Topic of the month.... The role of gamma knife in the management of benign brain tumors
Historically, radiation therapy has been used extensively in the treatment of malignant and aggressive
intracranial tumors, and the importance of its role has been repeatedly verified by prolonged patient
survival rates and increased tumor control. As more modern capabilities are employed in surgery and
radiotherapy, attention is being directed to the utility of radiation as either primary or secondary
treatment of benign tumors. Specifically, primary treatment encompasses irradiation of small benign
tumors without biopsy confirmation of tumor type; secondary treatment involves postoperative radiation
therapy, with the possibility that less-aggressive tumor resection may be performed in areas that have a
higher probability of resultant neurological deficit. Current literature suggests that this is not only a
possible treatment strategy, but that it may be superior to more radical resection in some cases, for
example, in vestibular schwannomas and meningiomas. This article provides an overview of factors to
consider in the use of radiation therapy and reviews the relationships between radiation and surgery,
notably the unique complementary role each plays in the treatment of benign intracranial tumors.
Excision has long been regarded as the definitive treatment of benign intracranial tumors, mainly
because it permits a rapid reduction in the intracranial mass effect and establishes a precise histological
diagnosis. Radiation therapy, in contrast to its long-standing role as a standard postoperative treatment
for malignant intracranial tumors, traditionally has been less accepted in the treatment of benign
neoplasms and is usually reserved, for the most part, for recurrent or residual tumors. That situation has
changed, however. Modern radiographic imaging techniques and advances in CRT delivery methods
have permitted alternative radiotherapeutic strategies to emerge for managing benign intracranial
neoplasms. For example, radiation therapy has increasingly become the primary treatment for patients
with small meningiomas or vestibular schwannomas, particularly in the elderly or in patients harboring
significant medical risk, but increasingly for other patients as well. This is possible because of the
introduction of contemporary neuroimaging capabilities, coupled with advanced computational power,
allowing for more definitive diagnoses to be made in the absence of histological confirmation, as well as
more refined targeting methods to be achieved, thus enabling the delivery of higher doses of radiation to
target volumes while reducing the risk to surrounding brain tissue. Today, as a consequence, both
surgery and radiation therapy are regarded as primary modalities for treating patients with some benign
intracranial tumors; these modalities may be used together as a planned intervention, or separately.
This article provides an overview of fundamental principles in the use of radiation to treat benign lesions
and discusses 3 common tumors that have an established history of management using both microsurgery
and radiation: meningiomas, schwannomas, and pituitary tumors. We review current methods of
radiation therapy and the complementary roles that radiation and surgery assume in the treatment of
these 3 benign intracranial tumors.
Principles of Delivering Radiation to Intracranial Tumors
Some Fundamental Concepts
Successful radiation treatment of intracranial tumors requires delivery of a sufficient total dose of
ionizing radiation to a target volume to ensure tumor control, while simultaneously sparing surrounding
neural tissue from radiation exposure to the greatest extent possible. The radiation team's task, in short,
is to deliver the maximum dose necessary to the targeted volume while minimizing the dose delivered to
normal tissues or avoiding exposure of those tissues entirely. This task implies the need to conform the
radiation dose to the tumor, which may be accomplished partly by designing a treatment plan that
configures the delivery portals precisely and partly by selecting a radiation particle and mode of delivery
that permits a high degree of conformation to the intended target volume and spares surrounding tissues.
Fortunately, rapid advances in computational and digital imaging capabilities have greatly enhanced the
radiation team's ability to conform targeting more accurately and with more flexibility.
There are 3 fundamental strategies of delivering ionizing radiation to benign intracranial neoplasms -- or
to any target volume -- that surgeons and radiation teams should be aware of: SRS, SRT, and
fractionated radiation therapy. The essential difference between these strategies is in the number of
fractions, or doses, that the physician uses to deliver the total dose to the patient. In SRS, the total dose is
typically delivered in 1 fraction, although the current definition permits a maximum of 5 fractions; in
SRT and in fractionated radiation therapy, tens of fractions might be required, depending on the total
dose to be delivered, and they are differentiated only by the fact that SRT is delivered stereotactically.
The decision regarding the strategy to employ depends primarily on the tissues that will be exposed to
radiation by whatever means delivered. The entire rationale for dose fractionation is contained in the fact
that normal cells are able to recover from relatively low-dose radiation damage if given time between
treatments to do so. This has been referred to as the quot;Four R'squot;: reoxygenation, reassortment,
repopulation, and repair. Hence, the radiation team attempts to concentrate the dose in the intended
volume and, if radiation exposure of intervening or surrounding normal tissues cannot be avoided, to
divide the total dose into a sufficient number of fractions to allow the intervening or surrounding tissues
the opportunity to repair radiation damage. It follows, then, that the decision as to whether to use SRS,
SRT, or fractionated radiation therapy for a given patient harboring a benign intracranial tumor
depends on the location of the tumor, the total dose needed to eradicate it, the volume of normal tissues
that will be exposed to radiation in the attempt to deliver the needed total dose, and, most importantly,
the ability of the normal tissues to tolerate (recover from) the dose to which they are exposed.[1,7,23]
Two of the strategies mentioned previously are quot;stereotactic.quot; Stereotaxis refers to the technology of
precisely localizing a target within 3D space; Radiation treatment of benign intracranial tumors, by
whichever of the modern means delivered, falls under this definition. The term is not traditionally
associated with fractionated radiation therapy, but it should be understood that modern methods of
positioning patients are highly precise and repeatable, such that precise localization of the target in 3D
space can be accomplished routinely for fractionated radiation therapy as well, in centers employing the
appropriate technology. Although the term tends to be associated with devices designed to deliver
radiation to tumors in the head, the concept applies to any method of radiation delivery wherein highly
precise, repeatable localization is achieved. Given modern techniques of delivering fractionated radiation
therapy, it does not stretch the definition too much to call that modality quot;stereotacticquot; as well.
Techniques Underlying the Strategic Alternatives
Modern radiotherapeutic practices are made possible by dramatic, relatively recent progress in the
development of computer technology that enhances the ability to target and deliver radiation due to
refinement in digital neuroimaging capabilities, and also by high-quality digital imaging in MR, CT, and
positron emission tomography (or in combination using image fusion techniques). Hence, exquisite target
imaging is available, enabling more precise treatment planning, verification, and highly accurate follow-
up. Two main methods of delivering radiation therapy with great precision, either of which can be
employed in SRS, SRT, and fractionated radiotherapy, have resulted from these advances: 3D conformal
radiotherapy and IMRT. The former method refers, quite simply, to radiation therapy that is planned on
an image-based, 3D, beam's-eye-view planning system. The latter method also uses image-based, 3D
planning but is delivered via a computerized system that varies the intensity of the beam.
Both 3D CRT and IMRT are conformal modalities. Both can employ photons (x-rays or gamma rays) or
heavy-charged particles (mainly protons) to deliver ionizing energy to the target volume. The essential
difference between the 2 methods, as the name of the latter suggests, is beam intensity. In the former
method (3D CRT), beam intensity remains uniform through the delivery portal; in the latter method,
beam intensity is modulated within each portal. Intensity-modulated radiotherapy is characterized by
many more delivery portals than 3D CRT; it thus exposes a larger volume of normal tissues to ionizing
radiation but relies on intensity modulation to concentrate the high dose in the target and minimize it to
the volume of the normal tissue.
From the radiation team's point of view, an essential point to understand about selecting either of these
options is that one would prefer to avoid radiation exposure of untargeted tissues as much as possible. As
noted, IMRT generally exposes a larger volume of normal tissues to ionizing radiation than does 3D CRT,
although intensity modulation enables the physician to deliver low doses to most of the untargeted tissues.
This difference is the result of a trade-off. To achieve the tight conformation of the high-dose region in the
targeted volume, IMRT must deliver the radiation beam through many portals. Delivering radiation
through many portals must result in radiation exposure of the tissues intervening between the target and
the beam's entrance region, and must also result in radiation exposure of tissues distal to the target, if the
radiation beam employed in IMRT cannot be made to stop in or just beyond the target. Noting this effect
is not to deny the desirability of achieving a conformal high-dose region, but the fact that a greater
volume of untargeted tissue (volume integral dose) receives some radiation dose should not be overlooked.
Radiation teams would prefer to avoid such a tradeoff if possible.
Another form of radiation delivery, TomoTherapy, is an implementation of 2 types of technology: spiral
CT scanning and IMRT. TomoTherapy allows patient positioning, treatment planning, and treatment
delivery to occur simultaneously. TomoTherapy can be thought of as IMRT carried to its logical
conclusion. An image-guided, moving beam is used to achieve the required high-dose conformation, but
with the limitation of using only coplanar beams. The same considerations of volume integral dose apply.
For any of these modalities, treatment planning begins with high-quality neuroimaging. This planning is
generally accomplished using CT but may be augmented with MR imaging and positron emission
tomography. The resulting images are then used to generate a 3D image of the patient and target volume
and thus to determine sophisticated shaping of dose distribution by means of collimation design.
Intensity-modulated radiotherapy may achieve intensity modulation by either constructed complex
physical compensators or by means of multileaf collimators.
Patient positioning and stabilization is of primary importance during treatment planning and delivery.
Patients are immobilized most commonly by means of either a face mask or some type of body molding
that ensures identical patient positioning during each treatment session. These immobilization methods
are designed for patient comfort and, for the most part, are fairly well tolerated during treatment. After
the patient is immobilized, radiotherapy simulation is initiated. First, planning imaging is obtained with
virtual simulation using 3D imaging techniques. Then the images are used to digitally define the gross
tumor volume (the tumor volume delineated on imaging studies); the clinical target volume,
encompassing the visualized tumor plus adjacent areas at risk; and the planning target volume, which is a
slightly enlarged clinical target volume that includes a margin of error for patient motion, setup errors,
and LINAC alignment errors. In some planning systems, a fourth dimension is added to compensate for
some of the latter factors, such as patient motion. Once planning is optimized and treatment devices are
fabricated and calibrated, treatment commences.
A variety of radiation sources, such as photons (high-energy x-rays or gamma rays) or charged particles
(electrons or protons, for example) may be used to accomplish the objectives of the therapy plan. X-ray
beams are generated by high-energy LINACs, and gamma rays are generated from a natural source, such
as cobalt-60. The photons that comprise x-rays and gamma rays have no mass or charge. They deposit
energy exponentially as they pass through tissue; depending on the depth of the intracranial target
volume, a single photon beam may deposit a significant part of its energy before reaching the target and
will continue to deposit energy beyond the target. This fact underlies the practice of using multiple beams
to accumulate the desired total dose in the target volume, a practice that is carried to its logical
conclusion in IMRT. If photons are used in such applications, however, the dose in distal normal tissues
cannot be eliminated and the volume integral dose is greater than that obtained with other delivery
Throughout the history of radiation therapy, a variety of subatomic particles and ions have been used for
therapy, including electrons, neutrons, negative pi mesons (pions), and heavy-charged particles such as
protons, helium ions, and ions of heavier atoms such as carbon. Pions are no longer used, and neutron
beams are not used for treating intracranial tumors, but any of the other particles may be employed.
Most centers around the world use photon beams for all radiotherapeutic applications, including
treatment of benign intracranial tumors, but an increasing number of centers have the option to use
heavy-charged particles (in most cases, proton beams). Protons and photons are similar in terms of their
radiobiological effect in tissue, but are vastly different in terms of their physical dose distribution; the
latter quality is the basis for their employment in centers that use them.
Protons are the nuclei (ions) of hydrogen atoms. They thus have both mass and charge; their mass
enables them to pass through tissue to reach their target without being deviated substantially, and their
charge enables the physician to direct them magnetically. In some delivery systems, such as those
employing scanning beams, this property of protons can thus be used to attain the required conformation
in tissue. In addition, protons have the intrinsic property of depositing the bulk of their energy near the
end of their travel. This point, called the Bragg peak, can be placed in the desired target volume by
modulating the energy of the proton accelerator to accommodate the required depth in tissue (Figure 1).
Distal to the Bragg peak, protons deposit no energy. Thus, the physician can control the proton beam in 3
dimensions, which is impossible with photon beams. These properties enable the physician to place the
conformal high-dose region where desired and to spare nearby normal tissues to a greater extent than is
possible with photons. Proton 3D CRT plans routinely achieve the target-volume conformality seen
with photon IMRT plans but with a much-reduced volume integral dose. That is, much more of the
surrounding normal tissue is spared radiation exposure.
Figure 1. Dose distribution curve for
radiation, comparing protons with
other radiation sources. Ortho =
Protons are not the only heavy-charged particles used. Some centers, mainly in Japan, employ beams of
carbon ions. These particles also have a Bragg peak but are more massive owing to a greater number of
protons in each particle. They thus have a potentially greater radiobiological effectiveness in tissue, in
terms of more intense ionization density per track length (higher linear energy transfer); this property
results in more lethal cell damage in all cells irradiated by such beams. Clinical research into the optimal
applications for these particles is required. Protons, which, like photons, are low linear energy
transfer particles, allow irradiated normal cells a greater opportunity to effect cell repair, thus exploiting
the greater capacity for repair of normal cells than tumor cells.
Specific Technologies of Delivering Radiation to Treat Intracranial Tumors
Given the exquisite proximity of intracranial structures to each other and the great need to eliminate or
minimize radiation exposure of all structures except for those that are diseased, stereotaxis has always
been a prime concern in treating intracranial neoplasms, benign or otherwise. The development of SRS,
SRT, and modern fractionated radiation therapy arose from this concern.
Historical Perspectives of Stereotactic Radiation
Stereotactic radiation treatment for intracranial tumors was first performed using the proton beam.
Leksell, in Sweden, reported on the use of the Uppsala research beam for intracranial SRS in the late
1950s and Kjellberg used the Harvard Cyclotron Laboratory research machine for similar purposes in
the 1960s, as did Fabrikant on the West coast.[8,19,25,52] The Harvard experience continued for several
years and that group accumulated a large patient database. Some of these early attempts made in the era
before modern 3D imaging were limited to treatment of intracranial structures that could be well
localized without benefit of such imaging; pituitary adenomas were notable examples. These attempts
established the value of a proton beam in which the high-dose region could be configured to encompass
the target without greatly damaging the nearby structures.
The Gamma Knife
When the Uppsala research cyclotron became less available for therapy, Leksell, a neurosurgeon,
introduced the Gamma Knife. Initially conceived and developed for the treatment of movement
disorders, it quickly became adapted for use in intracranial tumors and arteriovenous malformations.
Since that time, it has been used to treat > 200,000 patients worldwide with a wide variety of intracranial
The Gamma Knife is a large, cast-iron sphere containing multiple cobalt-60 gamma-ray sources
(currently 192) into which a patient's head is introduced through a metal entrance door. These sources
are housed in individual beam channels within the central core and are directed convergently toward the
isocenter. Collimation is provided by means of a collimator helmet containing a separate collimator for
each cobalt source. Initially the patient is immobilized in a rigid stereotactic head frame, and then the
patient undergoes high-resolution imaging (CT, MR imaging, or angiography), which is used for
targeting and treatment planning. Once this planning is optimized, the patient's head, still rigidly fixed
within the frame, is introduced into the collimator helmet and the stereotactic frame is oriented within
the helmet in such a way that the beam channels and collimators align with the specific target site.
Creating several different isocenters that are then treated in sequence during the treatment session
attains target conformity. The Gamma Knife can achieve target accuracy to as small an area as 0.3 mm,
and offers the advantages of single-session treatments, high special accuracy, and a long history of use
and treatment experience. Relative drawbacks include the inability to treat tumors below the skull base,
relative target size limitation to < 35 mm, and the need for invasive, rigid fixation directly onto the
patient's skull. Recent advances with the Gamma Knife, however, enable physicians to now treat tumors
well below the skull base, allowing treatment of cervical spine and head and neck tumors.
The CyberKnife System
A more recent development, the CyberKnife, is a LINAC-based, robotic SRS system that is capable of
treating tumors anywhere in the body with submillimeter accuracy, thus minimizing exposure of adjacent
normal tissue to the high dose delivered to the target. Using advanced image-guidance technology and
computer-controlled robotics, the CyberKnife continuously tracks, detects, and corrects for tumor and
patient movement throughout the treatment. It uses a proprietary stabilization quot;couchquot; that maintains
patient positioning without the need for fiducial screw placement or a stereotactic frame. While the
Gamma Knife creates a stereotactic space within the cranial frame, the CyberKnife transforms the entire
treatment room into 3D (stereotactic) space, thus enabling the use of precise image guidance for the
patient's entire body. When coupled with computer-controlled robotics, this image guidance enables
complete and precise treatment. In addition, the CyberKnife has patented a method of tracking
respiration and heart movement that synchronizes treatment delivery to the motion of the tumor
throughout the respiratory or cardiac cycle. This is especially helpful for patients with lung tumors, for
example, that would previously require patients to hold their breath to facilitate appropriate radiation
treatment, but is also useful for treating intracranial sites. The CyberKnife also continually updates its
correlation model with each new x-ray image, automatically correcting for any changes in the patient's
breathing patterns. It is able to deliver high-dose photon radiation in either single or multiple fractions
with highly precise and accurate targeting even in patients with geometrically complex tumors.
Modern Proton-Beam Radiotherapy
As previously noted, the intrinsic properties of proton beams enable the radiation team to substantially
reduce the amount of energy deposited outside of the target volume in normal healthy tissue. Protons can
be used for SRS, SRT, and fractionated radiation therapy. Modern means of planning and delivering
proton radiation therapy make this modality, for all practical purposes, another form of stereotactic
treatment. During the past several decades, > 46,000 patients have been treated with proton-beam
radiotherapy at centers equipped for this type of therapy.
There are several advantages of using heavy-particle radiation. As noted previously, primarily there
is greater controllability due to the particle's higher charge and mass. This characteristic allows not only
control in targeting tumor volume, but also in targeting the tumor margins, thus minimizing damage to
adjacent tissue. While other types of radiation therapy require multiple beams to produce a highly focal
dose distribution, the Bragg peak phenomenon allows this to be done with only a few beams, usually
between 2 and 6 (Figure 1). As also previously noted, the reduced volume integral dose obtainable with
protons permits the radiation team to spare much normal tissue altogether, thus reducing the probability
of long-term sequelae from radiation treatment. Further, given that the precision of protons enables the
radiation team to employ fractionated SRT or radiation therapy, the physician can exploit the normal-
tissue-sparing effects of dose fractionation while still delivering the high total dose to a conformal volume.
Surgery and Radiation in the Treatment of Specific Tumor Types
In cases in which a histological diagnosis cannot be obtained, advanced neuroimaging enables clinicians
to predict tumor type with reasonable accuracy based on characteristic imaging properties and/or MR
spectroscopy. This advanced neuroimaging thus permits the use of radiation, by means of SRS, SRT, or
fractionated radiation therapy, as the primary treatment for benign intracranial tumors. Furthermore,
for large tumors requiring surgery, evidence of durable local tumor control enables surgeons to perform
less-aggressive tumor resection in areas at a higher risk for neurological injury, with the expectation that
radiation therapy can be employed subsequently.
Meningiomas account for ~ 20% of intracranial tumors, roughly 94% of which are regarded as benign.
According to the Central Brain Tumor Registry of the United States, meningioma was the most
frequently reported benign tumor from 1998 to 2002 (at ~ 30%), with ~ 8600 new cases expected in the
US in 2002. Meningiomas occur in a female/male ratio of ~ 2:1, with peak age incidence between 50 and
Since Cushing's description of a wide variety of meningioma subtypes, this variety has been simplified to
the present WHO classification ( Table 1 ). Most meningiomas are unilateral, although some large
tumors may cross the mid-line at either the parasagittal region or at the skull base. Multiple tumors are
uncommon, with reported rates of 5-9%. Metastases are rare, but when they do occur they are mainly
reported in lung and bone. Intracranial locations of meningiomas are varied but tend to be close to dural
venous sinuses and the tentorial edge.
Table 1. WHO Classifications of Meningioma
Type I Meningioma, meningothelial (syncytial), fibrous (fibroblastic), transitional (mixed), psammomatous,
angiomatous, microcystic, secretory, clear cell, chordoid, lymphoplasmacyte-rich, metaplastic
Type Atypical meningioma
Type Anaplastic (malignant) meningioma
1. Variants of Types I and II
The classic approach to meningioma treatment has been tumor excision. The standard of care for
convexity meningiomas continues to be gross-total resection, as this treatment course continues to offer
the greatest likelihood of attaining permanent tumor-free survival. Gross-total resection has been shown
to result in 5-, 10-, and 15-year overall survival rates of ~ 85, 75, and 70%, respectively, and 5-, 10-, and
15-year progression-free survival rates of 90, 80, and 67%, respectively.[16,34,37] In many tumors that
infiltrate surrounding structures (such as the major venous sinus or tentorium), however, gross-total
resection is either not feasible or invites an undue risk of neurological compromise to the patient.
Postoperative adjuvant low-dose radiation therapy results in excellent long-term progression-free
survival and low morbidity.[13,50,51,54]
Recently, Friedman and colleagues demonstrated an actuarial local control rate of 100% at Years 1
and 2 and 96% at Year 5 following LINAC-based radiosurgery for meningiomas. Flickinger and
colleagues reviewed 219 cases of meningiomas diagnosed using imaging criteria that were then treated
using GKS, and found an actuarial tumor control rate of 93% at 5 and 10 years. Kondziolka and
colleagues[9,22] also reported a 93% tumor control rate at 5 and 10 years after radiation treatment, with
a 96% satisfaction rate. Lee and associates recently updated this patient series and found no
significant change in tumor control rates. Milker-Zabel et al. reported overall local tumor control of
93.6% following IMRT for meningiomas of the skull base, with a mean follow-up of 4 years in 94 patients.
Radiation teams at Loma Linda University, who employ proton SRT or fractionated radiation therapy
for patients with benign, atypical, and malignant meningiomas, are assessing the results of their
interventions. Results have not yet been published, but indications are that proton SRT or fractionated
radiation therapy achieves local control rates for benign meningiomas similar to those reported in
surgical patient series and SRS patient series (Figure 2).
Figure 2. Axial (left and center) and
coronal (right) T1-weighted MR
images with Gd enhancement
showing a subfrontal meningioma.
Colors represent dose planning prior
to proton-beam therapy.
A challenging issue in deciding on treatment for these patients is patient selection. It is apparent that
elderly patients and those with comorbidities are excellent candidates for radiation therapy. Treatment of
younger patients, which in the past has been believed to be the province of surgery, is now open to
question; either modality may be suitable as primary treatment, depending on factors associated with
individual presentations. As noted earlier, although radiation teams have historically been reluctant to
irradiate tumors without histological confirmation of tissue type, characteristic imaging properties and/or
evidence seen on MR spectroscopy offer the opportunity for a definitive diagnosis in the absence of
histological confirmation, thus permitting the use of SRS, SRT, or fractionated radiation therapy as
primary treatment for meningiomas in patients of any age. And in large tumors requiring surgery, the
ability of radiation to effect local tumor control enables surgeons to perform less-aggressive tumor
resection in areas with a higher risk for neurological injury, given the expectation that radiation therapy
can be employed thereafter. It is generally true that younger patients are healthier, have smaller tumors,
and display more rapid recovery, and thus are optimal candidates for surgery. In these patients, clinical
decisions are probably more likely to include the extent of surgery, with small remnants possibly left in
the sagittal or cavernous sinus, optic apparatus, or densely attached to the brainstem. These small
remnants may then be treated effectively with postoperative irradiation. Even with apparent gross
resections of meningiomas in the base of the skull, there is a higher incidence of recurrence; thus,
immediate postoperative irradiation is indicated or close monitoring should be undertaken, with
radiation therapy offered to the patient at the earliest indication of recurrence, before the patient
becomes symptomatic. Patients with atypical and malignant meningiomas are generally referred for
Intracranial schwannomas are uncommon. Vestibular schwannomas, arising from CN VIII, are the most
common of these tumors, yet they comprise only 8% of intracranial tumors even though they account for
80% of cerebellopontine angle masses. Other forms of intracranial schwannomas, such as lesions of the
trigeminal nerve, the jugular foramen, and the facial nerve, are even less common. These tumors arise
from the margin of the CN where central, glial myelin merges with peripheral, Schwann-cell myelin (the
Obersteiner-Redlich zone). The vast majority of these tumors are benign and relatively slow growing, and
thus many tumors have achieved a fairly large size by the time of diagnosis.
The major factors dictating treatment for intracranial schwannomas are patient age, general medical
condition, degree of symptoms, and the size and location of the mass. Another factor is patient choice. In
this age of widespread Internet medical information, patients are more informed than ever and play a
major role in treatment selection.
In tumors that compress the brainstem, there is a risk of increased pressure both from brainstem edema
and from tumor swelling during radiation therapy. For tumors involving brainstem compression
(generally > 2.5 cm in diameter), surgical decompression or complete excision is the preferred treatment
method. These tumors respond well to radiation, however, and this information is key in choosing the
treatment strategy for individual patients and should be presented to the patient as a factor in selecting
treatment. Patients > 70 years of age, patients < 70 years of age but with additional medical concerns, or
patients with tumors < 2.5 cm in diameter are ideal candidates for radiation therapy, which has been
shown to be effective in both SRS and fractionated radiotherapy.[38,41] Additionally, radiation therapy
has been shown to be useful for adjunctive post-surgical therapy for recurrence or residual tumor. This
finding has some importance for determining the extent of surgery when faced with a large tumor densely
attached to the accompanying CN. Leaving a small tumor remnant on the CN, yet preserving critical
neurological function, followed by radiation therapy is a choice that may have significant benefit.
Additionally, irradiation of tumors located within the cavernous sinus or the jugular foramen has a
reduced risk of cranial neuropathy when compared with excision. If the patient has significant symptoms
that can be reversed drastically by surgery, then that should be the treatment of choice, as long as the
patient is medically stable for surgery. Postoperative radiation therapy can be employed if a significant
residuum exists. If patients' symptoms are minimal and they risk a higher likelihood of morbidity with
surgery, then they are candidates for definitive radiation therapy. Available choices include SRS, SRT,
and fractionated radiation therapy, any of which can be accomplished using photons or protons.
Over the past 2 decades, the standard dose of radiation in SRS given for intracranial schwannomas has
been reduced substantially. This reduction has been mainly driven by cranial neuropathies caused by
higher radiation doses, specifically, CN V, VII, and VIII dysfunction. Lower radiation doses have been
shown to control tumor recurrence while resulting in a lower incidence of cranial neuropathy.
The use of fractionated radiation therapy has traditionally been associated with the sparing of
dysfunction in CNs V, VII, and VIII. Excellent control of acoustic neuromas has been achieved with both
fractionated radiotherapy, and more recently, with radiosurgery. Maire and colleagues reported a 10-
year tumor control rate of 88% using a fractionated mean radiation dose of 51 Gy. Sakamoto and
associates reported a 5-year actuarial tumor control rate of 92% using a fractionated radiation dose
range of 36-50 Gy.
Photon radiosurgery for schwannomas has also yielded excellent results. Kondziolka and associates
reported a tumor control rate of 98% at 10 years' follow-up after GKS. Facial and trigeminal nerve
function were preserved in 79 and 73% of patients, respectively. In patients with serviceable hearing
(Gardner-Robertson Class I or II) prior to treatment, useful hearing was preserved in 47%. Recently,
Friedman et al. reported the results of LINAC-based radiosurgery with 1- and 2-year control rates of
98% and a 5-year control rate of 90% with minimal complications. Similar results have been confirmed
in other patient series.[2,6,10,15,21,29,48,49,55]
Sheehan and colleagues have reported excellent results using GKS in 26 patients with trigeminal
schwannomas, and Hasegawa and associates found similar results in 37 patients. Kida et al.
reported a 100% tumor control rate of facial neuromas after a mean follow-up of 31 months with GKS.
Litre et al. reported that 10 of 11 patients with facial schwannomas were stable after this same
treatment. This group suggests that, given the advantages noted in the results of their study, these results
should lead to the consideration of GKS as a primary treatment option for small-to medium-sized facial
schwannomas. Recently, Martin et al. published a report on a series of 34 patients with jugular
foramen schwannomas treated with GKS. They concluded that the procedure was a safe and effective
treatment and that CN function remained stable or improved along with long-term tumor control.
Bush et al. reported their experience with fractionated proton-beam radiation therapy of acoustic
neuromas in 2002 (Figure 3). A total of 31 acoustic neuromas were treated in 30 patients. Patients were
divided into 2 treatment groups based on pretreatment hearing assessment. Patients with Gardner-
Robertson Class I or II hearing received a conformal fractionated radiation dose of 54 CGE over 30
treatments, whereas those without useful hearing received a conformal radiation dose of 60 CGE
fractionated over 33 fractions. Twenty-nine patients were available for follow-up at a mean of 34 months,
with no patients showing tumor progression and 11 showing tumor regression. Of the patients with useful
hearing prior to treatment, only 31% retained useful hearing. No damage to CNs V or VII was detected.
Figure 3. Axial T1-weighted MR
images with Gd enhancement
showing a vestibular schwannoma.
Colors represent dose planning prior
to proton-beam therapy
Pituitary adenomas are primarily benign neoplasms arising from cells of the anterior hypophysis. These
cells produce a variety of hormonal substrates that, with the development of the tumor, cause
hypersecretion of that particular hormone with resultant physiological consequences. Non-secreting
tumors cause more symptoms that are related to bulk effect due to compression of the optic chiasm or
cavernous sinus contents. In the past several decades these tumors have been preferentially treated using
transsphenoidal microsurgical techniques and, more recently, with endoscopic resections. Transcranial
resections have primarily been reserved for large or recurrent tumors with extrasellar extensions.
Radiation therapy has been used in the treatment of pituitary tumors since the time of Harvey Cushing.
In 1939, Henderson reviewed the records of 338 pituitary patients who had undergone operations by
Cushing and found that of the recurrent tumors, 56% had not received radiation, whereas only 13% of
irradiated tumors recurred. This trend has been confirmed in all but 2 published series.
Radiation therapy can be used to treat pituitary adenomas of the secreting and nonsecreting types. In the
case of the latter, however, even with modern radiographic technology, the differential clinical diagnosis
is rather extensive and the probability of obtaining a correct diagnosis in the absence of histological
confirmation is low. Definitive irradiation (that is, treatment undertaken without such a diagnosis) is
therefore usually not indicated.
The significant risk associated with pituitary tumor irradiation is damage to the optic apparatus,
temporal lobes, normal pituitary gland, and hypothalamus. Precisely targeted radiosurgery or
radiotherapy reduces this risk, but the overall dosage is limited by these structures to the tolerance dose
of these structures. In a review, the rate of visual loss following pituitary irradiation was only 1.5% in
471 patients; this rate was reduced by using SRS. Additionally, there is a risk of panhypopituitarism
following radiation therapy, even when fractionated to fairly low total doses. There is evidence, however,
that SRS produces more rapid correction of endocrinopathies when compared with fractionated photon
radiotherapy. Complications of radiosurgery are relatively low.[43,53] Compiled data from > 1300
patients by Shrieve and colleagues demonstrated that 0.3% developed subsequent blindness, 0.7%
developed visual field defects, and 0.9% developed oculomotor deficits after radiosurgery for pituitary
tumors. Evidence has been presented that suggests radiotherapy for pituitary tumors does not reduce the
quality of life or cognitive function in these patients.[24,53] Several LINAC-based trials report similar
Recent experience with GKS has been reported in the treatment of Cushing disease, acromegaly, and
Nelson syndrome. Jagannathan and colleagues reported a 54% endocrine remission rate and 96%
tumor control rate in 107 patients with Cushing disease. Pollock and associates demonstrated
actuarial rates of biochemical remission at 2 and 5 years to be 11 and 60%, respectively, in 46 patients
with acromegaly. Additionally, these investigators commented on the benefits of discontinuing pituitary
suppressive medications at least 1 month prior to radiation therapy, because it significantly improved
endocrine outcome. Mauermann et al. reported no change or a reduction in tumor size in 20 of 22
patients following treatment for adrenocorticotropic hormone-producing adenomas in patients with
adrenalectomies; there were variable adrenocorticotropic hormone results. Sheehan et al. reported
that GKS was effective in patients with Cushing disease following failed transsphenoidal surgery.
As noted earlier, one of the first applications of the proton beam was for the treatment of pituitary
adenomas, an application that was feasible in the era before CT because of the location of these tumors.
In 1991, Levy et al. reported on 840 patients who were treated at the Lawrence Livermore
Laboratory using heavy-charged-particle radiosurgery of the pituitary gland. Indications for treatment
included pituitary tumors and pituitary suppression. The first 30 patients were treated with proton-beam
irradiation, and the remaining patients were treated with helium-ion irradiation. Complications included
temporal lobe necrosis, transient visual problems, and pituitary dysfunction. These investigators
concluded that the Bragg peak radiation therapy was an effective means of suppressing pituitary function
or controlling tumor growth while preserving a rim of functional pituitary gland.
Ronson and colleagues from the Loma Linda University Proton Center described 47 patients with
pituitary adenomas treated with fractionated proton SRT. Forty-two patients underwent prior surgical
resection, and 5 were treated with primary irradiation. Approximately half the tumors were functional.
The median radiation dose was 54 CGE. Tumor stabilization occurred in all 41 patients available for
follow-up imaging; 10 patients had no residual tumor, and 3 had a > 50% reduction in tumor size.
Seventeen patients with functional adenomas had normalized or decreased hormone levels, and tumor
progression occurred in 3 patients. Six patients died, and 2 of these deaths were attributed to functional
tumor progression. Complications included temporal lobe necrosis in 1 patient, new significant visual
deficits in 3 patients, and incident hypopituitarism in 11 patients. The authors concluded that
fractionated conformal proton-beam irradiation achieved effective radiological, endocrinological, and
symptomatic control, and significant morbidity was uncommon, with the exception of postirradiation
hypopituitarism, which they attributed in part to concomitant risk factors for hypopituitarism present in
their patient population.
Although excision remains the overall definitive treatment of benign intracranial tumors because it
enables rapid reduction in the intracranial mass effect and establishes a precise histological diagnosis,
recent advances in a range of focused-beam radiation modalities as well as improved radiographic
imaging capabilities have permitted alternative treatment strategies to emerge. It is now possible, based
on imaging characteristics, to treat specific benign tumors definitively using fractionated radiation
therapy, SRT, or SRS. The availability of highly conformal modalities makes fractionated SRT or
fractionated radiation therapy increasingly attractive as a treatment modality that combines the high-
dose conformation associated with SRS with the traditional benefits of dose fractionation. Candidates for
SRS or SRT would typically be those patients with smaller tumors and imaging characteristics of a
benign tumor. There is also the ability to use SRS or SRT to treat small tumor residua following surgery
that are purposefully left attached to critical structures by the surgeon to preserve critical neurological
CGE = cobalt gray equivalent; CN = cranial nerve; CRT = conformal radiation therapy; CT = computed
tomography; GKS = Gamma Knife surgery; IMRT = intensity-modulated radiotherapy; LINAC = linear
accelerator; MR = magnetic resonance; SRS = stereotactic radiosurgery; SRT = stereotactic
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A new version of topic of the month publication is uploaded in my web site every month (it remains for a
month and is changed with the monthly update of the neurology bulletin
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The author: Professor Yasser Metwally, professor of neurology, Ain Shams university, Cairo, Egypt