For decades, the successful care of a patient with a vestibular schwannoma (acoustic neuroma), has been gratifying to the neurosurgeon. Decades ago, Kenneth McKenzie, Canada’s first neurosurgeon, chose to have himself painted, with arm outstretched, pointing to an acoustic neuroma specimen within a glass jar, successfully removed. Such an accomplishment was considered one of the true achievements in neurosurgery.

Over the next decades, technical advances led to improved clinical outcomes. By the 1970’s, use of the operating microscope significantly assisted safe tumor resection. Neurophysiological monitoring, improved anesthetic care, and new instrumentation, improved outcomes further. The goal of saving the life of the patient was changed to the avoidance of hemiplegia, and later the avoidance of facial weakness. In the 1990’s, a new era of hearing preservation began.

Over that time, others were working to develop radical new concepts for tumor management. In 1971, Lars Leksell described the indications and technique of acoustic tumor radiosurgery, first performed in a patient two years prior (1). Since the initial radiosurgical concept (1951), many basic studies were performed to determine the effects of different radiosurgery doses in normal brain, particularly as they applied to functional radiosurgery. The management of selected patients with pituitary tumors and pineal region tumors, lesions that could be identified using plain x-rays or studies such as cisternography or ventriculography, ushered in a new era. Leksell was challenged by disorders that were associated with high rates of management morbidity, and surgery for an acoustic neuroma certainly met that criteria. Despite improvements in resection, hearing loss was the norm, facial weakness was common and hemiparesis, significant ataxia and death still occurred. In a large resection series reported by Olivecrona in 1967, the overall mortality was 22%, but in the smaller tumors, only 9%. Facial nerve function was preserved in only 21% of patients (2). In 1957, Pool stated that acoustic neuroma resection was, “not only one of the most exacting and laborious, but also one of the most dangerous and unpredictable operations in the entire neurosurgical repertoire”. In a 1969 series reported by House 200 patients underwent surgery; there were 56 partial removals and a mortality rate of 7%. Leksell believed that stereotactic radiosurgery offered a new approach to this problem. Using his first generation gamma unit with 179 cobalt-60 radiation beams, the tumor was targeted with air or contrast encephalography. He stated that doses of 5-7 krad were administered to the center of the tumors in the first three patients.

Later, Noren et al reported a comprehensive evaluation of the initial Swedish patient series (3). He and his colleagues described 14 patients who were managed over a six month period in 1975, who had at least four years follow up. Two of these patients had prior partial resections. Radiosurgical planning was aided by pre-operative CT scanning, metrizamide cisternography and in some cases, pneumoencephalography. These patients received a radiosurgical dose at the tumor margin that varied between 7 and 45 Gy. Such high doses may have followed work from an early laboratory study that evaluated human vestibular schwannoma cells in culture irradiated with 30 – 150 Gy (4). On imaging after radiosurgery, 8 tumors decreased in size, 2 were unchanged and 3 had increased. Later, questions were raised regarding the accuracy of early radiosurgery targeting with such crude imaging and calculations performed without computer assistance.

The modern era of acoustic tumor radiosurgery was ushered in at the University of Pittsburgh under Dr. L. Dade Lunsford. As the fifth center in the world to use the Gamma Knife, and the first in the United States to install a 201 source unit, radiosurgery was performed using higher resolution imaging techniques. Lunsford began a commitment to rigid outcomes evaluations, publication and presentation of results, and education. An early evaluation of results (5,6) were reported. Lunsford was also the first to report the economic benefits of radiosurgery, noting an average 65% reduction in hospital charges compared to the cost of microsurgical removal. Within two years, both Linskey et al (n=26 patients) and Kondziolka et al (n=85 patients) reported the expanding Pittsburgh experience (7,8). In the latter paper, Kondziolka noted a 3% development of new trigeminal deficits and a 20% onset of facial weakness, although these usually were mild and transient (7). In that report, 11 patients had excellent pre-radiosurgery hearing and at follow up six were unchanged. This report was the first to emphasize the role of radiosurgery as primary management to achieve preservation of cranial nerve function. Prior to that time, radiosurgery had been seen as a therapeutic tool to reduce overall treatment risks particularly for elderly patients, those with concomitant medical problems, or those that had already failed surgery. The concept that radiosurgery could be used in younger patients in order to provide effective treatment with lower risks than those associated with resection was novel. Reports on acoustic neuroma radiosurgery then spread outside the neurosurgical or otolaryngology literature. Flickinger et al published a comprehensive review of the Pittsburgh experience in Cancer (9). Noren continued his detailed review of the Stockholm experience with a report on 254 patients managed from 1969 through 1991 with a minimum follow up of 12 months (10).

Evolution of Radiosurgery Techniques

Prior reports in this monograph have focused on the evolution of radiosurgical techniques. These changes included improvements in stereotactic imaging, dose planning, and refinements in dose prescription. Tumor imaging (beginning with pneumoencephalography and angiography, and even early-generation computed tomography [CT]), was inadequate for fully defining the tumor by today’s standards. The intracanalicular portion of the tumor was usually not covered in the plan. The early radiosurgery dose plans were not created with the assistance of computers, and the calculation of the integral dose with multiple isocenters was likely an estimate.

By 1992, high resolution-stereotactic MR imaging was used for targeting by many Gamma knife centers (11,12,13). Because treatment-planning programs were faster and fully integrated with imaging, elaborate, highly conformal, multi-isocenter treatment plans could be developed in minutes. Surgeons began using 6-13 isocenters in more than half the patients to achieve high conformality (14). The stereotactic use of multiple isocenters to achieve conformality represents the most precise and ultimate form of intensity-modulated irradiation. By 1994, some linac centers were adopting multiple isocenter techniques, switching to multiple static conformal fields to improve conformality, or switching to fractionated techniques with lower radiation doses (15). Later years saw the introduction of inverse treatment planning wherein the computer itself was programmed to indentify a treatment volume based on three dimensional tracing of the tumor volume. Such a method may not be intuitive for the physician, and has not been shown to improve results.

Prescription doses for radiosurgery declined until the early 1990’s. Initially minimum tumor doses of 16-20 Gy were prescribed at Pittsburgh according to tumor volume. Prescription doses were lowered slowly, because of the fear of compromising long-term tumor control for lower morbidity. So far that has not occurred. Since 1992 the most commonly used prescription doses (marginal doses) today are in the range of 12-13 Gy, with no known compromise in tumor control seen so far in prospective analysis (16,17,18,19,20). How much further radiosurgery doses for vestibular schwannoma may be safely lowered is unclear (21,22). Fractionated stereotactic radiotherapy has been used with doses as low as 20 Gy in five fractions. The single-session equivalent for a dose of 20 Gy in five fractions predicted by the linear quadratic formula with alpha/beta ratios of 0, 2.5, or 5 would be 8.9, 9.2, or 11.1 Gy respectively. Arguing against using doses this low, is the observation by Foote of a trend (p=0.207) for poorer tumor control with radiosurgery doses less than 10 Gy in the University of Florida series (23). Results for modern Gamma knife radiosurgery techniques are found in recently published series from Pittsburgh, Baltimore, Marseille, and Osaka (18,21,22,24,25,26).

Current Management Options
Patients with acoustic neuromas have several management options including observation, surgical resection, stereotactic radiosurgery, and fractionated radiation therapy (27). Many patients choose between radiosurgery and resection based on their own specific goals and their understanding of possible results. The expected results after modern microsurgical resection are well reported (28,29,30,31,32,33,34). The decision can be difficult for some patients and easier for others, depending on the sources of information given to the patient (35). These include discussions with surgeons and other physicians, written material from peer-reviewed medical journals, handouts from support groups, internet based reports (of variable reliability), and discussions between patients. A decision analysis study concluded that radiosurgery would be a more desirable choice for most patients (36). We believe that information provided from the peer-reviewed medical literature is the most reliable for patient education. Nevertheless, some patients become confused by what they perceive as conflicting opinions amongst physicians.

We do not favor observation for younger patients with acoustic neuromas. Yamamoto et al followed twelve patients who chose observation. A significant increase in tumor volume was found in seven patients during a mean observation period of 19 months (37). Most schwannomas will show demonstrative tumor growth within five years of follow-up, although the growth rate during this period may be variable. On the other hand, we commonly see patients who have been followed with serial imaging, in an attempt to delay the use of a specific procedure for as long as possible. Unfortunately, many demonstrate a significant decline in hearing function during this time, and therefore lose the opportunity for hearing preservation.

Resection is indicated for patients with larger tumors which have caused major neurological deficits from brain compression. In the future, as is the case now, the surgeon together with the patient will discuss the options of attempted complete tumor removal or planned subtotal removal followed by radiosurgery. The patient may specifically request that tumor be left along the facial or cochlear nerves, rather than attempting a dissection in that area. Since it is clear that the consistency and vascularity of tumors in different patients can vary widely, intraoperative decision making is important to obtain the best functional outcome. For tumors that seem more adherent to cranial nerves or more vascular, a decision to perform a partial removal may be wise.

Surgeons perform stereotactic radiosurgery for small or medium-sized tumors with the goals of preserved neurological function and prevention of tumor growth. The long-term outcomes of radiosurgery, particularly with gamma knife technique, have proven its role in the primary or adjuvant management of this tumor. Fractionated radiation therapy has been suggested by some as an alternative for selected patients with larger tumors for whom microsurgery may not be feasible, or for some patients in an attempt to preserve cranial nerve function. At present, the available published data does not support the conclusion that fractionated radiation therapy provides any advantage (38). In some reports, the results have been poorer, but this may reflect selection of patients with larger tumors. The results will vary depending on tumor size, radiation dose, conformality, and the unknown factors of nerve related ischemia or individual tumor differences. Patients who receive low biologic doses of irradiation may have low rates of early side effects, but should be expected to have higher rates of later tumor growth, and concomitant neuropathy. Some centers also offer radiosurgery, but most do not.

Patients with neurofibromatosis type 2 pose specific challenges, particularly in regard to preservation of hearing and other cranial nerve function (39). The primary clinical issues for all patients include avoiding tumor-related or treatment-related mortality, prevention of further tumor-related neurologic disability, minimizing treatment risks such as spinal fluid leakage, infections, or cardiopulmonary complications, maintaining regional cranial nerve function (facial, trigeminal, cochlear, and glossopharyngeal/vagal), avoiding hydrocephalus, maintaining quality of life and employment, and reducing cost. All choices should strive to meet all of these goals. Several reports and surveys evaluated patient outcomes, particularly in regard to quality of life (40,41,42). Our single-center analysis of outcomes following radiosurgery or resection showed either equal or better results with gamma knife radiosurgery (43).

Issues in Decision Making
When we evaluate patients with acoustic tumors, many ask the following two questions. First, is the tumor more difficult to resect if radiosurgery fails? The answer to this is not clear (44,45). Few patients have required resection, and the opinions of the surgeons we have asked indicated that some tumors were less difficult, some about the same, and some more difficult. A tumor may be less difficult if it has lost much of its blood supply. In a report on this issue that included thirteen patients who had resection after radiosurgery, eight were thought to be more difficult. However, five of these eight patients had failed resection before they had radiosurgery (45). Second, patients inquire about the risk of delayed malignant transformation. Malignant schwannomas are rare, but have been reported de novo, after prior resection (46,47), and after irradiation. We answer that this is always a risk after irradiation, but that the risk should be very low (48). We have not seen this yet in any of our 7,500 patients during our first 18 years experience with radiosurgery, but quote the patient an estimated risk of 1:1000, significantly less than the risks for developing cancer on their own or for the risk of death after resective surgery. One report from Japan found a malignant tumor four years after resection, and six months following radiosurgery. The time interval after irradiation was too short to be causative (46). A second report noted the development of a temporal lobe glioblastoma 7.5 years after radiosurgery for a nearby acoustic neuroma. The temporal lobe had received a low radiation dose (47). In contrast, we have a patient who had initial resection and irradiation of a frontal lobe astrocytoma, and years later this patient developed an acoustic neuroma. Is there a relationship? Were these tumors related in some oncogenetic way, or were they radiation related?

Is there a specific role for fractionated radiation? Optimally, appropriate doses of radiation should be delivered precisely to the tumor and the regional brain structures should be spared of radiation. This is not usually the case with fractionated techniques where larger volumes of regional tissue are irradiated (49-56). We believe that any advantage in fractionation in limiting toxicity only makes sense if the target volume contains normal brain or nerve. Sophisticated stereotactic radiosurgical instruments allow regional brain or nerve to be spared through frame-based, single-session, image guidance. Some centers have used a more extensive fractionation regimen over weeks (38), whereas others have used limited fraction numbers over a few days (57). At present, the available data does not show that fractionation provides any useful advantage over radiosurgical techniques that have been in use for the last 14 years. In order to confirm a significant difference, a prospective trial likely would require hundreds of patients in each arm to detect a difference.

Future Concepts
It is clear that more and more patients are choosing radiosurgery for their acoustic neuroma, (58). The technology is becoming increasingly available and patients in many countries are demanding it. It is reasonable to believe that as more outcomes studies are published, fewer patients will choose to undergo surgical resection. There are now four matched cohort studies (non-randomized) that compare Gamma knife radiosurgery to resection (24,43,25). Consistent across all four studies is that clinical outcomes are better or equal after radiosurgery.

In the future, clinical results following radiosurgery could be improved in several ways. First, studies that define the lower dose limit may enable us to better meet the goal of tumor growth arrest with functional preservation. Although there is now much data for the tumor margin dose of 12 Gy, future studies might evaluate the 10-11 Gy range. Second, pharmacological radioprotection during irradiation has been evaluated in normal brain and experimental tumor models, but has not reached the clinical setting. Agents such as the 21-aminosteroid family of drugs work through membrane stabilization and free radical scavenging effects, particularly in endothelial cells (59, 60). The drug tirilizad has been tested in subarachnoid hemorrhage and spinal cord injury and is free of significant side effects. It should be tested in tumor radiosurgery.

Third, can we halt an adverse radiation effect once it occurs? We should test new anti-inflammatory agents such as the cyclooxygenase-2 inhibitors to see if they are as effective in the brain as they are with joint inflammation. Animal models may be useful to test effects (61). Fourth, we should work to develop new management strategies for patients with large tumors that include planned tumor resection followed by radiosurgery for the residual mass. This would hopefully lead to improved neurologic outcomes in patients with the most difficult tumors. Fifth, we should perform studies that evaluate the effects of radiation on adjacent anatomic structures such as the cochlea (62).

As the number of patients who choose radiosurgery or radiotherapy increases, there will be occasional patients with tumors that continue to grow despite irradiation. In some the enlargement may be minimal and transient, likely related to radiation effects on the tumor and the replacement of tumor with granulation tissue. In a recent report by Pollock et al, such transient enlargements were quantified and recommendations made for continued observation in most patients (63). Some patients will exhibit a small expansion of the tumor volume, and then no further change. These patients do not require additional procedures, but do require continued observation. In others with continued tumor growth, the possibility of a second radiosurgery may be raised. Although there is little available data after a second radiosurgery, we have used this approach in a few patients with good early results (up to four years at present). Stereotactic radiosurgery has transformed the management of patients with acoustic neuromas with proven and consistent longer term results (64,65). New biological approaches for schwannomas that target molecular or genetic tumor substrates will represent the next revolution.

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