Authored by Mitchell K Schwaber, MD, Consulting Staff, Department of Otolaryngology, Nashville Ear, Nose and Throat Clinic
Mitchell K Schwaber, MD, is a member of the following medical societies: Alpha Omega Alpha,
American Academy of Otolaryngology-Head and Neck Surgery,
American Auditory Society,
American Laryngological Rhinological and Otological Society,
American Medical Association,
Association for Research in Otolaryngology, and
North American Skull Base Society
Edited by Robert A Battista, MD, FACS, Instructor, Department of Otolaryngology, Northwestern University Medical School; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine;
Karen Hall Calhoun, MD, Vice-Chair, Professor, Department of Otolaryngology-Head and Neck Surgery, University of Texas Medical Branch at Galveston;
Christopher L Slack, MD, Consulting Staff, Department of Otolaryngology-Head and Neck Surgery, David Grant Medical Center;
and Arlen D Meyers, MD, MBA, Professor, Department of Otolaryngology-Head and Neck Surgery, University of Colorado Hospital
eMedicine Journal, November 26 2001, Volume 2,
Number 11
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INTRODUCTION
| Section 2 of 10    |
Over the last decade, the efficacy and utilization of stereotactic radiation has increased dramatically because of improvements in medical imaging, computer technology, and advanced delivery devices. As a result, stereotactic radiation has become a viable and useful primary management alternative for patients with cerebellopontine angle/skull base tumors, including acoustic neuromas, meningiomas, and paragangliomas. In addition, stereotactic radiation is increasingly used for secondary management of recurrent or planned residual disease, ie, in cases where tumor is specifically left on cranial nerves to avoid loss of function. It is imperative that contemporary neurotology/neurosurgical teams have an understanding of this tool and utilize this information for the benefit of patients. This chapter is intended to be a concise resource for the neurotologist, with a basic introduction to the technology available, the applications in the management of acoustic neuromas (including the role of the neurotologist intreatment planning), and the controversies in the use of radiation for the management of these tumors.
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RADIATION THERAPY
| Section 3 of 10 |
Traditional external beam radiation therapy (EBRT) is in most cases generated by either a photon unit or a cobalt 60 unit. The radiation beam is then delivered through a collimator, which shapes the beam. In traditional EBRT, the field or treatment area is defined by the size and shape of the collimator, and usually 2 or 3 portals or fields are used to direct the radiation beam to the tumor and the surrounding tissue. Some variation in beam intensity, location, angle, and shielding can be used to protect surrounding tissue, but in general, the entire field receives the treatment dose. Because normal tissues are typically more resistant to the effects of radiation, tumor cells are killed while the surrounding tissue eventually recovers.
While traditional EBRT is useful for certain tumors, results using traditional EBRT in the past were often complicated by adverse effects associated with treatment, particularly loss of function of adjacent normal tissues. Furthermore some tumors were said to be resistant to radiation, often because of dose limitations of the surrounding or adjacent tissues. As a side note, meningiomas and acoustic neuromas were not treated with traditional radiation therapy because they were thought to be radiation resistant and because of their proximity and contact with the brainstem.
Stereotactic radiation is the term used to define the method of delivery of a precise dose of high-energy radiation through stereotactically directed narrow beams. Dr Lars Leksell formulated the term stereotactic radiosurgery for this method, and in the literature, stereotactic radiosurgery is the term used for single-dose stereotactic radiation treatment. Today, through the use of sophisticated imaging devices and 3-dimensional treatment planning computers, stereotactic radiation allows much more specific targeting of a lesion, with significantly less radiation delivered to surrounding normal tissues. Stereotactic radiation allows dynamic beam shaping as well as intensity modulation, providing flexibility and optimal tumor dosing. Furthermore, specialized collimators and treatment plans have been developed for a variety of unusual and rare tumors. As a consequence, much higher doses can be delivered accurately to the tumor, resulting in greater control and cure rates as well as decreased complications.
In the past, stereotactic radiation could only be delivered in a single dose. The first step in the single-dose procedure is to attach the patient’s head to a fixation head ring or stereotactic head frame, which establishes a reference frame with a coordinate system for target determination, as well as a means of precise patient positioning. Next, a series of images are taken with the head ring in place; typically used are CT scan, MRI, single-photon emission computed tomography (SPECT), or positron emission tomography (PET) scans. The images are transferred with the underlying coordinate system to the computer workstation. Each scan has specific reference coordinates attached to it. The physician, working on the virtual tumor on the computer, then prescribes an individual treatment plan by carefully outlining the lesion(s) to be treated, using the computer mouse in a “paintbrush” fashion. The neurotologist’s role here is to analyze the cross-sectional anatomy of the scans, to determine the tumor area
to be treated, and to note the vital or significant structures nearby that should be avoided. This might include avoidance of the facial nerve in the lateral portion of the internal auditory canal or the brainstem, for example. The workstation then processes the treatment plan, including the isocenters and the optimal dose to the lesion.
One recent technological advance in stereotactic radiation is the development of 3-dimensional images of the tumor and surrounding tissues. Sophisticated software and workstations take 3-mm cuts from either CT or MRI scans and converts them into 3-dimensional images. Three-dimensional treatment planning delivers a high-precision dose to the tumor with normal tissue sparing and is better than that achieved with 2-dimensional planning. Notably, continued evolution in this technology will directly translate to improvements in accuracy and predictability of 3-dimensional stereotactic radiation.
Irradiation is delivered to the patient only after final verification methods have ensured the accuracy of the beam angle and dose. Final verification is performed with a target positioner, and a trial run is performed on the positioner prior to treating the patient. Several types of target positioners are available, including simple stereotactic hardware with radiographic film, laser-guided systems, and newer electronic detector systems. A collimator is then selected and attached to the radiation unit. In some cases, conformal blocks are placed inside the collimator to further shape the beam. Recently, disease-specific collimators and software programs have been developed and are available for purchase by treatment facilities. Finally, the patient is placed in the radiation unit, the head frame (and the patient’s head) is secured into position, and necessary monitors are applied. The planned radiation treatment is then administered.
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SINGLE DOSE VS FRACTIONATED TREATMENTS
| Section 4 of 10 |
Today, because of noninvasive fixation devices, it is no longer mandatory that stereotactic radiation be delivered in a single treatment. Because the treatment plan can now be reliably duplicated day-to-day, multiple fractionated doses or fractionated stereotactic radiation can be delivered. For acoustic neuromas, 5-30 fractionated treatments typically are given. The main advantage of fractionation is that it allows higher doses to be delivered to the tumor because of increased tolerance of the surrounding normal tissues to these smaller fractionated doses. In other words, while single-dose stereotactic radiation takes advantage of differences in the pattern of radiation given, fractionated stereotactic radiation takes advantage of not only the pattern, but more importantly of the differing radiosensitivities of normal and surrounding tissues. Another advantage is so-called ”iterative” treatment, meaning the shape and intensity of the treatment plan can be modified during the course of therapy.
Radiation therapy planning currently takes 2 forms, beam first or dose first. Beam-first therapy means that the target volume of radiation is determined first, then the surrounding tissue volume is planned. Also known as forward planning, this works extremely well in cases where the tumor has a regular or spherical shape. Alternatively, dose-first or inverse planning determines the safe dose for the surrounding normal tissues first, and then the computer workstation determines the required beam intensity and shape for each portion of the field. Inverse planning works very well for irregularly shaped lesions and allows for modulating the intensity of treatment to the lesion. This method is often referred to as the Peacock plan or Peacock tomotherapy. Beam-first (2-dimensional and 3-dimensional planning) and dose-first (inverse planning) radiotherapy have become standard at both academic and community centers.
A number of alternatives in noninvasive fixation devices are available, including frameless technology and masks/head immobilizers. Frameless technology utilizes implanted 2-mm gold fiducial markers, which are readily inserted about the head to provide a coordinate system. Image detectors utilize these markers as well as the patient’s bony skeleton as a reference frame for localization. The computer updates the treatment plan based on this reference. Newer systems have on-line continuous updating of the patient’s position during the treatment itself. Mask systems use a meshed thermotransformable material to create an individual mask molded for each patient. The patient’s head is placed in a horseshoe-shaped frame, and the forehead and maxilla are secured first with snug plastic strips. The nasal bridge is then firmly secured using the mask. The mask system gives reproducible positioning with less than 1 mm variation between sessions for a cooperative patient and less than 2 mm for a noncooperative
patient. Head immobilizers use vacuum-attached markers to secure the upper jaw and the occiput into a stable position.
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LINEAR ACCELERATOR VERSUS GAMMA KNIFE
| Section 5 of 10 |
Three methods are used to deliver stereotactic radiation, including high-energy photon irradiation produced by linear accelerators, gamma irradiation from a fixed-array cobalt 60 source, and heavy charged particles including protons. All 3 systems are based on the procedures described above, ie, stereotactic reference and positioning devices, imaging, 3-dimensional target and treatment planning computers, and finally, delivery of the radiation with specialized collimators. With respect to the different types of irradiation energy, each has similar, predictable effects on tumors. Proton beams provide the best control of the depth of penetration as compared with photon or gamma irradiation. Linear accelerator (LINAC) systems are by far the most frequently used (67% of patients), as most radiation oncology departments either have modified existing equipment or purchased less expensive, dedicated units. Gamma knife units, which are considerably more expensive, represent the majority of the remainder.
LINAC systems achieve radiation targeting and rapid dose fall-off by rotating the patient and the treatment unit gantry simultaneously. Specialized dynamic collimators and beam intensity modulation enable literally hundreds of sources to be aimed at the tumor through a series of noncoplanar arcs. On the other hand, Gamma knife units have 201 fixed cobalt 60 sources aimed precisely at the center of the unit; collimators are placed near the treatment unit as well as in a collimator helmet surrounding the patient’s head. Gamma units are thought to have a superior mechanical precision over LINAC units, but to date, this has not been shown to offer a clinically meaningful advantage.
While no radiation unit is entirely comfortable, Gamma units are inherently less so because of the unusual angle of the head position during treatment. Recently, Gamma knife units have been adapted for fractionated multi-dose treatments. One downside to fractionated stereotactic radiation using either a LINAC system or Gamma knife is that multiple patient visits are required, although this provides the significant advantage of higher dosing to the tumor itself.
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TUMOR BIOLOGY
| Section 6 of 10 |
Certain terminology is used in the radiation oncology literature to denote specific target volumes for treatment. Gross tumor volume (GTV) is the term used for all known disease visible on CT scan or MRI, including adjacent nodes. Clinical tumor volume (CTV) is the term for GTV plus the surrounding tissue that presumably harbors microscopic disease. Planning target volume (PTV) provides a margin around CTV to allow for movement and treatment setup variation. Most radiation therapists include a small additional margin around PTV to allow for machine beam characteristics. The goals of stereotactic radiation are to achieve the highest probability of local tumor control with the lowest achievable incidence of adverse effects and to prolong the life of the patient with the best quality of life and as few as possible anatomic and physiologic defects.
Following stereotactic radiation of an acoustic neuroma, little change is detected over the first 6 months. By 12 months, follow-up MRI scans show the loss of central enhancement of the tumor, which usually indicates a favorable response. During the initial 12 months, the tumor may exhibit initial swelling or edema, but over time, this process declines. These patients usually are treated with supportive measures, including steroid administration or ventriculoperitoneal shunting if indicated. By 2 years after radiation, partial involution of the tumor is often noted. Stereotactic radiation can completely eradicate tumor, but in most cases, residual enhancing tumor is noted on MRI scan. This residual tumor usually remains stable for long periods of time, and this is often reported as "local control" in the radiation oncology literature.
Acoustic neuroma growth is controlled by 2 main mechanisms: direct cellular injury and vascular fibrosis. In the higher-dose central region, tumor histopathology has revealed necrosis, decreased tumor cell population, and fibrosis. In the lower-dose peripheral region, vascular occlusion, macrophage infiltration, fibrin deposits, and thrombus formation have been identified. In general, apoptosis is the mechanism of cellular death and tumor control.
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RESULTS AND COMPLICATIONS OF SINGLE-DOSE THERAPY
| Section 7 of 10 |
Reports by Perez indicate a close relationship between the dose of radiation given and the probability of tumor control. The effects of radiation on most normal tissues have been well documented, including the interrelationship of total dose, fractions used, volume and function of the organ irradiated, and mechanisms of cellular repair. While a number of studies have reported the radiation tolerance of normal tissues, the data preceded 3-dimensional planning and fractionated treatments and thus must be viewed cautiously. It is reasonable to assume that accurate stereotactic radiation will lead to a higher probability of tumor control, but imprecise systems could lead to problems with necrosis of surrounding tissues.
Kondziolka, Lunsford, et al reported their results in the management of 162 consecutive patients with acoustic neuroma treated from 1987 to 1992, using single fraction gamma knife radiation. Patients were evaluated using serial imaging tests, clinical evaluations, and a survey between 5-10 years after the procedure. The average dose of radiation to the tumor margin was 16 gray (Gy), and the mean transverse diameter of the tumor was 22 mm (range 8-39). Resection had been performed previously in 42 patients (26%); in 13 patients, the tumor represented a recurrence of disease after a previous total resection. The rate of tumor control (with no resection required) was 98%. One hundred tumors (62%) became smaller, 53 (33%) remained unchanged in size, and 9 (6%) became slightly larger. Resection was performed in 4 patients (2%) within 4 years after radiation. These authors report hearing loss in 49% of patients, facial palsy in 21%, and trigeminal nerve problems in 27%. Of patients working at the time of
treatment, 31% were no longer working after treatment. No new neurologic deficits occurred later than 28 months after treatment. Stereotactic radiation was believed to have been successful by 95% of patients in whom this was the primary treatment. Thirty-six of the 115 patients (31%) described at least one complication, which resolved in 56% of those cases.
Some of the criticisms of the report by Kondziolka, Lunsford, et al include the following: failure to analyze age as a variable, a lack of detail regarding tumor size and preoperative growth rates, inclusion of previously operated tumors in the study group, which under-reports the incidence of facial palsy and hearing loss because they were pre-existing, actual evaluation of just 38 patients at 7-8 years after treatment, failure to use a validated instrument to determine health status, use of a change of 2 mm in size as a measure of outcome, and failure to mention the risk of cancer after treatment. Many of these criticisms have been addressed in the literature.
Noren reported 254 patients (193 of whom had a unilateral tumor) who underwent single-treatment gamma radiation at Karolinska Institute. In the unilateral cases, 55% of tumors shrank, 33% were unchanged, and 12% continued to enlarge at least temporarily. Those that enlarged did so over 6-18 months post-treatment and then either shrank or stabilized. This study indicates a control rate of 94% at 1 year. Noren reported a 15% incidence of facial palsy and a 33% incidence of hearing preservation.
Miller et al have reported their findings in a prospective study of 82 acoustic neuroma patients, the first 42 treated in a high-dose single-treatment protocol, the next 40 treated with a reduced-dose protocol. They found that a tumor margin dose 18 Gy or greater is the most significant risk for facial and trigeminal nerve complications. Tumor margin doses 16 Gy or less pose a significantly lower risk for permanent facial palsy. Interestingly, 2 of the patients undergoing a higher-dose protocol continued to progress and required microsurgical decompression. Flickinger et al reported similar findings, in that tumors treated with less than 14 Gy had 0% incidence of facial palsy, and those treated with 16-20 Gy had an incidence of 53%. Many had permanent palsies at House-Brackmann grade 5 or 6.
As noted in these prior reports, unchanged tumor size was considered evidence of tumor control. Pitts and Jackler and Yamamoto et al have questioned whether this assertion is correct. These authors note that 50-60% of cases demonstrate either no growth or slow growth prior to treatment, and therefore no or slow growth after treatment does not necessarily represent control. The authors have performed salvage microsurgery on 1 patient following single dose stereotactic radiation. In this previously unreported case, a large cyst developed more than 1 year after treatment. This cyst protruded from the wall of the tumor and compressed the brainstem. Histopathology of the tumor showed no specific effect from the radiation. Clearly, longer follow-up is needed to be certain that unchanged size indeed represents long-term control.
With respect to brain, because it has serial architecture, damage to even a small area could have significant repercussions. Werner-Wasik et al found that one third of stereotactic radiation patients had an immediate posttreatment adverse effect, including nausea, headache, and dizziness. Rarely, acute swelling of the tumor occurs, necessitating supportive therapies such as ventriculoperitoneal shunting, steroid administration, and seizure control. Dizziness and vertigo occurred in 4 of 12 acoustic neuroma cases, and this complication did not appear to be related to dose or technique. Flickinger et al reported that the acoustic nerve was the most sensitive cranial nerve to radiation doses between 12 and 16 Gy, while the facial nerve was the least sensitive. Finally, most reports indicate that serviceable hearing is preserved in 60-65% of patients with single-dose protocols.
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RESULTS AND COMPLICATIONS OF FRACTIONATED THERAPY
| Section 8 of 10 |
Fractionated stereotactic radiation for acoustic tumors developed primarily because of the incidence of trigeminal and facial nerve palsies that occurred after treatment with single-dose stereotactic radiation. Lederman et al reported no permanent facial or trigeminal nerve problems in 39 acoustic tumors treated with 20 Gy given in weekly fractions of 4-5 Gy. Among smaller tumors (<3cm), 61% shrank in size, and the remaining 39% showed no growth over 27 months. Among larger tumors (>3cm), 81% shrank in size, and the remainder showed no further growth. Only 1 patient had a transient facial palsy. These authors concluded that fractionated stereotactic radiation offers high control rates while avoiding the morbidity frequently seen after single-dose stereotactic radiation or microsurgery.
Song and Williams reported similar data treating 31 acoustic tumors using a total dose of 25 Gy given in 5 consecutive daily fractions of 5 Gy. The tumor shrank in 29% of cases and was unchanged in 71%. No facial palsies developed, but 2 cases developed trigeminal neuropathy. Balance improved in 3 patients, was unchanged in 20, and was markedly worse in 7 patients. Of the 12 patients with serviceable hearing before treatment, 9 (75%) retained useful hearing after therapy. Of 25 patients with any hearing before treatment, 2 improved, 10 were unchanged, and 13 were worse. While this protocol may provide good control of the acoustic neuroma, it does have a much greater incidence of cranial nerve dysfunction as compared to that of Lederman et al.
Poen et al reported results in 33 patients receiving 21 Gy in 3 fractions over 24 hours. Tumor control was documented over 2 years in 97% of cases. The single case of tumor progression remains asymptomatic not requiring surgery. With this protocol, 16% of patients developed trigeminal neuropathy, and 3% developed mild facial palsy. All patients with serviceable hearing maintained it after therapy.
It can be surmised that fractionated therapy is associated with fewer cranial nerve complications as compared to single-dose treatment. Furthermore, the various reports tend to indicate that the use of multiple smaller-dose fractions over a longer time period perhaps gives the greatest possibility of hearing preservation, avoidance of facial palsy, and tumor control. It should be remembered, however, that use of multiple-dose fractionated radiation therapy results in large areas receiving multiple low doses of radiation, which may carry a long-term risk of carcinogenesis.
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CONCLUSIONS
| Section 9 of 10 |
Comparing stereotactic radiation and microsurgery, studies show substantially less cost for radiation treatment of acoustic tumors smaller than 3 cm in diameter, with comparable results in terms of postoperative outcomes. Fractionated stereotactic radiation is a reasonable method to treat some acoustic neuromas, but patients must be willing to have careful follow-up including MRI scans over a long period of time. The authors always recommend this treatment modality in older patients and in medically infirm patients, such as those on anticoagulants or with other significant illnesses. The authors also recommend this treatment in only hearing ears. In patients with serviceable hearing, fractionated stereotactic radiation is the preferred treatment, particularly in small but enlarging intracanalicular tumors, intracochlear tumors, and in cerebellopontine angle tumors that are 2 cm or smaller in size, ie, those that barely touch the brainstem or smaller. The authors currently use a protocol of 20-24 Gy given
over 28 daily treatments, usually in about 5 weeks and have uniformly preserved hearing and have not demonstrated growth on MRI in the 4 cases treated this way.
The authors do not usually recommend fractionated stereotactic radiation in small tumors with poor hearing, preferring the transtemporal translabyrinthine surgical approach in these cases. Furthermore, brainstem compression by acoustic tumor is not improved by radiation, so that in these cases, surgery is the preferred option. However, the authors do utilize fractionated stereotactic radiation in the management of planned residual or recurrent acoustic neuroma. Pollock, Lunsford, et al have reported that 94% of residual tumors were controlled by single-dose stereotactic radiation. Finally, patients with significant dysequilibrium or recurrent vertigo are not improved at all by fractionated stereotactic radiation to the tumor and in fact may become worse, so this circumstance is a specific contraindication in our opinion. However, patients who are not candidates for fractionated stereotactic radiation should be informed of the availability of the therapy and told why they are not a candidate in the
physician's opinion.
In summary, patients that have serviceable hearing, no vertigo, and an acoustic tumor 2 cm in diameter or smaller are the preferred candidates for this treatment. With these criteria, the authors recommend fractionated stereotactic radiation as primary treatment in about 40% of our cases. If the patient chooses to have fractionated stereotactic radiation, we actively participate in treatment planning with the radiation oncologists, and then carefully follow a posttreatment protocol for clinical examination, repeat imaging, audiovestibular testing, and management. While we do not have any long-term follow-up data with fractionated stereotactic radiation, we have had none of the acute or immediate effects that we experienced with single-dose protocols in 17 patients.
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BIBLIOGRAPHY
| Section 10 of 10  |
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NOTE:
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Medicine is a constantly changing science and not all therapies are clearly established. New research changes drug and treatment therapies daily. The authors, editors, and publisher of this journal have used their best efforts to provide information that is up-to-date and accurate and is generally accepted within medical standards at the time of publication. However, as medical science is constantly changing and human error is always possible, the authors, editors, and publisher or any other party involved with the publication of this article do not warrant the information in this article is accurate or complete, nor are they responsible for omissions or errors in the article or for the results of using this information. The reader should confirm the information in this article from other sources prior to use. In particular, all drug doses, indications, and contraindications should be confirmed in the package insert. FULL DISCLAIMER
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eMedicine Journal, November 26 2001, Volume 2,
Number 11
© Copyright 2002, eMedicine.com, Inc.
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