Obsessive compulsive disorder	154	0.03
Epilepsy	2,399	0.48
Other functional targets	1,015	0.20
Total indications	502,726	100.0

Note: These figures include cases treated at gamma knife sites throughout the world from 1968 through December 2008.

Source: Elekta Radiosurgery Inc.

History

Clarke and Horsley developed the first stereotactic system,⁷ and the method was first applied clinically by Spiegel et al.⁸ This system allowed for the localization of intracranial structures by their spatial relationship to Cartesian coordinates relative to a ring rigidly affixed to the skull. This was a prerequisite to the development of radiosurgery by Lars Leksell. His ambition was to develop a method of destroying localized structures deep within the brain without the degree of coincident brain trauma associated with open procedures. The convergence of multiple ionizing beams at one stereotactically defined point was the result. A nominal dose is delivered to the paths of each incident beam. However, at the point of intersection of the beams, a dose proportional to the number of individual beams is delivered. The physical specifications of the device would be designed to ensure steep drop-off of delivered radiation at the edge of the intersection point. This would allow precise selection of the targeted lesion and minimization of trauma to surrounding tissue. He named this concept radiosurgery in 1951.⁹

Various sources of ionizing radiation were tried. Leksell first used an orthovoltage x-ray tube coupled to a stereotactic frame in the treatment of trigeminal neuralgia and for cingulotomy in obsessive compulsive disorders.⁹ A cyclotron was then used as an accelerated proton source and used to treat various pathologies.^10,¹¹ The cyclotron was too cumbersome and expensive for widespread application. A linear accelerator was evaluated but found at that time to lack the inherent precision necessary for this work. Fixed gamma sources of cobalt-60 and a fixed stereotactic target fulfilled the requirements of precision and compactness. The first gamma knife was built between 1965 and 1968.

The use of a single high dose of ionizing beams to treat neurosurgical problems was a novel and creative concept 40 years ago, which changed the direction of development in many fields of neurosurgery. However, a creative innovation is not perfect in its inception. The gamma knife was not an exception. Contributions of excellence by numerous neurosurgeons and physicists, and utilizing advances in computer technology to improve the software used in planning have over the years defined the present use of the tool. For instance improvements in the planning system now allow for systematic shielding of the optic apparatus from exposure during treatment of parasellar masses. In lesions only 2 to 5 mm away, the dose to sensitive structures can be limited to less than 2% to 7% of the maximum dose. However, in spite of all the changes in application of gamma surgery the underlying concepts behind it have not changed since its inception. This speaks for the sagacity of Lars Leksell and his invention.

Doses delivered and indications for the various pathologies treated were all empiric initially. In the subsequent discussions this should be considered when doses, both minimal and maximal are discussed, as well as results.

Pathophysiology

The effects of single high-dose gamma radiation on pathologic and normal tissue have been studied on clinical human and experimental animal tissue. These studies are incomplete because the human material tends to come from treatment failures and the experimental material is from normal animals. However some conclusions as to the method of effectiveness and of tissue tolerances can be drawn.

Normal Tissue

The relative radioresistance of normal brain relates to its low mitotic activity. Also, the rate at which a total dose of radiation is applied affects the damage caused by the dose. This is due to the ability of the cell to effect repairs during the actual time of irradiation. A higher dose rate (same total dose applied over a shorter period of time) consequently increases the lethality of the dose. The normal tissue surrounding the stereotactically targeted pathologic tissue receives a markedly lower dose but over the same time. Therefore, not only is the total dose lower, but the dose rate is lower as well. The radiation effect is seen most clearly at doses above and below 1 Gy/min.¹² This radiobiological phenomenon explains part of the relative safety of single dose radiation with steep gradients at the edge of targeted tissue on the surrounding structures. There are likely additional mechanisms of such sparing.

The steep gradient of dose and consequently dose rate described above does not exist in conventional radiotherapy. When treating tumors the radiation oncologist uses “fractionation” or dividing the total dose into smaller portions, which allows repair of normal tissue as well as transition of dormant cells within the target to cells in division (at which time they are more sensitive to radiation). Creating a dose gradient at the lesion’s margin not only eliminates the need for fractionation but also improves the effectiveness of the delivered dose within the target (high-dose rate zone) 2.5 to 3 times that of the same dose delivered in a fractionated manner. The gamma knife stereotactically excludes normal tissue from the high-dose rate zone as much as possible. It may also take advantage of the natural difference in susceptibility of pathologic versus normal tissue.

In order to understand the radiobiology of a single high-dose of radiation on normal brain the parietal lobe of rats treated by a gamma knife was studied at our center. It was found that a dose of 50 Gy caused astrocytic swelling without changes in neuronal morphology or breakdown of the blood–brain barrier at 12 months. There was fibrin deposition in the walls of capillaries. At 75 Gy, necrosis was seen at 4 months as was breakdown of the blood–brain barrier. More vigorous morphological changes were seen in astrocytes and hemispheric swelling coincident with the necrosis occurred at 4 months. With the dose increased to 120 Gy, necrosis was seen at 4 weeks but not associated with hemispheric swelling. Astrocytic swelling occurred at only 1 week postirradiation.¹³ These findings are consistent with earlier reports on the effective dose to produce well-defined lesions in the thalamus in patients treated with the gamma knife.^14,¹⁵

Tumor Response

Little is known about the pathophysiologic changes induced by gamma surgery at the cellular level in tumors. Division of tumor cells is presumably inhibited by radiation induced damage to DNA. Also it has been shown that the microvascular supply to tumors is inhibited by changes resulting from gamma surgery. In meningiomas studied after this treatment there was reduction of blood flow over time.¹⁶ Tumors responding early showed the greatest reduction in blood flow. Other authors have proposed that the induction of apoptosis by gamma radiation to proliferating cells may be responsible for at least a portion of the effect of gamma surgery on tumors.^17,¹⁸ Although such contentions may be premature they may point the direction to future research.

Thus the pathophysiologic effect of gamma surgery seems not to be tumor necrosis. For this, higher doses than typically used would be required. Necrotic doses are rarely used for gamma surgery (e.g., in functional cases). Ideally following gamma surgery, tumors begin to shrink without changes in the normal tissue. The rate of shrinkage in general is slower in more benign tumors.

The effectiveness of the therapy is most dependent on the ability to define and treat the entire lesion. However, the result can also be obtained at times by treating the nutrient or feeding vessels of tumors (e.g., meningiomas). Malignant gliomas do poorly with any surgical technique, including gamma surgery because of the inability to include all of the microscopic disease within the treated area. Individual metastatic deposits and small benign tumors are adequately handled with both open resection and with the gamma knife because the tumor margin can be well-defined intraoperatively or on neuroimaging studies.

In order to conformally cover the target more than one isocenter is nearly always utilized. When multiple radiation fields are made to overlap the radiation dose distribution becomes inhomogeneous. The resulting areas of local maxima are called “hot spots.” Controversy exists as to whether the presence of “hot spots” in gamma surgery is beneficial or detrimental. An even dose distribution is an essential and basic concept in radiotherapy. There is some evidence that these areas may be of benefit in gamma surgery. The factors to keep in mind to understand this line of reasoning are as follows: due to radiation geometry hot spots are usually located in the deep portions of the target. In tumors this is usually the area that receives the poorest blood supply and is therefore relatively hypoxic and radioresistant. Furthermore the ability of a cell to respond to otherwise sublethal dosages of radiation can be affected by its own condition as well as the state of the cells near it. Cells that are sublethally injured and are in the vicinity of similar cells recover more often than cells that are in the vicinity of lethally injured cells. The hot spots therefore create islands of lethally injured cells that will enhance the cell kill in the sublethal injury zone.¹⁹ Oxygen is a radiosensitizer, and the relatively high-dose rate of the hot spots will act to offset any loss of efficacy in the hypoxic core of the target. This position is supported by the work of other authors.²⁰

Cranial Nerves

The susceptibility of cranial nerves to injury from gamma surgery is of great interest. Tolerance is dependent on the particular nerve and the individual nerves involvement by the pathologic process requiring treatment. Because of these it is difficult to extrapolate exact numbers in many instances. Some statements can be made with some certainty.

The optic and acoustic nerves are the most sensitive to radiation of the cranial nerves. Being central nervous system tracts, containing oligodendrocytes, and carrying complex information is thought to be the source of their vulnerability. These tracts are unable to regenerate following injury. Optic neuropathy has been reported as a complication following single doses greater than 8 Gy.²¹ The tolerable level of radiation to the optic apparatus is still a subject of debate. Some advocate that the optic apparatus can tolerate doses as high as 12 to 14 Gy.²²^–²⁴ Others recommend an upper limit of 8 Gy.^21,²⁵ Small volumes of the optic apparatus exposed to doses of 10 Gy or less may be acceptable in some cases.^26,²⁷ Both the tolerable absolute dose and volume undoubtedly vary from patient to patient. This degree of variability likely depends upon the extent of damage to the optic apparatus by pituitary adenoma compression, ischemic changes, type and timing of previous interventions (e.g., fractionated radiation therapy and surgery), the patient’s age, and the presence or absence of other co-morbidities (e.g., diabetes).

On the other hand the trigeminal and facial nerves are significantly more resilient. Few developed profound hypoesthesia in trigeminal neuralgia patients treated with gamma knife using doses of 80 to 90 Gy. Vey few facial pareses were reported in several large groups of vestibular schwannomas treated with radiosurgery.

The cranial nerves in the cavernous sinus are relatively robust. Low incidence of neuropathies has been reported with doses up to 40 Gy.²¹ We have not observed any neuropathies of CN IX through XII in the treatment of glomus jugulare tumors.

Normal Cerebral Vasculature

There is both clinical and experimental data regarding the effect of single high-dose gamma irradiation of normal cerebral vasculature. In treating 1,917 arteriovenous malformations we have seen only two incidences of clinical syndromes possibly associated with the stenosis of normal vessels. This low incidence has occurred even though occasionally normal vessels are included in the treatment field. One case was reported after treating a glioma with 90 Gy gamma surgery followed by 40 Gy of fractionated whole brain irradiation of a middle cerebral artery occlusion. Steiner et al. described two cases in which disproportionate white matter changes might have been ascribed to venous stenosis and occlusion.²⁸ Another case, of a diencephalic AVM, demonstrated marked edema associated with venous outflow occlusion. This patient suffered visual and cognitive deficits but over the course of months his neurologic status returned to baseline (Fig. 5-1).

FIGURE 5-1 A, Thalamic AVM shown with lateral vertebral arteriography. B, Similar view obtained 17 months after gamma surgery shows partial obliteration of the nidus. The basal vein of Rosenthal, the vein of Galen, and the straight sinus were not visualized. Venous drainage of the residual AVM appears to be through ascending choroidal veins and the internal cerebral veins. Early (C) and late (D) filling vertebral arteriogram obtained 37 months after gamma surgery shows obliteration of the AVM and complete absence of the deep venous system.

In our treatment of pituitary adenomas with cavernous sinus extension or parasellar meningiomas, we have not observed occlusion of normal vasculature. This absence of stenosis is noted even though the internal carotid artery or portions of the circle of Willis, or its proximal branches, are often included in the treatment field. The only incidence of treating an intracranial aneurysm by us with a gamma knife did lead to narrowing and eventual occlusion of the adjacent small posterior communicating artery segment.²⁹ Whether this was associated with the obliteration of the aneurysm neck or primary changes in the artery is unknown. It is possible that the incidence of occlusion of smaller vessels is more common than recognized as the occlusion would occur slowly and compensatory changes could take place preventing clinical syndromes from occurring. Regardless, the clinical impact is minimal. Others have noted injury to the cavernous segment of the carotid artery following radiosurgery for pituitary adenomas. A total of four cases have been reported and in only two of these cases were the patients symptomatic from carotid artery stenosis.³⁰^–³² Pollock et al. have recommended that the prescription dose should be limited to less than 50% of the intracavernous carotid artery vessel diameter.³² Shin et al. recommended restricting the dose to the internal carotid artery to less than 30 Gy.³³

Experimental studies done on normal vasculature in the brains of rats and cats showed similar findings.^34,³⁵ The primary injury was endothelial necrosis and desquamation, muscular coat hypertrophy and fibrosis at lower doses (25 to 100 Gy). At doses up to 300 Gy necrosis of the muscular layer was seen in cats. In only one instance, a rat anterior cerebral artery treated with 100 Gy was occlusion of a vessel seen. Similar studies on hypercholesterolemic rabbits treated with 10 to 100 Gy showed no histologic changes in the basilar arteries and no instances of occlusion after 2 to 24 months.³⁶

Arteriovenous Malformations

The minimal clinical and only moderate histologic change in the normal cerebral vasculature after high doses of gamma radiation is in sharp contrast to the response of the vessels of an arteriovenous malformation (AVM). Complete radiographic obliteration can be achieved after appropriate gamma surgery. The effects of ionizing radiation and a role in the management of AVMs was first reported in 1928 by Cushing and Bailey.³⁷ During craniotomy for an AVM he had to interrupt surgery due to major hemorrhage from the lesion. He then treated the patient with fractionated radiation. At reoperation 5 years later only an obliterated avascular mass was discovered. This early success was overshadowed by numerous series of failures.³⁸^–⁴⁰ In this early period, Johnson was the only one to report reasonable results with a 45% angiographic obliteration.⁴¹ The introduction of the gamma knife rekindled interest in the treatment of AVMs with radiation.⁴²

The pathologic changes in AVMs treated with the gamma knife have been described by several authors.⁴³^–⁴⁵ The earliest change is damage to the endothelium with swelling of the endothelial cells and subsequent denudation or separation of the endothelium from the underlying vessel wall. The most important changes are seen later in the intima with the appearance of loosely organized spindle cells (myofibroblasts) and an extracellular matrix containing collagen type IV, not seen in the intima of untreated vessels. Expansion of the extracellular matrix and cellular degeneration define the final stage prior to luminal obliteration. The occlusion of the vessels is not a thrombotic process but rather the culmination of concentric narrowing of the vessel by an expanding vessel wall.

Gamma Surgery Procedure

Perioperative Management

Patients are routinely evaluated the day prior to gamma surgery. Preoperative consults are obtained as necessary including evaluation by the neuroradiology service. The patients are loaded with anti-seizure medications and levels drawn prior to therapy. Patients already on medication for seizures also have their levels evaluated. Although we have never had a patient have a seizure during therapy, the small but serious risk of a generalized seizure while the patient is secured within the gamma unit makes every precaution reasonable. Patients are also started on systemic dexamethasone the evening prior to therapy and this is continued until the following evening. The use of high-dose peri-operative dexamethasone is empiric. Although we have used steroids throughout our experience with the gamma knife, their original purpose, to minimize vasogenic edema at the time of therapy, has never been documented as a problem. Hence its prophylactic use is debatable.

Frame Placement

The placement of the head frame is done in the operating room at our institution. The patient is given intravenous sedation, usually short acting narcotics (e.g., fentanyl) and propofol, until they are no longer responsive to verbal or moderate physical stimuli. The anesthesia service monitors the patient throughout the procedure. We have found this far superior to the previous practice of applying the frame using only local anesthesia. Patients that were treated both before and since we have applied the frame in this way have provided clear feedback preferring frame placement under anesthesia.

We have fashioned a simple strap with Velcro ends that is placed across the patients head and then fastened above the frame after it has been lowered into the desired position. This holds the frame in position while the pins are secured. This eliminates the need for the earplugs in the auditory canal, which can be painful.

The space available within the gamma knife is limited as is the three dimensional coordinate system within the frame itself. For these reasons care must be taken to skew the placement of the frame in the direction of the pathology if it is far off the center of the brain. The shifting of the frame is of less importance with the latest gamma knife model, Perfexion, which has a much larger radiation cavity.

Imaging and Dose Planning

The accuracy of a gamma surgery is ultimately dependent on the neurosurgeon’s ability to visualize the intended target. Thus, the technique would be impossible without imaging studies that allow three-dimensional views of anatomic structures in the brain. Magnetic resonance image (MRI) is the most used imaging modality because of its superior visualization of soft tissue structures and solid tumors. Typical MRI protocols include T1-weighted pre- and postcontrast (Gadolinium-enhanced) images through the entire volume of the head. Sequences may be a collection of 2D image slices, or a true 3D acquisition such as the MP-RAGE or its successors. Specialized sequences such as constructive interference in steady state (CISS) protocols may be used for circumstances such as visualization of the internal auditory canals, the cerebellopontine angle, and parasellar regions.

In planning the treatment of an AVM, digital subtraction angiography remains the imaging modality of choice. As with the MRI and computed tomography (CT), images are acquired using a fiducial system. However the digital subtraction angiography is based on projections rather than tomographic information. Images need to be geometrically corrected to account for the curvature of the image intensifier screen before importing the images into the treatment planning system. Gadolinium-enhanced MRI is currently often used to correlate the extent of the AVM nidus with angiography. It helps to define the shape of the AVM and confirms angiographically obtained information. However, it is sometimes difficult to differentiate the nidus from the feeding arteries and draining veins so the MRI tends to overestimate the size of the AVM. The capability to incorporate CTA and MRA data into the planning process is under investigation.

The Gamma Knife

The gamma knife assembly is comprised of unit that contains the radiation source and treatment couch that delivers the patient into the unit. Within the unit are 201 cobalt-60 source capsules aligned with two internal collimators that direct the gamma radiation toward the center of the unit. A third external collimator helmet is attached to the treatment couch. Four external collimator helmets are provided, and they have fixed diameter apertures that create a 4-, 8-, 14-, or 18-mm diameter isocenter. By changing external collimator helmets, the diameter of the roughly spherical isocenter can be varied. The 201 individual collimators within the helmet are machined to exact standards to direct the 201 beams of gamma radiation to a common point where they intersect, creating the isocenter. The frame attached to the patient’s head is adjusted within the collimator helmet so that the area to be treated is at that point of intersection.

In the new gamma knife model, Perfexion, the central body contains 192 cobalt-60 sources that are grouped into eight independent source sectors and collimators are entirely internal to the radiation body. Each source sector is housed in an aluminum frame that is attached to sector drive motors at the rear of the radiation body via linear graphite bushings. There are 576 collimators machined into 12 cm-thick tungsten in five concentric rings to align with the source assembly configurations. Each source has three available collimators (4, 8, and 16 mm) as well as shielded positions (‘‘blocked’’) to shield a critical structure. To achieve a particular collimation, the sector drive motors move the sources along their bushings to the correct position over the appropriate collimator opening. These changes allow a single isocenter composed of different beam diameters to optimize dose distribution shape for each individual shot.

Treatment Execution

After the treatment plan has been made the patient is moved on to the gamma knife couch and the y and z coordinates for the first exposure are set on the frame attached to the patient’s head. The patient’s head is then placed within the collimator helmet and secured on either side by trunions and the x coordinate is set. The head at this point is suspended by the frame within the helmet. The exposure time of the corresponding isocenter is entered at the control panel twice for confirmation and the session then commences with the entire couch being mechanically pulled into the body of the unit. The external collimator helmet locks into place with the internal collimators. After each exposure the patient is withdrawn from the collimator helmet and the process is repeated. Necessary changes of the collimator helmet are made as needed according to the plan. The introduction of the Automatic Positioning System (APS), a system that sets the coordinates by six independent motors just outside the irradiation field, has led to shorter treatment times, enhanced selectivity, and better physician work-flow. In the gamma knife Perfexion, the treatment table itself acts as a positioning device (the Patient Position System, or PPS). The stereotactic frame is attached to the treatment table via a removable frame adapter that attaches to the frame and acts as an interface with the treatment table. Treatment execution with Perfexion is a fully automated process including set up of the stereotactic coordinates, alignment of different sector positions and set up of exposure times. Obviously these changes will not affect the efficacy of the treatment but will make the process simpler for the operator.

At the end of the treatment the frame is removed from the head within the suite. There is usually a sensation of tightening and discomfort reported by the patient during removal. At least two pairs of hands should be available to steady the frame and prevent injury by a pin as they are removed. Venous bleeding when it occurs can be controlled with hand held pressure for a few minutes. The occasional arterial bleeder might require a suture. After frame removal the pin sites are dressed in a sterile fashion, steri-strips are used to oppose the skin edges for optimal cosmesis, and a modest head wrap applied.

Indications

Vascular Malformation

Arteriovenous Malformations

The indications for gamma surgery of arteriovenous malformations (AVMs) versus other treatment options are in many cases unclear at best. Small asymptomatic inoperable AVMs are clearly best treated with the gamma knife while AVMs with a large symptomatic hemorrhage in noneloquent superficial brain are best treated with open surgery. The reason for this is that the risk-benefit value is clear in both of these situations. In other situations it is more ambiguous. Knowledge of the capabilities of various treatments to effect cure, the associated morbidity and mortality associated with the treatment and the natural history of the disease following various treatments must be known to accurately prescribe the most efficacious treatment plan. Unfortunately these are in most instances not known. The natural history of AVMs is not fully understood. Some authors believe that size matters, with smaller AVMs bleeding at a higher rate than larger ones or at a lower rate.⁴⁶^–⁴⁹ There is also evidence that size is independent of the hemorrhage rate.⁵⁰^–⁵² Similarly the rate of hemorrhage of an AVM following a previous hemorrhage is thought to be higher than the rate in unruptured AVMs by some authors^46,^52,⁵³ but not by others.^47,^54,⁵⁵ The effects of age, gender, pregnancy and AVM location also confound the question of risk of rupture.^{50–52,56–58}

The results of microsurgery published in the literature tend to come from centers of excellence and the patients they treat with open surgery are, by definition more amenable to this treatment. The effectiveness of the treatment by this manner and its co-morbid results are known shortly after surgery. The short-term morbidity of treatment with the gamma knife approaches zero but because the benefit and potential complications require time to become apparent follow-up of these patients is problematic. The quality of the AVMs treated with the gamma knife also varies in large series with those treated by microsurgery. All of these make comparison of the modalities difficult. Add to that the additional risks and benefits of preoperative embolization and the matter is that much less clear. It is paramount to the physician treating a patient harboring an AVM to be aware, as much as possible, of the options that are available and the magnitude of the risks and benefits associated with each.

Early Experience

Since the first AVM case treated by Steiner et al. in 1972,⁴² we have treated over 2500 AVMs with the gamma knife. As experience with this tool grows the capabilities and limitations of the gamma knife are being defined.

Serendipitously the first AVM was treated by prescribing a 25 Gy peripheral dose. Subsequent changes in protocol showed a significant decrease in success with doses less than 23 Gy and small improvements in obliteration rates but with significantly more radiation associated complications with higher doses. Optimally, therefore, we treat most AVMs with 23 to 25 Gy at the margin. While more patients with relatively large AVMs were treated, dose lower than 23 Gy was quite often used in hopes of achieving a total obliteration with reasonable risk of complications.

As in microsurgery, also when performing gamma surgery, feeding arteries or draining veins should be left alone and only the nidus should be treated. In very large AVMs, only partially treated due to the excessive dose necessary to treat optimally, occasional cures have been achieved. This is thought to be due to fortuitous inclusion of all the pathologic shunts within the higher dose treatment field. Targeting only the feeding vessels to the AVM have had very limited success because of recruitment of small angiographically occult feeding arteries. Interestingly, the first patient ever treated had only the feeding vessels targeted and a cure was obtained.⁴² The early success with this strategy has not been reproduced.

The results of gamma surgery on AVMs is affected by the minimum dose applied to the AVM and the size of the AVM. These two factors are interdependent. It has been shown that the limitation of the allowed margin dose by the size of the malformation decreases the rate of obliteration. There are reports contending that low-dose gamma surgery with large malformations results in obliteration rates that are comparable to smaller lesions treated with a larger margin dose. It is doubtful that these results will hold up with larger series. Thus far at our center, larger AVMs have had a lower obliteration rate.

Between 1970 and 1990, 880 AVM patients were optimally treated. Optimally is defined as at least 25 Gy at the margin of the entire nidus of the AVM. Of these patients the age range was 3 to 76 years. Approximately 15% were pediatric patients (<18 years old). The presenting symptoms were hemorrhage (70%), seizures (16%), headache (5%), neurologic deficits not associated with acute hemorrhage (4%), and other symptoms (5%). The majority of referrals were for AVMs deemed operable only with unacceptable morbidity explaining the fact that 73% of the AVMs were located in deep areas of the brain or within eloquent cortex. Patients treated earlier were subjected to a vigorous protocol of repeated angiograms. Later with the introduction of CT and then MRI, angiography was not performed until nidus was no longer evident on these screening examinations. The angiogram should be complete, of high quality, and should be reviewed by an experienced and interested neuroradiologist or neurosurgeon.

Imaging Outcomes

Following gamma surgery, angiography reveals hemodynamic changes occur before changes in the size and shape of an AVM.⁵⁹ First, the flow rate decreases progressively. This may be related to the changes in the sizes of the feeding arteries and outflow veins. The outcome of an AVM following radiosurgery may be a total, subtotal, or partial obliteration of the nidus.

Total obliteration of the AVM after radiosurgery was defined as “complete absence of former nidus, normalization of afferent and efferent vessels, and a normal circulation time on high-quality rapid serial subtracted angiography”⁵⁹ (Fig. 5-2). Any remaining nidus, regardless of its size, is considered partial obliteration (Fig. 5-3). Subtotal obliteration of an AVM means the angiographic persistence of an early filling draining veins without demonstrable nidus (Fig. 5-4).⁶⁰

FIGURE 5-2 Obliteration of a midbrain AVM. Vertebral arteriogram showing (A) frontal and (B) lateral views before and (C and D) two years after gamma surgery. There was no neurologic deficit.

FIGURE 5-3 Partial obliteration of an AVM. Left sylvian AVM shown in anteroposterior (A) and lateral (B) views of a left carotid angiogram. Same views 4 years later (C and D) show a decrease in the size of the nidus but persistent shunting of blood through the partially obliterated malformation (arrowheads). The residual AVM was recently retreated.

FIGURE 5-4 Subtotal obliteration of an AVM after gamma surgery. Anteroposterior (A) and lateral (C) vertebral angiograms demonstrating AVM located within the vermis of the cerebellum. Control angiography with the same views (B and D) obtained 3 years after gamma surgery shows no demonstrable nidus but the presence of an early filling vein (arrowheads).

Of the 880 patients treated 461 had adequate angiographic follow-up. Of these 461 patients, 80% were found to be cured within 2 years. At the time of the last evaluation of the results only 5% of patients had no change in the status of their AVMs. Ten percent had subtotal obliteration and 5% were partially obliterated. In this group of patients obliteration rates were affected by the size of the nidus. The rate for AVMs less than 1 cm³ in volume was 88%. For 1 to 3 cm³ it was 78% and for greater than 3 cm³ it was 50%.

No patient that was harboring an angiographically proven obliterated AVM has ever hemorrhaged in our experience. Nor has a patient with a subtotally obliterated AVM sustained a postradiosurgery hemorrhage. Regardless of this we do not consider a patient cured until he has total obliteration of the AVM. The early draining vein represents persistence of the shunt.

Some studies had proposed that in pediatric patients the response to radiosurgery seems to be less favorable.⁶⁶ Hypotheses such as the immature vessels in pediatric cases more likely to recover from radiation induced damage and neovascularization in response to radiation have been proposed. Our experience show comparable result in children compared to adults. Additionally, we observe that adverse radiation induced damage seems to be more tolerable for kids, which proves that radiosurgery has a favorable benefit risk profile in the management of pediatric AVMs. However, the risk of hemorrhage remained in pediatric patients and the development of secondary tumor cannot be overlooked.

Gamma Surgery following Embolization of Arteriovenous Malformations

The effectiveness of partial embolization followed by gamma surgery in the management of relatively large AVMs still remains controversial. When comparing the outcome in patients treated with gamma knife alone to those with combined embolization and gamma knife treatment, recent studies reported less favorable outcome in patients with preradiosurgical embolization.^65,⁶⁸

Between 1989 and 2007, a total number of 217 AVMs with prior partial embolization were treated with gamma surgery at the Lars Leksell center. There were 107 males (49%) and 110 females (51%) with a mean age of 32.8 years. Most of the AVMs were embolized with liquid embolics such as NBCA or ethanol. In 167 patients the nidus was compact after the embolization, whereas the angiogram of 50 cases revealed that the nidus was broken apart after the endovascular procedures. The mean volume of the nidus at the time of GKS was 5.1 cm³ (range 0.02–24.9 cm³). The mean prescription dose was 19.6 Gy (range 10–28.0 Gy) and the mean maximum dose was 37.2 Gy (range 20–50 Gy).

After gamma surgery an angiographically confirmed total obliteration of the AVMs was achieved in 71 patients (27%) (Fig. 5-5). A total obliteration on MRI was observed in 26 patients (10%). In 157 patients (60%) only a partial obliteration could be obtained after a follow-up period of at least 2 years. Eight patients (3%) presented with a subtotal obliteration. The outcome after gamma surgery in embolized AVMs (obliteration rate 27%) is much less favorable than AVMs treated with gamma knife only (obliteration rate 72%).

FIGURE 5-5 Gamma surgery following a partial embolization of the AVM. A 24-year-old male diagnosed with a left-sided AVM at the left sensorimotor cortex following a hemorrhage (A and B lateral and frontal projections of angiograms). The patient underwent a partial embolization. The nidus obliterated completely 3 years following gamma surgery (C and D).

Recanalization of previously embolized parts of the nidus,⁶⁹ difficulty in nidus delineation following previous embolization,⁶⁵ and attenuation of radiation dose by embolization materials⁷⁰ have been proposed to explain the less favorable outcome in patients with preradiosurgical embolization. Theoretically, volume reduction following embolization affords a lower chance of radiosurgery-related adverse effect; however, our data do not show this. Additionally, the complications from embolization are not negligible. Therefore, the use of embolization before gamma knife treatment remains problematic and awaits further investigation.

Gamma Surgery for Large Arteriovenous Malformations

Recently, there has been much discussion of gamma surgery for large AVMs. The main problem with large AVMs is due to the dependence of the obliteration response on dose and volume; this dependency requires a delicate balance in deciding an efficient dose but low enough to avoid adverse neurologic deficits.

The following strategies are currently available to treat large AVMs with radiosurgery.

1. Embolization of a portion of the AVMs then performing radiosurgery if the nidus shrinks to a size manageable with radiosurgery. However, embolization should effectively shrink the nidus for radiosurgery to achieve good results; otherwise fragmentation of the nidus into a number of segments will make the radiosurgical planning difficult and increasing the probability of radiosurgery failure.

2. Staged radiosurgery to selected volumes of the AVMs. Sirin et al.⁷¹ used staged volumetric radiosurgery in 28 large AVMs. Out of the 21 patients, seven underwent repeat radiosurgery and were eliminated from outcome analysis. Of the remaining 14 patients, three had total obliteration on angiograms, and 4 had no flow voids on MRI but had no follow-up angiography. Four patients had hemorrhages after radiosurgery resulting in two deaths. Worsened neurologic deficits occurred in one patient.

3. Treating the whole nidus in one session with low-dose radiosurgery. Pan et al.⁷² reported an obliteration rate of 25% for AVMs with volume larger than 15 cm³. The obliteration rate increased to 50% at 50 months follow-up. The morbidity was 3.3%. Post-treatment hemorrhage occurred in 9.2% of cases.

4. At Lars Leksell center, we evaluated a protocol using combined radiosurgery and microsurgery for the management of large AVMs. Gamma surgery was performed for the deep medullary portion of the AVMs as a first step. The second step was planned as microsurgical extirpation of the superficial segment if the goal of the first step, obliteration of the deep segment of the AVM, was achieved. However, in less than 5% of the patients, this goal was achieved.

The management of large AVMs demonstrates that every treatment has its limitations. In an effort to solve the problems of the management of large AVMs, a cautious approach is warranted pending the development of new techniques and agents for embolization.

Hemorrhage Risk in the Treatment–Response Interval

Whether gamma surgery without obliteration of the nidus provides partial protection from hemorrhage is still controversial. It has been demonstrated by some authors that there may be some degree of protective effect.⁷³^–⁷⁵ Because the incidence of hemorrhage in a matched group of untreated patients will likely never be known and the timing of obliteration is not known except as being between diagnostic scans, it is a difficult position to support.

The incidence of hemorrhage following gamma surgery during the first 2 years was studied in 1604 of our patients and reported by Karlsson et al.⁷⁶ There were 49 hemorrhages for an annual incidence of 1.4%. This is slightly lower than the generally accepted rate of 2% to 4% per year but includes all 1604 patients, consisting of those known and not known to have obliterated AVMs. Of these hemorrhages, 14 were fatal (annual rate of 0.4%) and 9 had permanent neurologic deficits (annual rate of 0.3%).

Repeat Gamma Surgery for Incompletely Obliterated Arteriovenous Malformations

In general, the risk of hemorrhage persists as long as the AVM nidus is still patent. This provided the rationale for retreatment of still patent AVMs following the initial gamma surgery.

In our experience, 74 males and 66 females with a mean age of 33 years underwent repeat gamma surgery for still-patent AVMs following initial gamma surgery from 1989 to 2007. Causes of initial treatment failure included inaccurate nidus definition in 14, failure to fill part of the nidus due to hemodynamic factors in 16, recanalization of embolized AVM compartments in 6, and suboptimal dose (<20 Gy) in 23 patients. Nineteen patients had repeat gamma surgery for subtotal obliteration of AVMs. In 62 patients, the AVMs failed to obliterate in spite of correct target definition and adequate dose. At the time of retreatment, the nidus volume ranged from 0.1 to 6.9 cm³ (mean 1.4 cm³) and the mean prescription dose was 20.3 Gy. Clinical follow-up ranged from 15 to 220 months with a mean of 84.2 months after repeat gamma surgery.

Repeat treatment yielded a total angiographic obliteration in 77 (55%) (Fig. 5-6) and subtotal obliteration in 9 (6.4%) patients. In 38 (27.1%) patients, the AVMs remained patent. In 16 patients (11.4%) no flow voids were observed on the MRI. High prescription dose, small nidus volume, nidi with only superficial venous drainage, and a negative history of prior embolization were significantly associated with increased rate of AVM obliteration. Clinically, 126 patients improved or remained stable and 14 experienced deterioration (8 due to a rebleed, 2 caused by persistent arteriovenous shunting, and 4 related to radiation induced changes).

FIGURE 5-6 Repeat gamma surgery for AVM. A 33-year-old male with a left parietal AVM presenting with seizure. The patient underwent first gamma surgery with a prescription of 20 Gy in 1991 (A). The flow of the nidus seemed to be reduced but the overall size of the nidus had not changed (B). He had a repeat gamma surgery in 2002 with 18 Gy as a prescription dose and the nidus completely obliterated in 2005 (C). His seizure frequency decreased significantly.

We advise repeat gamma surgery in cases with still patent nidi 3 to 4 years after initial gamma surgery when open surgery or endovascular procedures were expected to yield higher risk of complications than gamma surgery. Our experience showed that when repeating gamma knife treatment a dose of at least 20 Gy led to a higher chance of subsequent nidus obliteration (77% vs. 47% with prescription dose less than 20 Gy).

Hemorrhage from Angiographically Confirmed Obliterated Arteriovenous Malformations

Some studies have noted AVM reappearance after apparent gamma knife surgery obliteration.⁷⁷ In our histopathologic analysis, gamma surgery of AVMs caused endothelial damage, proliferation of smooth muscle cells, and the elaboration of extracellular collagen by these cells, which led to progressive stenosis and obliteration of the AVM nidus.⁴³ In this same report, there was evidence of small trapped vessels that would have very little blood flow. It is unclear what histopathologic process would permit the formation of new vessels following radiosurgical-induced obliteration of the AVM nidus. However, it is clear that the infrequent and small trapped vessels observed by Schneider et al.⁴³ could not explain the angiographic findings reported by Linqvist et al.⁷⁸ Such inconsistent findings following radiosurgical treatment of AVMs suggest the need for further clinical and histopathologic investigation and the continued follow-up of patients, particularly pediatric ones, following gamma surgery.

In our series of AVMs treated with gamma surgery, we observed no recurrent hemorrhage after angiographically confirmed obliteration of the AVMs. In one case reported by Guo et al., a rebleed occurred after angiographic documentation of nidus obliteration.⁷⁹ The MRI findings suggested that hemorrhage possibly resulted from radiation-induced tissue damage. Furthermore, the histologic examination of the suspected recanalized AVM revealed channels that were one-fiftieth the size of the smallest vascular channels in AVMs, making it unlikely that these were vessels with significant blood flow. This view has been further confirmed by the fact that a repeat angiogram revealed no evidence of residual malformation or recanalization. Rebleeding, in spite of post-treatment angiograms interpreted as normal, may be explained by unsatisfactory quality of the neuroimaging studies or inadequate interpretation leading to the misdiagnosis of angiographic cure.

Subtotal Obliteration of Arteriovenous Malformations

Subtotal obliteration of an AVM following gamma surgery has been reported sporadically. This angiographic phenomenon implies a complete disappearance of AVM nidus but persistence of early filling drainage veins (see Fig. 5-4). Theoretically, the early filling venous drainage suggests that some shunting still persists.

We reported a series of 159 patients with subtotal obliteration of AVMs (SOAVMs).⁶⁰ The incidence of SOAVMs was 7.6% from a total of 2093 AVM patients who were treated with gamma surgery and had angiographic follow-up available. The diagnosis was made after a mean of 29.4 months (range 4–178 months) following gamma surgery.

During the cumulative period of 767 patient-years (a mean of 4.9 years per patient) after the diagnosis of SOAVMs, no SOAVMs had ruptured. Follow-up angiography was performed in 90 of 136 patients in whom SOAVMs had no further treatment. These studies showed a total obliteration of the original AVMs as well as disappearance of the early filling vein in 66 patients (73%). Twenty-four patients (27%) had persistent SOAVMs. Twenty-three patients with SOAVMs were treated with gamma knife targeting the proximal end of the early filling veins. In this group, follow-up angiography was performed in 19 patients, confirming disappearance of the early filling vein in 15 patients (79%) and persistent SOAVMs in four patients (21%). None of the patients suffered a rupture of the lesion. This suggests that the protection from rebleeding at the stage of subtotal obliteration is significant.

Our series shows that subtotal obliteration of the AVMs did not necessarily prove to be a premature stage of an ongoing obliteration, and instead might be the end point of the obliteration process. Earlier in our series, we repeated gamma surgery for SOAVMs, targeting the proximal segment of the early filling vein. After repeat treatment, 79% SOAVMs were obliterated. However, the necessity of retreatment remains to be determined given the fact that in the whole group no hemorrhage occurred and that 73% of SOAVMs obliterated spontaneously.

Complications

Radiation-Induced Changes

Radiation-induced change is an increased T2 signal around the AVMs on MRI following radiosurgery (Fig. 5-7). Radiation damage of glial cells, endothelial cells damage followed by breakdown of blood–brain barrier, excessive generation of free radicals or release of vascular endothelial growth factors have been proposed to explain this imaging finding. The severity of radiation-induced changes on images and associated neurologic deficits varied ranging from asymptomatic, a few millimeters increased T2 signal surrounding the treated nidus to massive brain edema with symptoms and signs of increased intracranial pressure. From our 1500 gamma knife procedures performed for AVM patients with follow-up MRI available for analysis, 34% of patients developed radiation-induced changes. Among them, 60% had mild (a few millimeters of increased T2 signal surrounding the nidus), 33% had moderate (compression of ventricle and effacement of sulci) and 7% had severe (midline shift) radiation-induced changes. The mean time to the development of radiation-induced changes was 13 months after gamma surgery. Resolution of these changes was the usual course and the mean duration of the changes was 22 months. Large nidus volumes, high prescription doses, history with preradiosurgical embolization, and nidus without previous hemorrhage were associated with higher risk of radiation-induced changes.

FIGURE 5-7 Onset and resolution of radiation-induced changes of normal brain tissue. Radiation-induced changes 6 months following radiosurgical treatment of a left basal ganglia arteriovenous malformation with a margin dose of 20 Gy. Appearance on (A) T2- and (B) T1-weighted MRI. These changes showed progressive regression and complete disappearance at 2 years following onset (C and D). Angiography documented total obliteration of the arteriovenous malformation.

Of the patients who developed radiation-induced changes, 122 (8.7%) patients had headache, worsening or new seizures, or neurologic deficits. Patients with severe radiation induced changes and nidus at eloquent areas were more likely to develop symptoms. Twenty six patients (1.8%) had permanent neurologic deficits.

Cyst Formation

A rare occurrence following gamma surgery for AVMs is the development of an expansive cyst at or adjacent to an obliterated AVM (Fig. 5-8). Cyst developed after resolution of previous hemorrhages or fluid cavities from encephalomalacia after surgeries should not be considered as complications related to gamma surgery. First reported in 1992 ⁴⁵ in two patients out of a series of forty, we found a total of 20 patients (1.6%) developing a cyst after a mean of 8.1 years postradiosurgery from our 1272 patients with follow-up MRI available.⁸⁰ Six patients had large cysts and three of them were symptomatic requiring surgery. Two cases underwent craniotomy and drainage of the cyst. The cyst wall showed no evidence of neoplasia. Direct radiation injury to the perilesional brain tissue, increased permeability of the blood–brain barrier with accumulation of the exudative fluid, hemodynamic perturbations during gradual obliteration of the nidus with subsequent ischemic tissue damage, and tissue destruction due to subclinical perilesional hemorrhages have been proposed as the possible mechanisms of cyst formation.

FIGURE 5-8 Delayed occurrence of cyst formation following gamma surgery for an AVM. This small, right-sided AVM visualized on anteroposterior (A) and lateral carotid arteriography (B) was cured as shown on this control angiogram obtained 2 years after gamma surgery (C). The development of headaches and personality changes prompted an MRI examination 7 years after gamma surgery (D and E). This cyst was surgically decompressed. Biopsy of the cyst wall did not reveal any evidence of tumor. (Follow-up MRI courtesy of Professor J. Camaert, Chairman, Department of Neurosurgery, Gent, Belgium.)

Radiosurgery-Induced Neoplasia

We found two meningiomas from 1333 AVM patients treated with gamma surgery (Fig. 5-9); however, follow-up imaging was performed over a period of at least 10 years in only 288 of these patients.⁸¹ If we conservatively estimate that radiosurgery-induced lesions would be evident within a 10-year time interval, then our incidence of radiosurgery-induced neoplasia is 2 in 2880 person-years or 69 in 100,000 person-years. Thus, there is a 0.7% chance that a radiation-induced tumor may develop within 10 years following gamma surgery. The long latency and relative rarity of these lesions following radiosurgery may defy a conclusive determination of the true incidence.

FIGURE 5-9 Radiation-induced neoplasia. Anteroposterior (A) and lateral (B) views of vertebral angiograms demonstrate a right temporal AVM before gamma surgery. Two years after treatment the nidus obliterated completely (C and D). Axial and coronal contrast-enhanced, T1-weighted MRI (E and F) obtained 10 years postradiosurgery show a meningioma adjacent to the superior surface of tentorium. It is located in the area where the previous AVM was situated.

Dural Arteriovenous Fistulas

Although dural arteriovenous fistulas (dAVFs) comprise approximately 15% of all intracranial vascular malformations, the precise mechanism of formation remains unknown. The leading theories include adjacent venous sinus stasis as well as alterations in local expression of vasogenic factors, such as vascular endothelial growth factor and fibroblastic growth factor.^82,⁸³

From a treatment standpoint, experience with dAVFs is distinct from AVMs. Studies have established that the flow dynamics of dAVFs are the most important indicator of the need to treat and modality to choose, be it embolization, open microsurgery, or radiosurgery. As the aggressive natural history of lesions with cortical venous reflux differs significantly from lesions without angiographic evidence of cortical venous reflux, early definitive therapy via endovascular procedures or open surgical resection appears to be preferable to radiosurgery as a first-line treatment. Although radiosurgery is thought to be an effective agent for decreasing neovascularization in dAVFs, the time interval needed for the desired effect is too great to justify radiosurgery as a first-line therapy.⁸⁴

The long-term analysis of radiosurgery for dAVFs over 25 years at the Karolinska University Hospital in Stockholm, Sweden included 52 patients treated between 1978 and 2003. The obliteration rate reported in this study was 68% with 16 dAVFs presenting as less aggressive Borden I or Cognard I/IIa lesions.⁸⁵ In a similar institutional experience at the Lars Leksell center between 1989 and 2005, 55 patients with dAVFs were treated with gamma surgery, primarily as an adjunct to surgery or embolization. Obliteration rates measured by angiography at 3 years ranged from 54% to 65%, with the 16 patients classified as Borden I lesions (Fig. 5-10). Unlike the Karolinska study, the majority of patients treated at the Lars Leksell center received gamma surgery as a secondary therapy, with 41 of the 54 patients receiving surgical or endovascular intervention prior to radiosurgery. Regardless of the difference in utilization of radiosurgery as a primary or secondary treatment modality, the results of these long-term studies indicate that gamma knife is an effective and safe treatment for intracranial dAVFs.

FIGURE 5-10 Total obliteration of dural arteriovenous fistula following gamma surgery. Left common carotid angiogram lateral (A) and (C) frontal projections of a dural arteriovenous fistula in the region of the left transverse sinus. Complete obliteration is demonstrated at 2 years following gamma surgery in the (B) lateral and (D) frontal projections.

Vein of Galen Malformations

We have treated nine patients with vein of Galen malformations. The patients ranged in age from 4 to 72 years of age. Among these patients, there were three with Yasargil Type I, one with Type II, two with type III, and three with type IV malformations. Prior embolization had failed in four of the cases. Three of the vein of Galen malformations were treated twice with radiosurgery. Follow-up angiograms were obtained in eight of the patients treated.⁸⁶ Four malformations were completely obliterated (Fig. 5-11). Another one seems to be obliterated but definitive confirmation could not be obtained as the patient refused a final angiogram. Another patient has some residual fistula not in the initial radiosurgical treatment field and has been retreated. Two other patients had marked reduction of flow through their malformations.

FIGURE 5-11 Gamma surgery for a vein of Galen malformation. A-P (A) and lateral (B) vertebral angiograms show direct shunting of blood into the primitive precursor (promesencephalic vein) of the vein of Galen. C and D, Stereotactic angiogram obtained at the time of treatment. E and F, Control angiography obtained 1 year later demonstrate cure of the malformation. (Courtesy of Hernan Bunge, MD, Clinica del Sol, Buenos Aires, Argentina.)

Cavernous Malformations

The success of treating AVMs prompted the treatment of cavernous malformations (CMs) with the gamma knife. Their tendency to be small in size, with the lack of intervening normal brain tissue and relatively low rate of clinically significant hemorrhage made CMs a natural target for the gamma knife. The rate of hemorrhage for cavernomas is widely disparate in the neurosurgical literature reported as between 0.1% and 32%.⁸⁷^–⁹⁰ This is largely due to semantic differences in defining a hemorrhage with some authors counting the presence of a hemosiderin ring on MRI as evidence of a hemorrhage as well as in determining the date from which patients were at risk for hemorrhages.

Gamma surgery of CMs appears to have a histologic effect on them, which is not evident on imaging studies. In a case reported earlier,²⁹ a gamma surgery treated CM followed for 5 years showed no change on MRI studies. Histologic examination following surgical removal of the lesion showed it to be partially obliterated (Fig. 5-12).

FIGURE 5-12 Hematoxylin and eosin stained histologic section of a cavernous malformation that was treated with gamma surgery. Because no change was observed on serial MRI examinations over 5 years, the lesion was excised. Except for a single persistent capillary channel, the malformation was obliterated.

A total of 23 patients have been treated by us for CMs between 1985 and 1996, 22 of which are available for follow-up evaluation.⁹¹ Maximum treatment dose varied from 11 to 60 Gy (mean 33 Gy). Peripheral dose varied from 9 to 35 Gy (mean 18 Gy). Nine symptomatic hemorrhages occurred in this group after therapy for an annual incidence of 8%. Four of these patients were subsequently operated upon. Six patients suffered neurologic decline secondary to radiation-induced changes, five of which were permanent. Two patients subsequently underwent surgery. Thus the permanent radiation-induced complication rate is 22%, nearly 12 times higher than expected for a similarly treated group of AVM patients. The high incidence of post-treatment hemorrhage and radiation-induced complications is greater than the expected morbidity from an untreated group. For this reason the routine use of the gamma knife in the treatment of CMs cannot be supported at this time.

There have been observations in literature that demonstrate a protective effect of gamma surgery on the rate of hemorrhage in these lesions. Based on 38 cases, Kondziolka et al.⁹² maintain that radiosurgery offers benefit to these patients. They reported that 6 patients (15%) had significant reduction in size with a 13% hemorrhage rate; 10 of the patients (26%) developed neurologic deficits, 2 of these underwent surgery and succumbed to the illness. The rate of complications reported by them in the face of the fact that only 15% of the patients in this series had any reduction in the size of the lesion does not, in our opinion, constitute grounds for justifying radiosurgery for CMs. Furthermore, their contention that the complications reported by us may in part be due to the high doses used in treatment does not get support from their statistics with a lower dose. These 38 patients were a part of a later report on 47 patients from the same authors detailing the outcome. They found a postradiosurgery annual hemorrhage rate of 8.8%, which is high when compared to the risk reported by the same authors at 0.6% to 4.5%, even if the difference is not statistically significant. They chose, however, to compare their postradiosurgery hemorrhage rates with the preradiosurgery rate in the same subjects, making the assumption that the rate could be based on an epoch starting from first observation or first hemorrhage. This is fallacious since the malformation was present before the presenting hemorrhage and most likely from birth. Recomputed on this basis the preradiosurgery annual bleed rate comes to 5.9%, which is more congruent with expected natural history. Once again the incidence of hemorrhages postradiosurgery seems spuriously higher.

During the past decade, gamma knife has been widely used in some centers to treat CMs. Since the lesions cannot be precisely visualized by any imaging studies, the outcome of radiosurgery was universally evaluated based on the hemorrhage rate before and after radiosurgery using the same group of patients as control. There are methodological flaws in such study design. As been demonstrated in publications,⁹³ patients with previous hemorrhages tend to bleed more often. By calculating the clustering number of hemorrhages in the short period of follow-up time, which was prematurely terminated by radiosurgery prompted by the hemorrhage, the preradiosurgical hemorrhage rate was erroneously high ranging from 17% to 36%.^64,^88,⁹⁴^–⁹⁶ The hemorrhage rate after gamma surgery is these series ranged from 2% to 4%, which seems to be significantly low compared to the preradiosurgical bleeding rate but actually is not much different while comparing to the number reported in series studying natural course of CMs. Of note, the complications in these series remained to be high.

Developmental Venous Anomalies

The natural history of developmental venous anomalies (previously named venous angiomas) is benign ⁹⁷ and clearly not a surgical lesion. Prior to clear elucidation of this prognosis, 19 patients were treated for this entity by us.⁹⁸ One patient was cured and three were partially obliterated. Three patients suffered radionecrosis, and one had symptomatic edema. One patient with radionecrosis underwent subsequent debridement. A 5% cure incidence with a 30% complication incidence for a benign entity is unacceptable.

Tumors

Treatment of tumors with gamma surgery introduces a new approach to the evaluation of the endpoint of the treatment. Unlike microsurgery no actual debulking of tissue occurs, and, in the short term, there are no visible changes. However, in the long term, the tumors often shrink, and some even disappear entirely on follow-up neuroimaging studies. Success is therefore established by a pattern of reducing tumor size over serial follow-up studies or the lack of growth. With benign tumors, the natural history may be one of no growth for many years. As such, longer follow-up is necessary to ascertain whether gamma surgery affords true tumor volume control in slow growing tumors.

In an attempt to eliminate some of the subjectivity of naked eye observations and the obvious fallacy resulting from the estimation of a three dimensional object on the basis of three linear measurements in orthogonal planes, we have developed software that allows estimation of lesion volume based on MRI or CT.⁹⁹ The procedure involves scanning the study into a computer program and outlining the pathology in each slice. The computer then measures the area within the contour and calculates a volume based on slice thickness, the process is repeated for each slice and the total volume calculated by integrating the individual slice volumes. The error of this method was determined by comparing various hand-partitioned volumes with volumes estimated using polyhedrons to approximate the regions of interest on each slice. The average relative error is strongly dependent on the number of axial slices obtained through the object of interest and is fairly independent of the size of the object itself. For objects varying in volume from 0.1 to 10 cc, the average relative errors per number of slices through the object have been computed as follows: 3% for 7 slices, 4% for 6 slices, 6% for 5 slices, 11% for 4 slices, and 21% for 3 slices. Volumetric estimation based on 1 or 2 slices through the region of interest produces unacceptable average relative errors of more than 40%. We now require all follow-up studies to be performed with a slice thickness of 3 mm with zero overlap or gap between adjacent slices. Such a protocol generally helps ensure the acquisition of 3 or more slices through the region of interest. Even though the technique of volume estimation has an acceptable level of accuracy, we prefer to ignore changes of less than 15%.

Pituitary Adenomas

The efficacy of radiation in the treatment of pituitary adenomas was well-documented before gamma surgery was used for this disease.^100,¹⁰¹ Reduced fractionation techniques had been shown to have effectiveness in the treatment of Cushing’s disease and were the impetus for the use of radiosurgery. MRI has replaced less exact invasive localization procedures such as cisternography and CT in the planning of gamma surgery in patients with pituitary adenomas. There still remain difficulties with the use of gamma surgery. The peripheral dose that can be delivered for macroadenomas is limited if the optic apparatus is in proximity with the tumor. Localization of microadenomas can be difficult with even the best MRI examinations (e.g., a fat suppression MRI protocol) and amelioration of hypersecretory syndromes is delayed.

One of the best indications for gamma surgery of secretory or nonsecretory pituitary adenomas is residual tumor that is not removable with microsurgical techniques (i.e., tumors within the cavernous sinus). If it is known before microsurgery that the cavernous sinus is involved and a debulking procedure is considered, then every effort to clear the tumor away from the optic nerves and chiasm should be made in order to make gamma surgery postoperatively more effective. A suprasellar approach should be considered if there is doubt that this can be accomplished through a trans-sphenoidal approach. There is some difficulty in differentiating residual tumor from postoperative changes on MRI. A thorough operative note concerning any foreign material or grafts left behind is important, as well as a high-quality preoperative scan for comparison.

Another indication for gamma surgery is persistence or recurrence of elevated hormone levels after microsurgery. In the presence of residual or recurrent tumor that is not readily amenable to further extirpation, either because of its location or the inability to localize the tumor within the sella, gamma surgery can be applied. Tumor within the cavernous sinus can be treated. Difficulty in localizing the tumor usually requires radiosurgical targeting of all the contents within the sella, and such an approach carries a fair risk of postradiosurgical hormonal insufficiency.¹⁰² If the patient has a secretory microadenoma but the symptomatology is not urgent and microsurgery is for some reason not considered, then gamma surgery can be used as the primary therapy.

In preparation for treatment with high-dose, narrow beam radiation, many centers have recommended a temporary cessation of antisecretory medications in the peritreatment time period. In 2000, Landolt et al. first reported a significantly lower hormone normalization rate in acromegalic patients who were receiving antisecretory medications at the time of radiosurgery.¹⁰³ Since then, this same group as well as others has documented a counterproductive effect of antisecretory medications on the rate of hormonal normalization following gamma surgery.^32,¹⁰⁴ The degree to which and the mechanism by which antisecretory medications lower hormonal normalization rates is unknown, but Landolt et al. have hypothesized that these drugs lower the tumor’s metabolic rate and decrease their radiosensitivity.^105,¹⁰⁶ Moreover, the optimal time period to hold antisecretory medications in conjunction with gamma surgery is not clear. Landolt and Lomax recommend that dopamine agonists be withheld 2 months prior to the procedure.¹⁰⁴ For acromegalics, they recommend altering antisecretory medication administration as early as 4 months prior to radiosurgery and completely halting all antisecretory medications 2 weeks prior to radiosurgery.¹⁰³ Although many centers have incorporated such methodology into their treatment regimen, the potential risk and benefits of halting antisecretory medication administration should be weighed. The functional adenoma may be more likely to respond to gamma surgery. However, in the absence of antisecretory medication control, it may also enlarge thereby risking adjacent structures (e.g., the optic apparatus), necessitating a lower prescription dose, and making effective treatment more difficult.

Most centers have observed effective growth control of pituitary adenomas following gamma surgery. However, there have been a wide range of outcomes with regard to hormonal normalization of secretory adenomas. The varied outcome results for hormonal normalization may arise from the following reasons:¹⁰⁵ early studies utilized CT rather than more precise MRI for dose planning;¹⁰⁶ different criteria for defining an endocrinologic cure have been applied in various studies and there is little consensus even within the neuro-endocrinologic community for precise defining criteria¹⁰⁷; and many studies had short or intermediate follow-up periods and may not have been long enough to observe patients with an endocrinologic recurrence following an initial remission.

Nonsecretory Tumors

We have treated 100 patients with nonsecretory pituitary tumors, 90 of which have imaging and endocrinologic follow-up of a minimum of 6 months and an average of 45 months ¹⁰⁸ (Tables 5-2 and 5-3). Of these, 59 (65.6%) had a decrease in the volume of their tumors (Fig. 5-13) and 24 (26.7%) had no change in the size. In seven (7.8%) patients, the tumors increased in size. Of note, among 61 tumors involving the cavernous sinus, 39 shrank, 17 remained unchanged, and five increased in size. The minimal effective peripheral dose was 12 Gy; peripheral doses greater than 20 Gy did not seem to provide additional benefit. In 61 patients with residual pituitary function at the time of gamma surgery, new hormone deficiency occurred in 12 patients (20%).

TABLE 5-2 Gamma Surgery for Pituitary Adenomas Outcomes at University of Virginia

TABLE 5-3 Imaging Outcomes of Radiosurgery for Nonsecretory Pituitary Adenomas

FIGURE 5-13 Nonsecretory pituitary adenoma treated with gamma surgery following three microsurgical resections. Sagittal T1-weighted MRI of a nonsecretory pituitary adenoma in a 34-year-old man (A), demonstrating marked reduction at 30 months after radiosurgery (B). Patient recovered his visual acuity and had resolution of his visual field defect, and returned to his job as a policeman.

Growth Hormone–Secreting Tumors (Table 5-4)

We have performed gamma knife procedures on 137 patients with growth hormone secreting adenomas (Table 5-4). Follow-up of at least 18 months was available for 95 of these patients. There was normalization of IGF-1 in 53% of cases at an average time of 30 months after radiosurgery. Three patients developed recurrence of their acromegaly after initial remission, with a mean time to recurrence of 42 months. New endocrinologic deficiencies developed in 34% of patients, with hypothyroidism and low testosterone levels being the most common new endocrinopathies.

TABLE 5-4 Hormone and Imaging Outcome of Radiosurgery for Growth Hormone–Secreting Pituitary Adenomas

In five patients the tumors could not be identified on MRI and the whole sella was targeted. Of the remaining 90 tumors treated with gamma surgery, a decrease in tumor size was seen after 83 (92%) gamma procedures. Tumor growth was seen after 2 (2%) procedures. No change in tumor volume was seen after 5 (6%) procedures. Four patients developed the new-onset of visual acuity deficits; three of these patients had received prior conventional fractionated radiation therapy and their vision recovered following a short course of steroids. One patient developed deterioration in visual fields secondary to tumor growth. His vision continued to deteriorate in spite of repeat trans-sphenoidal surgery. One patient developed temporal lobe epilepsy 15 months following radiosurgery with MRI showing temporal enhancement. She is free of seizure with normal MRI scans and off antiepileptics 45 months after gamma surgery. No instance of ophthamoplegia occurred in any patients.

Prolactin-Secreting Tumors

Prolactinomas are usually well-controlled by dopamine agonists (Table 5-5). Nonetheless, this medication occasionally fails to achieve remission and is not tolerated by all patients. Alternative for these patients not responding to medical therapy is surgery. Patients who are refractory to medical and/or surgical therapy may be treated with gamma surgery. Of the 37 prolactin secreting tumors treated by us at the Lars Leksell gamma knife center,¹⁰⁹ 28 have imaging follow-up of 1 year or more. Thirteen (46%) had a decrease in the size, 12 (43%) were unchanged and three (11%) were increased. Excluding patients with normal prolactin level before gamma surgery and those with normal level at the last follow-up while still receiving dopamine agonists, endocrine follow-up was available for 23 patients. There was remission (serum prolactin level <20 ng/ml) in 26% of cases. New onset endocrine deficiency developed in 29% of patients. Two patients had new onset extraocular movement problems; one developed an oculomotor and the other an abducens nerve palsy. In both cases, the cavernous sinus was involved and both cases received a prescription dose of 25 Gy.

TABLE 5-5 Hormone and Imaging Outcome of Radiosurgery for Prolactin-Secreting Pituitary Adenomas

ACTH-Secreting Tumors

A total of 107 patients with Cushing’s disease underwent gamma surgery at our institution (Table 5-6). Seventeen patients who had less than 12 months follow-up were excluded, leaving 90 patients evaluable.¹¹⁰ All but one patient had undergone previous trans-sphenoidal operations. Of note, in 23 patients in which no tumor can be identified on planning MRI, the entire sellar content and adjacent cavernous sinuses were targeted. The mean prescription dose of gamma surgery was 23 Gy (range 8–30 Gy). Of 67 patients with visible tumors, imaging follow-up demonstrated a decrease in the size of the tumor in 62 cases (92%), no change in 2 (3%), and an increase in size in 3 (5%). However since the hypercortisolism defines the dangerous character of the ACTH-secreting tumor, the control of endocrine abnormalities is the true measure of tumor control. Normal 24-hour, urine-free cortisol levels were achieved in 49 patients (44%), at an average time of 13 months post-treatment (range 2–67 months). Ten patients who achieved remission after gamma surgery suffered a recurrence. Seven of these patients had repeat gamma knife procedures, with three patients achieving another remission. New endocrine deficiencies developed in 20 patients (22%), with hypothyroidism being the most commonly found new endocrinopathy. Five patients developed new-onset ophthalmoplegia (four of them with visual acuity deficits). One of them had received prior conventional fractionated radiation therapy, three had two gamma knife surgeries, and one had fractionated radiotherapy and subsequently two gamma procedures. Evidence of radiation-induced changes presenting as increased enhancement of parasellar area was seen in three patients but only one had symptoms attributable to these changes.

TABLE 5-6 Hormone and Imaging Outcome of Radiosurgery for ACTH-Secreting Pituitary Adenomas

The results of 35 patients treated at the Karolinska Institute have been reported.¹¹¹ Of the 29 patients that had follow-up of up to 9 years, 22 (76%) had normalization of their endocrine abnormalities, 10 within 1 year and the remainder within 3.

Nelson’s Syndrome

Patients with an ACTH-secreting pituitary tumor may require a bilateral adrenalectomy to treat their Cushing’s disease when surgical extirpation and radiosurgery for the pituitary tumor failed to normalize hormonal production (Table 5-7). Approximately one third of these patients will experience Nelson’s syndrome, namely, enlargement of residual pituitary adenoma, developing hyperpigmentation and/or having an elevated level of serum ACTH. At the Lars Leksell center, we have performed gamma surgery on 23 Nelson’s patients. Five patients had previously received conventional fractionated radiation therapy, and two patients had received prior gamma surgery for Cushing’s disease. Median prescription dose to the tumor margin was 25 Gy (range 4–30 Gy). Twenty two patients had imaging follow-up and the mean imaging follow-up was 20 months (range 125–124 months). Fifteen patients had elevated ACTH level before gamma surgery and follow-up ACTH level was available. The mean endocrine follow-up was 50 months (range 13–166 months). Tumors decreased in 12 (55%) patients, remained unchanged in 8 (36%), and increased in 2 (9%). ACTH levels decreased in 10 patients (67%) with a median decrease of 75% (range 29%–93%). Three patients (31%) achieved normal ACTH levels with a mean time to remission of 9.4 months postradiosurgery. New endocrinopathies were seen in 4 out of 10 patients with residual pituitary function before gamma knife procedures, growth hormone deficiency being the most common new hormonal deficit. One patient suffered from a permanent oculomotor nerve palsy.

TABLE 5-7 Hormone and Imaging Outcome of Radiosurgery for Nelson’s Syndrome

It is worth noting that there is a wide variation in both the rates of endocrinologic cure and hypopituitarism following gamma surgery. The difference in cure rates between modern radiosurgical series is likely due to the definition of cure employed and the length of follow-up. However, the discrepancy in the reported rates of hypopituitarism is more likely a function of the degree to which there is rigorous endocrinologic follow-up testing.

Craniopharyngiomas

Craniopharyngiomas are very difficult tumors to treat. Their benign histology is misleading. The near impossibility to resect completely and usual location in and about the hypothalamus make them difficult to cure. Microsurgery, intracystic instillation of radioisotopes, radiation therapy, and now radiosurgery have all been used. Long-term evaluation of patients with craniopharyngiomas is available after various treatment protocols.^112,¹¹³ The general consensus is that as complete a surgical resection as possible, without creating significant morbidity, should be performed; this is followed by radiation therapy and gives reasonable long-term survival. The ill effects on children after receiving fractionated brain irradiation are well-known.^114,¹¹⁵ Good results with resection alone have been achieved but only in the hands of a few neurosurgeons. Even so, long-term results of children with subtotal resection followed by radiation therapy has been shown to be superior to complete resection alone¹¹⁶ and the deficits incurred with aggressive surgery can be considerable.

Gamma surgery as an adjunct to microsurgical resection has been used in lieu of radiation therapy, or in addition to it, at several centers. The instillation of radioisotopes (e.g., P32) into large, nonloculated cystic components of the tumor and gamma surgery for the solid portion is the treatment policy for craniopharyngiomas at our center.

We treated 37 craniopharyngiomas in 35 patients. The prescription doses ranged from 6 to 25 Gy (mean 13.3 Gy). The follow-up ranged between 8 and 212 months with a mean of 62.5 months. Four tumors increased in size. A decrease in the solid component of the tumor was seen in 29 (Fig. 5-14) and no change was seen in 4. However, of the patients whose solid tumors decreased or remained unchanged, 10 developed new or enlarged cystic component with 4 of them requiring further surgical resection and 4 receiving intracavitary P32 instillation. In total, 23 patients improved or remained stable clinically. Twelve deteriorated and 10 of them died from complications of disease or surgeries. The mean 5-year survival rate was 71%.

FIGURE 5-14 Reduction in size of craniopharyngioma treated with gamma surgery. Residual craniopharyngioma following microsurgery treated with the gamma knife. Contrast-enhanced T1-weighted images before (A) and 4 months after treatment (B). Marked reduction in tumor size. Patient has a normal neurologic examination and endocrine profile.

Several other series have been reported in the use of gamma surgery in the treatment of craniopharyngiomas ^117,¹¹⁸ with results similar to ours. As larger series with longer follow-up become available it is likely that gamma surgery will either take the place of less discriminate radiation therapy, or be a useful adjunct to it.

Meningiomas

Meningiomas are usually benign, circumscribed tumors that arise from the coverings of the central nervous system and therefore tend to be superficial. Because of these attributes microsurgical extirpation of the entire tumor as well as any involved meninges is the treatment of choice. Unfortunately many meningiomas do not have one or more of the mentioned attributes. Aggressive, locally invasive tumors, especially those invading or involving critical or difficult to control neural or vascular structures and those at the skull base can be problematic in their complete removal. The use of radiation to lower the recurrence rate following microsurgical removal of meningiomas was shown to be beneficial.¹¹⁸^–¹²⁰ Recurrence rates were found to be dramatically decreased, and for patients with residual tumor following surgery the progression of tumor growth was significantly decreased.

We have treated 750 meningiomas at the Lars Leksell center since 1989. The most recent evaluation of our material was for 206 patients with a follow-up of 1 to 6 years. Tumor volume ranged from 1 to 32 cm³. These patients received an average of 38 Gy maximum dose (range 20–60 Gy) and an average peripheral dose of 14 Gy (range 10–20 Gy). There were 142 patients treated for residual tumor and 64 treated with gamma surgery primarily. Imaging follow-up was available for 151 patients. Of the evaluated patients 94 (63%) showed a decrease in the volume of their tumor greater than 15%. No change in size was seen in 40 (26%) and an increase in size in 17 (11%).

Tumors within the parasellar compartment, which is a part of the extradural neural axis compartment, can be difficult to remove with microsurgery without significant morbidity.^121,¹²² Residual tumor attached to still patent vascular or critical neural structures can be targeted with gamma surgery and allows less radical microsurgical resection and a lower incidence of morbidity.

We have recently reviewed the central skull base meningiomas involving the sellar-parasellar space in 138 patients. There were 107 females (78%) and 31 (22%) males. The mean age was 54 years (range 19–85). Mean tumor volume at the time of radiosurgery was 7.5 cm³ (range 0.2–55 cm³). Eighty-four patients had prior microsurgery with partial resection of the tumor. Fifty-four had an upfront gamma procedure. In our assessment, the gamma treatment was optimal in 109 (79%) and nonoptimal in 29 cases (21%). We defined nonoptimal treatment as follows: the part of the tumor close to the optic apparatus did not receive the desired prescription dose, typically because there was no distance between the tumor and the visual pathways. The mean prescription dose used in this series was 13.7 Gy (range 4.8–30 Gy). The mean maximum dose was 34.2 Gy (range 16–60 Gy). The mean MRI follow-up was 82.4 months (range 24–216 months). Sixty-six tumors (48%) shrank (Fig. 5-15), 52 (38%) remained unchanged and 20 (14%) increased in size. Fourteen patients developed new or deteriorated cranial nerve deficits; 11 due to tumor progress and 3 in spite of good tumor control. There was no mortality. Young age, optimal treatment, and smaller tumor size were correlated with better outcome. The tumor progression–free survival at 5 years was 95.4% and at 10 years was 71%.

FIGURE 5-15 Large left parasellar meningioma residual following microsurgery visualized on postcontrast, T1-weighted axial (A) and coronal (B) MRI. MRI obtained 6 months following gamma surgery shows that the tumor has disappeared (C and D). Repeated control MRI examinations at 5 years show no recurrence of the tumor.

We have long-term follow-up of 10 to 21 years for 31 meningiomas treated with the gamma knife. Two thirds of these tumors have either shrunk significantly or remained stable, and among these were cases where only the vascular supply for the tumor was targeted (Fig. 5-16). This has resulted in significant tumor shrinkage and lasting effect even in the long term. Our practice has been to obtain a stereotactic angiogram prior to gamma surgery for large tumors. This allows treatment to include the vascular supply when ideal treatment is not possible because of radiation dose constraints imposed by the treatment volume or proximity of the tumor to the optic apparatus. Recently we have used MRA source images instead of angiograms to conduct treatment planning. Using MRI, the group from Heidelberg proved that radiation occluded small nutrient vessels of meningiomas providing the rationale for the treatment we have used since 1976.

FIGURE 5-16 Long-term result of gamma surgery for meningioma. CT scans of a right parasellar meningioma treated with radiation to the nutrient vessels as defined by a CT and angiogram (A and B, respectively). The original size of the tumor is depicted in the pre–gamma surgery axial CT (C), and the last follow-up at 18 years after gamma surgery is shown (D). The tumor has substantially decreased in size.

The primary therapy for meningiomas is microsurgery. The advantage of histologic diagnosis, debulking and reasonable chance of cure secures surgical extirpation as the procedure of choice for this tumor. The tumors most amenable to gamma surgery treatment are less than 10 to 15 cm³ in volume. The ability of gamma surgery to effectively treat small tumors with low morbidity argues strongly, however, for minimizing morbidity during open procedures. The option to treat residual tumor in critical or hard to reach locations should temper the ambition of total surgical removal. This is especially true in locations where complete meningeal resection is impossible and thus the chance of recurrence is high.

Vestibular Schwannomas

Historically and incorrectly referred to as an acoustic neuroma, we prefer the designation of vestibular schwannoma, which recognizes the anatomic and histologic origins of these tumors.¹²³ There may be no other intracranial neuropathology about which the proper treatment arouses as much controversy as the vestibular schwannoma. Neurosurgeons cite the series of surgeons with enormous experience removing these tumors to justify suboccipital removal, while otolaryngologists sacrifice the inner ear during the translabyrinthine approach in an attempt to better expose and preserve the facial nerve. Radiosurgery’s proponents cite excellent tumor control and low morbidity but must acknowledge that although the tumor often shrinks, it is still there. Therefore it is in the best interest of our patients that long-term outcome in patients treated with these three modalities be thoroughly evaluated.

The first vestibular schwannomas treated with the gamma knife were by Leksell and Steiner in 1969.¹²⁴ Since then more than 36,843 have been treated around the world through 2006. The indications for gamma surgery for this tumor vary. Some physicians advocate gamma surgery in medically high risk patients, patients who refuse microsurgery, and in patients with postoperative residual tumors. However, others advocate gamma surgery as the treatment of choice in nearly all cases of vestibular schwannomas. The usefulness of irradiation in the postoperative period was shown by Wallner in 1987 where external beam irradiation lowered the recurrence rate from 46 to 6% in Boldrey’s surgical series at the University of California at San Francisco.¹²⁵ By then, gamma surgery was already being widely applied to this disease under many circumstances. The fact is that for a number of reasons few neurosurgeons acquire the necessary competency to satisfactorily extirpate these tumors. This situation may change if a method to improve the acquisition of skills required for extirpation of these lesions is found.

The advent of MRI has made planning for gamma procedures much more exact. With a high-quality MRI scan and a relatively small tumor, the seventh cranial nerve can occasionally be visualized and carefully excluded from the treatment field. The trigeminal nerve can nearly always be identified except with the largest tumors, which in most cases should not be treated primarily with gamma surgery.

Small collimators are used to better match the isodose configuration to the size and shape of the tumor. We have had no brain stem–related complications. Previously we used minimum peripheral doses up to 20 Gy and maximum doses up to 70 Gy. Presently, we use a margin dose of 11 to 13 Gy at the 30% to 50% isodose curve. The incidence of cranial nerve palsies rose considerably at the higher doses without significant improvement in the degree of tumor control.

At the Lars Leksell center, we have treated 470 patients with vestibular schwannomas. A total of 153 of these patients with more than 12 months of follow-up have been reported.¹²⁶ Radiosurgery was the primary treatment for 96 of such patients and was the adjutant (following microsurgery) in 57. The volume of the treated tumors ranged from 0.02 to 18.3 cm³.

Of the patients treated primarily with gamma surgery a decrease in tumor size was seen in 81% (78 patients), no change in 12%, and an increase in size in 6%. Among those 78 patients with a decrease in the size of their tumors, the decrease was greater than 50% in 20 patients. It is our policy to not consider decreases in volume of less than 15% as significant. This is true of all tumors that we treat. Imaging follow-up for these patients ranged from 1 to 10 years.

Of the 57 patients treated with gamma surgery after microsurgery, a decrease in tumor size was seen in 65%, no change in 25%, and an increase in size in 10%. Among the 37 patients with a decrease in tumor size, the decrease was greater than 50% in 12 patients. The outcome in terms of postradiosurgical volume reduction in patients who had prior microsurgery is worse than those who were primarily treated with gamma surgery. This difference is likely a result of the increased difficulty with accurate targeting in those who have undergone prior microsurgery. Of note, although our experience with treating large vestibular schwannomas is small (n = 19), we have observed a 95% tumor control rate in these following gamma surgery.

In our patients, there were five with transient changes in trigeminal sensation and three with facial paresis. In the first patient, the facial paresis occurred 6 months after the gamma surgery. Unnecessary surgery was performed without asking for our advice and the facial nerve was cut during surgery. Another patient recovered completely in six weeks, and the third has nearly completely recovered at 10 months. Of the patients with useful hearing prior to gamma surgery, 58% retained their hearing following radiosurgery. The majority of hearing changes were observed at the 2-year checkup, and additional auditory changes were observed as late as eight years postradiosurgery.

Other centers report similar rates of tumor control (i.e., with no change or decrease in the size of the tumor) seen in 89% to 100% of patients.¹²⁷^–¹²⁹

Evaluation of the material from the Karolinska group included evaluation of radiographic changes besides size.¹³⁰ The most common change was loss of central enhancement within the tumor on either contrasted MRI or CT studies. This occurred in 70% of patients and typically was observed within 6 to 12 months of treatment. However, these changes were reversible. Another change that was observed and that we have often seen is a transient increase in the size of the tumor during the first 6 months after gamma surgery. This is commonly seen in tumors that then regress to their original size or smaller (Fig. 5-17).

FIGURE 5-17 A right vestibular schwannoma with a volume of 9.3 cm³ shown on a postcontrast, T1-weighted axial MRI prior to gamma surgery (A). Same lesion 6 months after treatment shows central nonenhancement and no change in size (B). At 36 months after treatment, the lesion is again homogeneously enhancing and is significantly smaller (69%) (C). Control MRI examinations for 6 years show that lesion has remained stable.

We have not seen an instance of cerebellar edema or hydrocephalus requiring spinal fluid diversion following gamma surgery for vestibular schwannomas, but both of these have been reported elsewhere.^130,¹³¹

Astrocytomas

The treatment of astrocytomas, whether low or high grade, is largely defined by the ability to effectively reduce the tumor burden as much as possible and to lessen the rate of recurrence. Except in the case of pilocytic astrocytoma cure is rare. Classically the goal of reducing tumor burden is obtained by gross total resection with a margin of “normal” brain when possible and postoperative radiation in the case of more malignant tumors. The indication for radiation therapy for intermediate grade tumors, chemotherapy, repeat surgical debulking, and other therapies is dependent on several factors, many of which are not clearly defined. Into this cornucopia of choices, gamma surgery has been introduced. Intellectually, we have difficulty accepting the application of a focused technique for an infiltrative process. Nevertheless, recent results showing improved survival indicate that this negative attitude may be inappropriate.

In the case of low-grade tumors, gamma surgery can be used in place of surgical resection when the tumor is in an inaccessible location (e.g., brain stem) or when the patient opts for this alternative. Their small size and relative circumscription make planning straightforward, and fairly good results have been obtained.

For high-grade tumors, gamma surgery may be employed in several ways. If the tumor is small and in an inaccessible location (e.g., thalamus), gamma surgery is used to treat the tumor primarily. Focal or whole brain irradiation is also used as an adjunct therapy. The incidence of radionecrosis is relatively high when aggressive protocols are used and differentiating recurrence from this phenomenon can be problematic. Gamma surgery can also be used as an adjunct to surgical resection. The incidence of residual postoperative tumor is unfortunately not uncommon after “total” surgical resections and care is often taken when the tumor abuts eloquent brain so as not to leave neurologic deficit even at the expense of incomplete gross tumor resection. In these cases, gamma surgery can be used to treat the residual tumor. Whole or focal radiation therapy has been used to lower the recurrence rate after these surgical therapies have been undertaken.

Low-Grade Astrocytomas

We treated 21 pilocytic tumors, 2 subependymal giant cell astrocytomas (Grade II), and 26 Grade II astrocytomas with gamma surgery between 1989 and 2003 at the Lars Leksell center. The median treatment volume was 2.4 cm³ with a range of 0.5 to 36.0 cm³. The median prescription dose was 15 Gy. The mean clinical follow-up was 63 months. Median clinical progression-free survival was 44 months (range 0–118 months). The 5-year clinical progression-free survival was 41%. Eight patients died of disease progression. No information on the cause of the death was available for one patient. The duration of imaging follow-up was 59 months (range 2–118 months). Median imaging progression-free survival was 37 months (range 0–80 months). Five-year, imaging progression-free survival was 37%. At the last imaging follow-up, 37 tumors decreased or remained unchanged and 12 tumors increased in size. Three patients experienced transitory neurologic deficits associated with increased T2 signal on MRI.

Yen et al. reported on a series of 20 patients with brain-stem gliomas presenting with clinical or imaging progression treated with gamma surgery.¹³² Sixteen tumors were located in the midbrain, four in the pons and one in the medulla oblongata. The mean tumor volume at the time of gamma surgery was 2.5 cm³. Tissue diagnosis was available in only 10 cases (50%). The cases without histology were treated based upon appearance on imaging as well-defined small tumors. Mean prescription dose was 15 Gy (range 10–18 Gy). The tumor disappeared in 4 patients (20%) (Fig. 5-18) and shrank in 12 patients (60%) after a minimal of 12 months of follow-up (mean follow-up 78 months). Transitory extrapyramidal symptoms and fluctuating times of consciousness occurred in one patient. Tumor progression occurred in four patients. One of these four patients required a ventriculoperitoneal shunt for hydrocephalus, two experienced neurologic deterioration, and one died of tumor progression.

FIGURE 5-18 A pilocytic astrocytoma shown on a postcontrast, T1-weighted sagittal MRI image (A). Annual control MRI examinations were obtained and the latest made 9 years following gamma surgery is shown (B).

High-Grade Astrocytomas

From an intellectual standpoint, it is difficult to understand how a patient with a highly invasive and diffuse tumor like a high-grade glioma can benefit from such a focused treatment as gamma surgery. However, when coupled with chemotherapy and fractionated radiation therapy, the gamma knife can be used to treat the largest concentration of the residual tumor based upon the neuroimaging studies. It seems clear that no single treatment modality in the neuro-oncology armamentarium is a magic bullet for such tumors, and, as such, this multimodality approach to high-grade gliomas is prudent.

We have treated 56 malignant astrocytomas. Our experience has been similar to other reported series ¹³³^–¹³⁵ with the majority of patients showing initial decrease in size or remaining stable for a period of time (Fig. 5-19); however, recurrence and progression is the rule with these tumors and no therapy is curative. Because of the differences in histology and the wide variety of therapies and protocols available for these tumors it is difficult to judge the benefit of gamma surgery. Although our group and Nwokedi et al.¹³⁶ have observed a statistically significant prolongation of life expectancy in the group of patients undergoing aggressive multi-modality treatment (e.g., including some or all of the following: radical tumor debulking, radiation therapy, chemotherapy, and gamma surgery), it remains to be seen if these findings will be borne out in larger, better controlled studies. The limit of the benefit that radiation can contribute to the treatment of these lesions seems to have been reached, hence it may be stated that the dose escalation with the gamma knife in the treatment protocol of this disease will change only marginally the clinical outcome. It is also conceivable that targeting tumor angiogenesis and finding ways to induce apoptosis will have some impact on the management of these cases.

FIGURE 5-19 Postcontrast, T1-weighted axial MRI demonstrating a right parietal glioblastoma multiforme and associated cyst on postcontrast, T1-weighted axial MRI (A). Same patient 11 months after gamma surgery shows complete radiographic disappearance of lesion (B).

Neurocytomas

Central neurocytomas were described by Hassoun et al. in 1982.¹³⁷ According to Brandes et al., 210 cases were reported in the literature.¹³⁸ The histology, biological behavior and clinical course of central neurocytomas may vary from benign to more aggressive patterns.¹³⁹ Surgical resection is the first choice of treatment. Rades and Fehlhauer compared 108 and 74 patients who underwent complete or incomplete resection.¹⁴⁰ At 5 years tumor control rates were 85% and 46%, respectively. If the surgical resection is not total, the residual tumor should be irradiated. The 5-year tumor control rate with postoperative radiotherapy increased from 46% to 83% after incomplete resection but radiotherapy did not seem to improve survival rate.¹⁴⁰

With the advent of radiosurgery, it was used as upfront or adjunct therapy following surgery. We used the gamma knife in 7 patients with a total of 9 neurocytomas.¹⁴¹ The mean tumor volume at the time of the gamma procedures ranged from 1.4 to 19.8 cm³ (mean 6.0 cm³). A mean prescription dose of 16 Gy (range 13–20 Gy) was used. After a mean follow-up period of 60 months, 4 tumors disappeared and 5 shrank significantly (Fig. 5-20). One patient had a hemorrhage in the tumor 1 year after gamma surgery and the tumor had decreased significantly at the last follow-up. This patient had a new tumor at some distance of the successfully treated one. Four patients were asymptomatic during the follow-up period and a patient with hemiparesis caused by a previous transcortical resection was stable. A patient died of sepsis due to a shunt infection.

FIGURE 5-20 Gamma surgery for central neurocytoma. T1-weighted, contrast-enhanced MRI reveals a moderately enhancing neurocytoma spanning both lateral ventricles (A). The last follow-up image obtained 14 years following gamma surgery shows that the tumor decreased in size significantly with only some residual tissue in the septum pellucidum (B).

Chordoma

Skull base chordomas are a rare neoplasm arising from the remnants of notochord. Although histologically benign, these tumors are locally invasive and present significant management challenges. There is consensus that surgical debulking should be performed. Proton radiotherapy has been the mainstay of treatment for recurrent or residual tumors.^142,¹⁴³

Fifteen patients (8 males and 7 females) had undergone gamma surgery between 1990 and 2007 at Lars Leksell center. The median age was 46 years (range 13–80). Twelve patients had undergone tumor resection. Mean tumor volume was 5.8 cm³ (range 1.03–15.6 cm³). The tumors were treated with a mean prescription dose of 12.7 Gy (range 12–20 Gy) and a mean maximal dose of 36.7 Gy (range 28–50 Gy).

Imaging follow-up was available for all patients with a median time of 88 months (range 8–167), and clinical follow-up was available for 11 patients with a median of 70 months (range 8–132). At the last follow-up, tumor control was achieved in five out of 15 patients (33.3%) after initial GKS (Fig. 5-21). Actuarial 5- and 10-year tumor control rates after one gamma surgery was 42.6% and 34%, respectively. Three patients who underwent a second gamma surgery achieved good tumor control. Actuarial 5- and 10-year tumor control rates after one or more gamma procedures improved to 50.3%. Symptomatic progression was seen in 75% of the patients.

FIGURE 5-21 Gamma surgery for chordoma. A 45-year-old male with chordoma was treated with gamma surgery. The size of the tumor progressively decreased. However, after 5 years, recurrence occurred. At the time of retreatment with gamma surgery, the tumor measured 3 cm³ on enhanced, T1-weighted MRI (A). It shrank progressively and, after close to 9 years, measured 0.1 cm³ (B).

For the management of intracranial chordoma, surgery as radical as possible is the main treatment alternative—a goal frequently not achieved and some forms of radiation have to be used as an adjunct. Chordoma is relatively radioresistant and respond best to high doses of fractionated proton radiotherapy. The physical and biological properties of the proton—it carries higher kinetic energy and as they slow down a higher release of energy (Bragg peak)—make it an excellent source of radiation for chordomas. Amichetti et al. in a review article presented the current data on the treatment of skull base chordomas with proton beam and compared the outcomes to those obtained with fractionated photon radiation, ion therapy, fractionated stereotactic photon therapy, and radiosurgery.¹⁴² With proton therapy, doses above 70 cobalt Gray equivalent can be applied safely, achieving local control rates at 3 years of 67.4% to 87.5%, at 5 years of 46% to 73%, and at 10 years of 54%. The estimated overall survival rates are 66.7% to 80.5% at 5 years and 54% at 10 years.

Chondromas and Chondrosarcomas

These are rare tumors in the skull base. We have treated four chondromas and eight chondrosarcomas with gamma surgery. More than 50% shrinkage was observed in two cases of chondrosarcomas and three tumors shrank 25% to 50%. None progressed at follow-up, ranging from 1 to 5 years (median 3.5 years).

Muthukumar et al. treated 15 patients (nine with chordomas and six with chondrosarcomas) with gamma surgery and reported their results with an average follow-up of 4 years. Four of their patients had died; only two deaths were related to progression of disease and both of these had progression outside of the treated area. Only one of the surviving 11 had tumor progression, and five had shrunk.¹⁴⁴ Gamma surgery seems to be a reasonable treatment alternative for these tumors, but longer follow-up and larger series are required before definitive statements can be made.

Hemangioblastomas

The gold standard treatment for hemangioblastomas is the surgical resection of the solid component of the tumor. It is not necessary to resect, if present, the cystic portion of the tumor. Similarly with gamma surgery only the solid portion of these tumors were targeted. We treated 16 hemangioblastomas with the gamma procedure. Five of them had von Hippel-Lindau disease. The mean prescription dose was 15 Gy. The patients were followed for an average of 21 months. In 12 patients (75%), the solid component of the tumor targeted did decrease in size. In 4 patients, it remained unchanged. It was not uncommon, however, for the cystic portion of the tumor to grow larger regardless of the behavior of the solid portion. During the follow-up, 6 of 16 patients (42%) required surgical drainage for expanding cysts. Although several patients responded well, the high incidence of second, open procedures indicates that the microsurgical removal of hemangioblastomas is in most cases the initial procedure of choice.

Hemangiopericytomas

Hemangiopericytomas are tumors of mesenchymal origin. They are recognized for their aggressive clinical behavior, high recurrence rates, and tendency for distant metastases even after a gross total resection. Initial treatment is usually resection. Upon recurrence, adjuvant treatment is frequently used. Chemotherapy has provided only marginal benefit.¹⁴⁵ Radiosurgery or fractionated radiotherapy has been used as alternatives.

Between 1989 and 2008, we treated 28 recurrent or residual hemangiopericytomas in 21 patients with gamma surgery. The median age was 47 years (range 31–61 years). Eight patients had prior fractionated radiotherapy. The mean prescription and maximum radiosurgical doses to the tumors were 17 and 40 Gy, respectively. Thirteen tumors had undergone repeat gamma surgery. The median follow-up period was 68 months (range 2–138 months). At the last follow-up, local tumor control was demonstrated in 10 of 21 patients (47.6%). Of the 28 tumors treated, 8 decreased in size on follow-up imaging (28.6%), 5 remained unchanged (17.9%), and 15 ultimately progressed (53.6%). The progression free survival rates were 90%, 60%, and 29% at 1, 3, and 5 years after initial gamma surgery. The progression free survival rate improved to 95%, 72%, and 72% at 1, 3, and 5 years after one or multiple gamma surgery. The 5-year survival rate after radiosurgery was 81%. In 4 (19%) of 21 patients, extracranial metastases developed.

Metastatic Tumors

Surgical extirpation of a solitary brain metastasis has been shown to significantly prolong survival if the primary disease is controlled. Likewise whole brain irradiation has been show to be of benefit for some tumor types. These conclusions and the well-defined limits on neuroimaging studies of most metastatic lesions make them very amenable to gamma surgery. Because of this as well as the high incidence of these lesions, the treatment of metastatic tumors is presently the most frequent indication for gamma surgery worldwide.

Except for solitary lesions causing mass effect, the treatment of metastatic brain tumors is primarily palliative. In the instance of solitary metastasis the occurrence of long-term survival is not unheard of; however, in general the guiding philosophy is palliation, reversal of neurologic deficits and maintenance of quality of life. There has been some disagreement regarding the total number and volume of tumors that can be treated with gamma surgery in the instance of multiple metastases. Our general guideline is not to treat more than five if that is known to be the case. We have treated more but usually when additional lesions were discovered on the treatment MRI. With the gamma knife model C, if metastatic deposits are located very far from one another in space the ability to treat them all with the same frame placement may be difficult due to the limitation of the space within the treatment helmet. Such consideration makes frame placement for widely separated metastases a challenge at times. The large radiation space within the gamma knife model Perfexion basically eliminates this concern.

Most reports regarding gamma surgery for metastatic tumors report a 7- to 15-month survival following treatment. Local tumor control rates range from 71% to 98.5%. The histology, dosages, and previous treatments vary considerably through the literature. Most centers are using a peripheral dose of 18 to 22 Gy. These doses are adjusted down if whole brain irradiation has been given previously. The reduction of dose in the instance of tumors that appear after whole brain irradiation is possibly not necessary or desirable. In a study comparing the efficacy of surgery plus whole brain radiotherapy with radiosurgery alone in the treatment of solitary brain metastases less than or equal to 3.5 cm in diameter, local tumor control and 1-year death rates did not statistically differ between the two groups.¹⁴⁶ In a large, multi-institutional study, the omission of upfront fractionated radiation therapy did not compromise the overall length of survival in brain metastasis patients who had undergone radiosurgery.¹⁴⁷ Radiosurgery even appears to be efficacious for treating traditionally relatively “radioresistant” brain metastases such as melanoma and renal cell carcinoma.

We have treated more than 1,000 patients for metastatic tumors to the brain. Evaluation of our series demonstrated an 81% to 97% control rate of treated lesions (disappeared, shrank, or did not change) and a median survival of 8 to 14 months. The usual cause of death was systemic disease.

Lung Carcinoma

Lung carcinoma is the leading cause of death from cancer and the most common source of brain metastases (Table 5-8). Depending on the actual histologic subtypes, lung carcinoma metastasizes intracranially between 13% and 54% of the time. The overall frequency of brain metastasis in patients with lung carcinoma is approximately 32% and between 54% and 64% of patients with lung carcinoma metastatic to the brain harbor or eventually develop multiple lesions.^148,¹⁴⁹ Treatment options include symptomatic medical management with corticosteroids and whole-brain radiation therapy, which lead to a median survival of 3 to 6 months. Patient with small cell lung cancer developed metastases quite early and adjuvant chemotherapy has also become well-accepted for the treatment of extracranial disease in small cell lung cancer. We have treated 903 metastases in 262 patients with lung carcinoma. The median survival was 15.4 months. Age of less than 65 years, a Karnofsky performance score of greater than 70, and controlled extracranial disease were associated with increased survival.

TABLE 5-8 Outcome of Radiosurgery for Metastatic Lung Carcinoma

Breast Carcinoma

While improved neuroimaging enable early diagnosis of brain metastases, better treatment of systemic disease increased the frequency of the diagnosis of intracranial metastases as well. Breast cancer is a paradigm in this regard (Table 5-9). The advent of an effective targeted therapy, such monoclonal antibody against HER-2, allows patients to survive much longer than before, thus increased likelihood of central nervous system relapse.

TABLE 5-9 Outcome of Radiosurgery for Metastatic Breast Carcinoma

Breast cancer is the second most common cause of cerebral metastases. Incidences of metastasis to the central nervous system ranging from 10% to 20% have been reported in clinical series and 30% in autopsy series.^150,¹⁵¹ Breast cancer is considered to be a relatively radiosensitive tumor and radiosurgery in the treatment of breast carcinoma that has metastasized to the brain has shown its effectiveness in prolonging overall survival.

We have treated 43 patients with a total of 84 metastatic lesions from breast carcinoma. Overall median survival was 13 months after gamma surgery.¹⁵² Analysis revealed that a high Karnofsky performance score and a single lesion correlated with increased survival. Overall median time to local tumor control failure was 10 months. The tumor control rate from the literature ranged from 81% to 94% and the median survival ranged from 13 to 19 months.^105,^152,¹⁵³

Melanoma

The incidence of melanoma has progressively risen over the decades (Table 5-10). Melanoma is now the third most common primary tumor associated with central nervous system metastasis. Brain metastases were found in up to 75% of melanoma cases at autopsy and involvement of the central nervous system is the cause of the death in approximately one third of all patients.¹⁰⁶ Radiosurgery seems to overcome the problem of radioresistance observed in melanoma. With a single high radiosurgical dose, the tumor control rate following radiosurgery for cerebral metastatic melanoma seems favorable ranging from 61 to 90%. However, the prolongation of survival is not promising with most series reporting median survival in the range of 5.7 to 7.1 months.¹⁵⁴^–¹⁵⁷

TABLE 5-10 Outcome of Radiosurgery for Metastatic Melanoma

We have treated 90 melanoma patients with a total of 133 tumors. Forty tumors (30%) disappeared, 45 tumors (34%) shrank, 23 tumors (17%) remained unchanged in size, and 25 tumors (19%) grew. Mean prescription dose to the tumor margin was 19 Gy (range 12–23 Gy). The median survival was 10.4 months. A single metastasis and absence of extracranial disease correlated with improved prognosis.

Renal Cell Carcinoma

Renal cell carcinomas are responsible for approximately 2% of cancer deaths in the United States annually, and they have a 10% incidence of developing into brain metastases ¹⁵⁸ (Table 5-11). The resistance to fractionated radiation therapy and a tendency for limited numbers of metastases make radiosurgery a rational alternative in the management of renal cell carcinoma metastases to the brain. The reported tumor control rate following radiosurgery for metastatic renal cell carcinoma ranged from 83% to 96%.^151,¹⁵⁹^–¹⁶¹

TABLE 5-11 Outcome of Radiosurgery for Metastatic Renal Cell Carcinoma

A series of 40 patients with 65 renal cell carcinoma brain metastases was treated by us. The average survival was 9.2 months after radiosurgery. A total of 41 tumors decreased in volume, 6 tumors disappeared, and 16 tumors remained unchanged in size (Fig. 5-22). Only 2 tumors increased in size following treatment. An unmatched control group of 119 patients that received external brain radiation therapy had an average survival of 4.4 months.¹⁶² Factors associated with longer survival in the group treated with gamma surgery included a higher Karnofsky performance status, absence of extracranial metastases, adjutant whole brain radiation therapy and prior surgical resection. The size and number of metastases did not have a significant effect on survival, although in cases of single metastasis with controlled local disease long-term survival could be achieved.

FIGURE 5-22 Gamma surgery for renal cell carcinoma. Postcontrast, axial T1-weighted MRI at time of treatment (A), and at 3 months (B) and 1 year (C) following gamma surgery. This patient developed two additional metastases that were subsequently successfully treated with gamma surgery. The patient survived 17 months before succumbing to metastatic deposits outside the brain.

Uveal Melanomas

The most common surgical treatment for uveal melanomas is enucleation, but several centers have relatively large series in the treatment of these tumors with gamma surgery.¹⁶³^–¹⁶⁶ Other therapeutic options include radium plaque therapy, and proton beam therapy. The first uveal melanoma treated with gamma surgery was in Buenos Aires¹⁶⁷ and gamma surgery has become a more frequently used procedure for this unusual pathology (Fig. 5-23). The use of gamma surgery and its stereotactic technique requires that the eyeball be fixated relative to the stereotactic frame. This is accomplished with retrobulbar blocks and external fixative sutures that are attached to the frame.

FIGURE 5-23 Gamma surgery for ocular melanoma. Postcontrast, axial T1-weighted MRI at time of treatment (A) and at 16 months (B) following gamma surgery. The tumor shrank significantly.

The Sheffield group reported a series of 29 patients treated and followed for an average of 14 months. The average peripheral dose was 73 Gy, corresponding to the 50% isodose line.¹⁶³ The dose was delivered in two sessions not more than 8 days apart. All but two patients had good local control. The two failures required later enucleation. Three patients died of metastatic disease. More recent work suggests that a lower margin dose of 41.5 Gy may be just as effective in terms of tumor control but be associated with a lower risk of neovascular glaucoma.¹⁶⁸ In a series of 75 patients with uveal melanoma followed for a minimum of 10 months, Simonova et al. reported 84% local tumor control and secondary glaucoma in 25%.¹⁶⁹