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CYBERKNIFE RADIOSURGERY FOR BENIGN INTRADURAL EXTRAMEDULLARY SPINAL TUMORS
Robert L. Dodd, M.D., Ph.D.
Department of Neurosurgery, Stanford University School of Medicine, Stanford, California
Mi-Ryeong Ryu, M.D., Ph.D.
Department of Radiation Oncology, Kangnam St. Mary’s Hospital, Seoul, Korea
Pimkhuan Kamnerdsupaphon, M.D.
Division of Therapeutic Radiology and Oncology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
Iris C. Gibbs, M.D.
Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California
Steven D. Chang, Jr., M.D.
Department of Neurosurgery, Stanford University School of Medicine, Stanford, California
OBJECTIVE: Microsurgical resection of benign intradural extramedullary spinal tumors is generally safe and successful, but patients with neurofibromatosis, recurrent tumors, multiple lesions, or medical problems that place them at higher surgical risk may benefit from alternatives to surgery. In this prospective study, we analyzed our preliminary experience with image-guided radiosurgical ablation of selected benign spinal neoplasms. METHODS: Since 1999, CyberKnife (Accuray, Inc., Sunnyvale, CA) radiosurgery was used to manage 51 patients (median age, 46 yr; range, 12–86 yr) with 55 benign spinal tumors (30 schwannomas, nine neurofibromas, 16 meningiomas) at Stanford University Medical Center. Total treatment doses ranged from 1600 to 3000 cGy delivered in consecutive daily sessions (1–5) to tumor volumes that varied from 0.136 to 24.6 cm3. RESULTS: Less than 1 year postradiosurgery, three of the 51 patients in this series (one meningioma, one schwannoma, and one neurofibroma) required surgical resection of their tumor because of persistent or worsening symptoms; only one of these lesions was larger radiographically. However, 28 of the 51 patients now have greater than 24 months clinical and radiographic follow-up. After a mean follow-up of 36 months, all of these later lesions were either stable (61%) or smaller (39%). Two patients died from unrelated causes. Radiation-induced myelopathy appeared 8 months postradiosurgery in one patient. CONCLUSION: Although more patients studied over an even longer follow-up period are needed to determine the long-term efficacy of spinal radiosurgery for benign extra-axial neoplasms, short-term clinical benefits were observed in this prospective analysis. The present study demonstrates that CyberKnife radiosurgical ablation of such tumors is technically feasible and associated with low morbidity.
KEY WORDS: CyberKnife, Image guidance, Meningioma, Neurofibroma, Radiosurgery, Schwannoma, Spinal tumors
Neurosurgery 58:674-685, 2006
John R. Adler, Jr., M.D.
Department of Neurosurgery, Stanford University School of Medicine, Stanford, California Reprint requests: John R. Adler, Jr., M.D., Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA 94305. Email: email@example.com Received, July 20, 2005. Accepted, December 7, 2005.
tereotactic radiosurgery (SRS) has become an important tool for managing a range of benign intracranial and cranial base tumors. Although similar tumor histologies can be found in and around the spine, the first generation of radiosurgical instruments was, by virtue of being frame-based, unable to treat such extracranial targets. The more recent emergence of image-guidance technology now makes it possible to use radiosurgical methods to ablate lesions throughout the body including in the spine (1, 45, 56). There are now several published studies that describe outcome in series of patients treated with spinal radiosurgery, primarily for metastases (9,
10, 14, 41, 45). Although these preliminary studies demonstrate safety and efficacy, follow-up is relatively short because these patients tend to die early from their underlying malignancies. The safety and effectiveness of microsurgical resection of most benign spinal neoplasms is well documented (8, 15, 24, 37, 48, 49). Nevertheless, certain patients are less than ideal candidates for standard surgical resection because of age, medical comorbidities, the recurrent nature of their tumor, or because multiple lesions occur in the setting of one of the familial phakomatoses. It is in such clinical circumstances that radiosurgery could be an attrac-
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tive clinical option. Despite this theoretical attraction, the literature on malignant spinal metastases provides an insufficient basis for judging the possible benefits of radiosurgical ablation of benign spine tumors. Because patients with such lesions have prolonged life expectancies, the potential for delayed and possibly catastrophic radiation myelopathy is a special concern. In addition, benign spine tumors have their own unique presentation, spatial relationship to the spinal cord, and radiobiologic response to radiosurgery, any of which could present unique challenges to the safe and effective application of radiosurgical ablation. Image-guided robotic radiosurgery, the CyberKnife (Accuray, Inc., Sunnyvale, CA), was introduced at Stanford University Medical Center in 1994 (1), and in 1997, the first patient with a benign spinal lesion (a hemangioblastoma) was treated. Since that time, 101 patients with a variety of benign spinal tumors and vascular malformations have undergone radiosurgical ablation at our institution. Among this group were 51 patients with meningioma, neurofibroma, or schwannoma who now have at least 6 months follow-up. In this report, we provide a prospective analysis of this cohort. Our primary objectives were to 1) document the relative safety of this procedure and 2) develop a preliminary understanding of the range of potential treatment doses and outcome measures that are appropriate for patients with benign spine tumors.
TABLE 1. Characteristics of patientsa Age (yr) Mean Range Sex, n (%) Female Male Previously resected (%) Subtotal Gross total NF1 NF2 Previously radiated (%)
46.5 12.6 – 86.5 23 (45) 28 (55) 24 (47) 2 (4) 7 (14) 10 (20) 4 (8)
PATIENTS AND METHODS
Fifty-one patients with 55 benign intradural extramedullary spinal tumors (16 meningiomas, 30 schwannomas, nine neurofibromas) were treated at Stanford University Medical Center from 1999 to 2005 as part of a protocol for spinal tumors approved by our institutional review board. A multidisciplinary team of specialists that included neurosurgeons, radiation oncologists, and neuroradiologists evaluated all patients. Spinal radiosurgery was only offered to patients for whom microsurgical resection was contraindicated because of medical comorbidities, underlying neurofibromatosis (NF) that resulted in multiple lesions developing over time, or, occasionally, strong patient preference. Selected cases also had well-circumscribed lesions, no evidence of overt spinal instability, and generally minimal compromise of spinal cord function (i.e., myelopathy). Several of the NF patients in this series had an aggressive form of this illness that resulted at the time of presentation in significant neurological compromise. All tumors were known or presumed to be spinal meningioma, neurofibroma, or schwannoma on the basis of prior pathological confirmation, characteristic appearance on contrast magnetic resonance imaging (MRI) scans, or history of NF. The general clinical characteristics for the 51 patients in this series are summarized in Tables 1–3. After signing an institutional review board-approved consent form, the image-guided CyberKnife radiosurgical system was used to administer spinal radiosurgery in every case. This instrument has been described previously in detail by Adler et al. (1). The device consists of a 6 MV linear accelerator mounted on a computer-
controlled robotic arm, which is coupled to an x-ray tracking system that monitors and adjusts in near real time on the basis of changes in the target’s position. Image-guidance eliminates the need for skeletal rigid immobilization. The process of CyberKnife spinal radiosurgery begins with an outpatient procedure that inserts small stainless steel markers percutaneously into vertebral segments above and below the radiosurgical target (45). Next, a custom alpha cradle mold is fabricated for the supine patient (Smithers Medical Products, Inc., Akron, OH). This device is used to noninvasively immobilize the spine during computerized tomographic (CT) imaging (used later in treatment planning) and also to restrict patient movement during the radiosurgery itself. For those tumors that enhanced poorly with iodinated contrast or when severe allergy precluded the acquisition of an enhanced CT imaging, a contrast MRI scan of the relevant spine was also acquired and fused to the pretreatment CT scan. Treatment planning begins with the treating neurosurgeon defining the target volume and critical structures within the CT/MRI scans using software tools provided on the CyberKnife workstation (Fig. 1, D–F). On imaging studies, the spinal cord volume was delineated as the primary “critical structure” beginning 1 cm cephalad to and ending 1 cm below the targeted lesion. A proprietary inverse planning computer algorithm uses the above inputs to determine the number, direction, and duration of treatment beamlets so as to optimize dose conformality and minimize irradiation of critical structures (Fig. 1G). Visual inspection and analysis of dose volume histograms for the target region and adjacent critical anatomy are used to of find the best radiosurgical solution. Just before the administration of radiosurgery, a library of digitally reconstructed radiographs (i.e., computer simulated x-rays) are calculated from the perspective of a pair of x-ray sources and cameras used throughout the operation. This array of images encompasses those vertebral elements, along with embedded fiducials, that are in close proximity to the radiosurgical target. During radiosurgery, the patient lies su-
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pine on the operating table in the alpha cradle mold. Sequential paired digital radiographs of the target region are then obtained by ceiling-mounted, orthogonally directed, rigidly fixed x-ray tubes. A computer workstation performs rapid image-to-image correlation between the acquired images and the previously calculated digitally reconstructed radiographs. Before each beamlet of radiation is administered, the x-ray imaging system determines target location and communicates the answer to the robot. The robot adjusts for small patient movements by automatically realigning the treatment beam with submillimeter accuracy (5). Postradiosurgical follow-up, typically performed at 3 months, 6 months, 1 year, and then annually thereafter, included clinical evaluation, physical examination, and radiographic imaging. The formula for an idealized ellipsoid, Vol ϭ 4/3 (length ϫ width ϫ height) was used to estimate tumor volume on contrast MRI scans. Pain was qualitatively assessed by patient report as either improved, stable, or worse and semiquantitatively by recording a patient’s analgesia requirement. This information was placed into a prospectively maintained computer database. The median follow-up after radiosurgery for the entire series was 23 months (mean, 25 mo; range, 6–73 mo). Similarly, the median follow-up for each histological subtype was 25, 23, and 21.5 months in meningioma, schwannoma, and neurofibroma, respectively (mean, 27.2, 26, and 19.9 mo, respectively).
TABLE 2. Characteristics of lesions No. of lesions (%) Level Cervical Thoracic Lumbar Sacral Histology Schwannoma Neurofibroma Meningioma 38 (69) 7 (13) 8 (15) 2 (4) 16 (29) 9 (16) 30 (54)
TABLE 3. Presenting symptoms Local or radicular pain Radicular sensory loss Radicular weakness Myelopathic weakness Axial sensory loss Bladder paresis Asymptomatic 34 (63%) 26 (48%) 22 (41%) 12 (22%) 4 (7%) 3 (6%) 8 (15%)
Fifty-one patients (28 men, 23 women; median age, 46 yr; age range, 12–86 yr) with 55 intradural extramedullary benign spinal tumors were treated with multisession radiosurgery using the CyberKnife radiosurgical system (Table 1). A female predominance was observed among spinal meningiomas, whereas the male to female ratio in schwannomas and neurofibromas was 1.6:1 and 2:1, respectively. Twenty-six (51%) patients had undergone a previous surgical resection and were being treated for residual or recurrent tumor. Four patients developed tumors in radiation fields for other cancers (e.g., Hodgkin’s lymphoma, breast adenocarcinoma). One patient developed a traumatic schwannoma (22, 43, 55) after surgery for removal of a synovial cyst. Seventeen patients carried a diagnosis of either NF Type 1 (NF1) or NF2. Tumors were observed throughout the entire spinal axis (Table 2) and varied in configuration from entirely intraspinal to dumbbell shaped to predominantly foraminal. Presenting symptoms (pain, radiculopathy, and myelopathy) varied depending on spinal location and the precise relationship between the tumor and adjoining nerves/spinal cord (Table 3). Very few patients had significant spinal cord compression and myelopathy before radiosurgery. Furthermore, most patients presenting with myelopathy developed this neurological deficit as a consequence of either previous tumor-related cord compression or spinal surgery. Eight (15%) asymptomatic patients underwent preemptive radiosurgical ablation because of the size, location, or growth of their tumor on serial MRI scans.
Radiosurgical Doses and Fractionation
The specific fractionation schedule (median of two sessions; range, 1–5) was based on the size and volume of the treated tumor as well as the length and total dose administered to the spinal cord. For intracranial meningiomas and nerve sheath tumors, it is widely accepted that an effective single dose can range from 12 to 18 Gy depending on the size of the lesion (6). Because with spinal lesions there is added concern about the dose tolerance of the spinal cord, and because of our previous lack of experience with paraspinal radiosurgery, we incorporated staging in our dose selection for a substantial number of these tumors. The choice of dose and staging schedule was selected to minimize the risk of spinal cord injury. With use of the concepts of the linear quadratic model, the biological equivalent dose (BED) is estimated by the following formula: BED ϭ nd(1 ϩ d/␣/␤). Multisession radiosurgical regimens were devised that achieved a BED of 53 to 180 Gy, depending on the proximity to the spinal cord, history of prior spinal cord irradiation, and total tumor volume. These BED values compare favorably with the single fraction guidelines. (60–126 Gy) for benign brain tumors. In most patients, radiosurgery was delivered in one (37%) or two sessions (42%). However, additional daily sessions were administered in three (eight patients), four (two patients), or five sessions (1 patient). Acute toxicity was rare and limited to short-lived nausea. Table 4 summarizes the radiosurgical dosimetry used in this series. Target volumes ranged from 0.136 to 24.6 cm3 (mean 4.29 cm3; median 2.18 cm3). Treatment plans were designed to
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sponding maximum intratumoral dose ranged from 1950 to 3435 cGy (mean, 2506 cGy). Similar amounts of radiation were delivered to all three tumor histologies because the ␣/␤ was believed comparable for these slow-growing benign lesions. The major limitation to maximizing tumor dose was the desire to limit the risk of injury to the adjacent spinal cord. Somewhat arbitrarily, but drawing from established optic nerve tolerance to radiosurgery, an attempt was made to construct treatment plans that limited the volume of irradiated spinal cord receiving more than a maximum single fraction dose of 1000 cGy to less than 0.2 cm3 (28, 52, 54). When this criterion could not be met, we opted to fractionate the radiosurgery over two to five sessions. In these situations, care was taken to limit the 80% reference dose per fraction to the spinal cord to below 800 cGy. Consistent with this objective, the volume of the spinal cord that received 80% of the prescribed dose was generally less than 0.4 cm3 (0.2 Ϯ 0.06 cm3; mean Ϯ standard error of the mean), and the volume that received 50% of the prescribed dose was generally less than 1.4 cm3 (0.9 Ϯ 0.15 cm3; mean Ϯ standard error of the mean).
Clinical Symptoms at Presentation
After radiosurgery, most clinical symptoms either remained stable or improved. Unfortunately, the small sample size for various symptoms precluded any significant findings, except for pain. Across all tumor histologies, pain (both local and radicular) was the most common presurgical clinical complaint. The treated spinal tumors were painful in 78, 66, and 53% of patients with neurofibromas, schwannomas, and meningioma, respectively. Collectively, 25 to 50% of patients reported significant reduction in pain 12 months after CyberKnife SRS. The next most frequent symptoms in this series were radicular weakness and sensory loss, present in one third and two thirds of patients, respectively. The likelihood of these symptoms was similar across all three tumor histologies. Treated spinal tumors caused radicular weakness in 67, 35, and 34% of patients with neurofibromas, meningiomas, and schwannomas, respectively; similarly, radicular sensory loss was observed in 67%, 53%, 41%, respectively. Trends toward modest improvements in these signs were also observed throughout postradiosurgical follow-up. Twenty-eight of the 55 lesions had greater than 24 months follow-up (one, Ͼ 6 yr; three, Ͼ 5 yr; three, Ͼ 4 yr; three, Ͼ 3
FIGURE 1. MRI scans showing temporal response to radiosurgery is demonstrated in a patient with C7/T1 schwannoma treated with 19 Gy to the marginal dose in two sessions. A, sagittal T1 postcontrast MRI scan before SRS. Comparable images at 12 (B) and 40 months (C) after SRS also shown. Artifact from implanted fiducials is also noted in posttreatment images. Axial (D), sagittal (E), and coronal (F) postcontrast CT images used in treatment planning. Tumor (red lines, with or without solid squares), 83% isodose (solid green lines), and 50% isodose curves (purple lines). Spinal cord (green line with squares) is identified as a critical structure. Three-dimensional reconstruction of actual beam paths used in treatment (G).
deliver 1600 to 3000 cGy to an average 80th percentile isodose line as defined at the margin of the treated tumor; the correTABLE 4. CyberKnife treatment dosimetry characteristicsa Meningioma Average Average Average Average
Neurofibroma 4.31 (0.61–14.5) 1978 (1800 –2100) 1061 (700 –2000) 2646 (2168 –2985)
Schwannoma 5.72 (0.68 –24.6) 1870 (1700 –2200) 1264 (500 –2100) 2399 (1950 –3000)
All 4.53 1960 1208 2507
tumor volume, TV (cm ) prescribed dose, TD (cGy) dose/session, Df (cGy) maximum tumor dose, Dmax (cGy)
2.44 (0.14 –7.57) 2031 (1600 –3000) 1188 (500 –1800) 2631 (1975–3435)
TV, tumor volume; TD, prescribed treatment dose; Df, treatment dose per session; Dmax, maximum dosage.
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yr; and 18 Ͼ 2 yr). The mean follow-up interval in this group was 36 months (median, 29 mo; range, 24–73 mo). All lesions in this group were either stable (61%) or smaller (39%) (Figs. 1 and 2). No tumor in this group increased in size.
Post-SRS Tumor Enlargement and Surgical Resection
Among the entire group of tumors treated in this series, three enlarged on MRI scans by less than 10% at either 6 (two patients) or 12 months (one case) on follow-up imaging. The former two lesions also demonstrated typical loss of central enhancement when contrast was administered and regressed in volume on subsequent MRI scans. Given this temporal course, tumor enlargement was deemed transient and inconsequential. The third tumor (a neurofibroma) was surgically removed (at 13 mo) with the primary goal of decompressing the spinal cord and reversing a pre-existing myelopathy. Analogous to the treatment of benign tumors of the brain, it is worth noting that radiosurgery was not very effective at reversing mass effect produced by intraspinal lesions. Although not enlarged on follow-up MRI scans, two lesions (one meningioma, one schwannoma) were resected (at 10 and 13 mo) because of persistent myelopathy. None of the surgeons reported anything unusual about these resections.
1.7 cm3 of the spinal cord received greater than 800 cGy per fraction. Posttreatment neurological deterioration also occurred in a 38-year-old patient with NF1 and multiple large cervical neurofibromas who underwent CyberKnife SRS to a large C2 neurofibroma secondary to neck and scapula pain. He had minimal response both clinical and radiographically to the treatment at 6 and 12 months. Fifteen months postradiosurgery, this patient suffered a fall that resulted in a complete C5 quadriparesis. The worsening neurological function in this patient was not counted as a complication of SRS. Two patients died from causes unrelated to their tumors. One was an 82-year-old woman who died from respiratory failure complicating a long history of chronic pulmonary obstructive disease, 7 months after radiosurgery for a C1 meningioma. A second patient with severe NF2 died 6 months after treatment of a C5 schwannoma. This 49-year-old woman experienced bilateral vocal cord paralysis and chronic aspiration before radiosurgery, a condition that finally led to her death. Histopathological examination of this patient’s postmortem tumor revealed hyalinized tumor vessels and central necrosis. Similar histology was observed after the removal of a neurofibroma in another patient 13 months after treatment (Fig. 4).
The only direct treatment-related complication occurred in a 29-year-old woman with a CyberKnife treated recurrent C7/T1 spinal meningioma, who developed the new onset of posterior column dysfunction 8 months after radiosurgery (Fig. 3). In this case of presumed radiation myelopathy, the peripheral dose was 2400 cGy, administered in three sessions to a tumor volume of 7.56 cm3, and a maximum dosage of 3435 cGy. The dose volume histogram revealed that approximately
Radiosurgery delivered with image-guided robotics is a minimally invasive method for ablating almost any small volume of pathological tissue that can be visualized on medical imaging studies. Its accuracy, short-term safety, and efficacy have been previously reported for patients with malignant lesions of the spine (1, 5, 10, 36, 45). Because the life expectancy of most of these patients is measured in months and because radiation injury can take years to manifest, the
FIGURE 2. MRI scans showing temporal response to radiosurgery in patient with recurrent T9 schwannoma treated with 22 Gy in three sessions. A, pretreatment sagittal T1 postcontrast MRI scan. B, 6-month
sagittal postcontrast MRI scan illustrating slight change in pattern of enhancement pattern. C, 24- and 73-month (D) sagittal postcontrast MRI scans illustrating size reduction and further loss of central enhancement.
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FIGURE 4. Hematoxylin-eosin stained specimen from a surgically removed C6 neurofibroma 13 months after CyberKnife radiosurgery. Despite 20 Gy delivered in two sessions, this patient experienced persistent pain and worsening myelopathy, necessitating surgical decompression. Hyalinized tumor vessels (A, arrows) and necrosis (B, arrows) are both observed (original magnification, ϫ20).
longer-term efficacy and safety of spinal radiosurgery is yet to be established. A primary objective of the current investigation was to clarify the risk of this procedure for spinal meningiomas, schwannomas, and neurofibromas, tumors that tend to occur in patients with prolonged life expectancies. The close proximity of these lesions to the spinal cord makes this question particularly relevant and was directly linked to our initial deep-seated apprehension about the potential for radiation
FIGURE 3. CT and MRI scans showing treatment plan of a patient with C7/T1 recurrent meningioma treated with 24 Gy to the marginal dose in three sessions A, axial, sagittal, and coronal postcontrast CT images used in treatment planning. Tumor (red lines, with or without solid squares), 71% isodose (solid green lines), and 50% isodose curves (purple lines). Spinal cord identified as a critical structure (green line with squares). Three-dimensional reconstruction of actual beam paths used in the treatment is shown. Pretreatment (B) sagittal and axial T1 postcontrast MRI scans along with posttreatment (C) sagittal and axial T2 images demonstrate location and size of ventral cervicothoracic tumor (B, arrow) as well as intramedullary spinal cord injury (C, arrow) observed 8 months after radiosurgery.
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myelopathy. Despite our concern, only one patient in this series developed delayed radiation-induced injury to the spinal cord. The following discussion will review the pertinent clinical attributes of benign spinal tumors, summarize our treatment rationale, and discuss our experience with both the clinical benefits and radiation toxicity.
spinal radiosurgery is feasible. The larger number of patients and longer follow-up in the present study make it unique.
Spinal meningiomas occur less frequently than intracranial lesions, account for approximately 7.5 to 12.7% of all meningiomas (50), and represent 25 to 46% of tumors of the spine (18). Most meningiomas arise from arachnoid cap cells embedded in dura near the nerve root sleeve and as a result, are predominantly lateral in location and have meningeal attachments (38). When they lie anterior to the spinal cord, particularly in the thoracic area, meningiomas provide a significant surgical challenge. Forty percent of the 16 meningiomas in the present study were anteriorly placed. Presenting symptoms were pain (53%), radicular sensory loss (53%), and radicular weakness (35%). The mean radiosurgical treatment dose across all meningioma in this series was 2031 cGy (range 1600–3000 cGy), which was administered to a mean tumor volume of 2.441 cm3 (range, 0.136–7.569 cm3), using an average of two sessions (range, 1–5). The mean follow-up interval in this cohort was 27.2 months (median, 25 mo). After radiosurgery, the majority of patients reported improvement in pain and strength but were without change in sensory loss. However, in 30% of cases, a minor degree of worsening in pain, numbness, or subjective weakness was described after radiosurgical ablation. Fifteen of the 16 meningioma patients in the current series had radiographic follow-up. The size of the treated lesions was either stable (67%) or decreased (33%) at last follow-up. Importantly, no tumor increased in size. However, the length of follow-up is still far from adequate to establish the durability of radiosurgery in this population. In this regard, the probability of recurrence after surgery or progression may be lower in cases involving meningiomas of the spine than for intracranial sites (23). Among a group of operated spinal meningioma patients followed for 7 years, Cohen-Gadol et al. (7) found a reoperation rate of only 5% in their older cohort but a rate of 22.5% in younger patients, leading them to speculate that the later may be innately more aggressive. Schick et al. (46) reported 8.6% of 81 operated spinal meningiomas recurred on average 5.25 years after surgery. Risk factors for recurrence included subtotal resection, younger age, location anterior to the spinal cord, extradural extension, calcification, en plaque appearance, and NF2. Postoperative mortality ranged between 0 and 3% (37), and morbidity ranged between 0 and 6% (37, 46), consisting mainly of wound infections and cerebrospinal fluid leakage. These studies serve to categorize temporal progression in symptomatic patients, delineate at-risk populations of asymptomatic patients, and suggest the minimum follow-up intervals required to assess tumor control after SRS.
Rationale for using Radiosurgery to Treat Benign Spinal Tumors
The majority of spinal meningiomas, schwannomas, and neurofibromas are noninfiltrative and can be completely and safely resected by experienced surgeons. Because advanced operative techniques provide surgical access to and the means for stabilizing nearly every spinal region (33, 34), even ventral and lateral tumors can now be removed with modest morbidity and mortality (2, 12, 37). When complete tumor removal is achieved, recurrence is unlikely (7, 8, 37, 46). Although surgical resection is the mainstay for managing benign spinal neoplasms, there are also sporadic accounts of radiation therapy being used successfully as a surgical adjuvant in small numbers of patients (15, 44). Since its conception, SRS has played an increasingly important role in the management of patients with intracranial meningioma and schwannoma (4, 30), particularly in cases of difficult to access cranial-based tumors, where the risks to the brainstem and adjacent cranial nerves from standard microsurgical resection are greatest. Kondziolka et al. (26) recently reported that the longterm tumor control rate in 85 benign intracranial tumor patients treated with SRS at the University of Pittsburgh was 93%, with 53% of lesions decreasing in size. Other studies have shown similar or better efficacy of SRS for cranial-based meningiomas, along with low rates of radiation injury (3, 26, 29). Although vestibular schwannoma are histologically distinct, the long-term rate of growth control (95–98% at 10 yr) after radiosurgical ablation is also excellent; up to 73% decrease in size (25, 39). Given their pathological similarities, one would expect benign spinal lesions to respond to radiosurgery much the same as intracranial counterparts. Armed with image-guided radiosurgical technologies, investigators have recently reported preliminary results for treating small numbers of benign neoplasms of the spine with radiosurgery. Ryu et al. (45) published the first description of SRS being used to treat such lesions. Their report of 16 spinal lesions included 2 schwannomas, one meningioma, and a hemangioblastoma. Subsequently, there was a series of 15 benign spinal tumors treated with the CyberKnife, 9 of which were either neurofibroma, schwannoma, or meningioma. Although no tumor progression was reported in either study, the minimum follow-up in both reports was only 6 months, and the mean follow-up period in the latter study was a mere 12 months. In DeSalles et al.’s (9) recent series of 14 patients, there were individual cases of neurofibroma and schwannoma, both of which were stable in size after a mean follow-up of 6 months. The small number of patients and the very short follow-up, for such a group of relatively slow-growing lesions make it impossible to conclude from these studies anything other than that
Schwannomas are the most common spinal tumor, accounting for almost one-third of primary spinal neoplasms (49). Because spinal schwannomas typically arise from the poste-
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riolaterally placed dorsal root, their removal via laminectomy is fairly routine. Nevertheless, the risks of surgery are likely increased in elderly patients and for some recurrent lesions. In the current study, 30 patients with schwannoma were treated with a mean dose of 1870 cGy, using an average of two radiosurgical sessions. The mean follow-up interval in this cohort was 26 months (median 23 mo). Forty-one percent were treated for recurrent or residual disease after surgical resection, 1 (3%) had undergone prior radiation, and 16 (53%) underwent radiosurgery as their primary treatment option. Twelve (40%) of the CyberKnife-treated schwannomas in the present series occurred within a setting of NF2, a group of patients who are routinely confronted with a succession of multiple brain and spine lesions over the course of their lives. As is typical for spinal schwannomas, the presenting symptoms in this series were pain (66%), radicular sensory loss (41%), or radicular weakness (34%). After radiosurgery, the majority of patients reported stabilization of their clinical symptoms, with one third describing improvement in pain, weakness, or improved sensation. However, 18% reported being clinically worse off than before treatment. Within the relatively short follow-up period of this study, tumor growth control was observed in all but one radiosurgically ablated spinal schwannoma; tumor was either stable (56%) or reduced (40%) in size. When the axial neck pain in a single patient with a slightly larger 3.4 cm C3 tumor was not improved by 13 months, he underwent an uncomplicated surgical resection. It is unclear whether the enlargement observed in this patient would have been transient if not resected (as observed in some vestibular schwannoma). Similar to other benign neoplasms, recurrence is unlikely (0– 12.3%) when a spinal schwannoma is extirpated completely (8, 37, 46, 49). However, it is important to note that spinal schwannoma, similar to their biological kin acoustic neuroma, have a variable rate of growth (21, 27, 49). Such intermittent growth is particularly relevant to postoperative and postradiosurgical follow-up. In a series of 65 resected schwannomas, 5 (7.7%) recurrences only became apparent after 57 months (46). NF is a significant risk factor for tumor recurrence. Despite evidence that schwannomas of patients with and without NF2 are indistinguishable histologically, tumors in patients with NF2 tend to behave much more aggressively (24). NF2 is characterized by an alteration of the gene sited on chromosome 22q that predisposes patients to the development of multiple tumors of the central and peripheral nervous systems. When the entire spine is scanned with MRI, spinal nerve sheath tumors will be found in approximately 90% of NF2 patients (32). Schwannomas are the most common type of neoplasm that occurs in these patients (17). The natural history of NF2-associated tumors is believed to differ from that of their sporadic counterparts, and data from Evans et al. (11) demonstrate that the NF2 genotype influences the number of spinal tumors per patient. The clinical course of NF2 patients harboring spinal schwannomas is as varied as their phenotypic expression of the NF2 gene, and Mautner et al. (32) reported that only 33% of spinal tumors actually cause symp-
toms. Symptomatic schwannomas occurring in association with NF2 tend to grow faster, are more likely to infiltrate nerve roots, tend to progress to severe neurological deficits sooner, and recur more frequently after resection (24). Klekamp and Samii (24) report a recurrence rate of 10.7% at 5 years and 28.2% at 10 years in patients without NF2. However, for patients with NF2, these investigators describe a recurrence rate at 5 years of 39.2%, and all of their patients experience recurrence by 9 years. Therefore, patients with NF2 need to be followed more vigilantly and may represent a cohort of patients for whom SRS may be particularly beneficial.
Neurofibromas are benign nerve-sheath tumors consisting of axons, Schwann cells, fibroblasts, perineural cells, mast cells, and collagen fibrils surrounded by extracellular myxoid matrix. These tumors can arise from either peripheral or spinal nerve roots and are common in the setting of NF1, an autosomal dominant disorder with highly variable expression. The NF1 gene, which is located in the pericentromeric area on chromosome 17, codes for a tumor suppressor that, when inactivated in both alleles, leads to tumorigenesis. Seppala et al. (49) found that spinal neurofibroma constitute approximately 3.5% all spinal tumors, but less than 2% are symptomatic. In the present study, seven NF1 patients underwent radiosurgical ablation of nine spinal neurofibromas with a mean dose of 1978 cGy and an average of two fractions. Follow-up time ranged from 7 to 29 months with a mean of 19.9 months (median, 21.5 mo). Fifty-six percent of these patients were treated for recurrent or residual disease after surgical resection, one (11%) had undergone previous radiation, and three (33%) had upfront radiosurgery as their primary treatment. The predominant presenting symptoms among NF1 patients were pain (78%), sensory loss (67%), or weakness (67%). However, it is important to note that a significant percentage of these cases presented with myelopathy, which in a few patients was significant. No NF1 patient was asymptomatic. Unlike the other pathologies treated in this study, radiosurgery did not improve preoperative clinical symptoms. Half of the NF1 patients described a worsening in pain, weakness, or numbness at last follow-up. However, the treated neurofibroma in six of the seven patients who underwent postoperative MRI were stable in size at last follow-up. One NF1 patient with significant pretreatment myelopathy required microsurgical resection at 13 months to decompress the spinal cord. Although the size of the tumor in this case had been controlled, this was insufficient for improving her symptoms. Interestingly, our experience with radiosurgical ablation of spinal neurofibroma correlates with the microsurgical literature. Seppala et al. (49) reported that only one of 16 patients in a series of such tumors were free of symptoms after surgical resection, and in all other cases pain, sensory deficits, or motor weakness persisted. This phenomenon may stem from the infiltrating nature of neurofibroma, whereby the tumor itself
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is intermingled with the native nerve root. In such a situation, neither surgical removal nor radiosurgical ablation is specific enough for tumor alone. Halliday et al. (17) have shown that the spinal nerve root tumors that occur in a setting of NF1 are typically neurofibromas, as compared with NF2 where schwannomas predominate. In contrast with NF2, where spinal tumors are a diagnostic hallmark and often lead to neurological deficits (30– 40%), neurofibroma are less clinically significant in NF1 (24, 53). Spinal tumors can be detected in 40% of NF1 patients by MRI scans, but they cause neurological symptoms in only 2% (53). Topographical classification of the neurological deficits is often difficult because of the multiplicity of lesions along a single nerve root and the often large number of affected roots. As a result, when confronted with a symptomatic NF1 patient, we typically resorted to treating either the largest lesion, the lesion with documented growth, or the lesion judged to be most closely associated with the clinical symptoms. However, the poorer overall improvement in symptoms that we observed in this patient cohort may stem in part from our inability to correctly identify the offending spinal tumor. Consistent with the literature, we found that spinal neurofibromas often present at a younger age (48) compared with spinal schwannoma. This phenomenon likely contributes to the overall poor outlook for these patients, which, in at least two studies, manifests itself as a reduction in life expectancy (48, 51). Because spinal neurofibromas are typically multiple, are associated with persistent symptoms even after surgical removal, have an increased likelihood of recurrence, and occur in a setting of lower life expectancy, an alternative treatment to surgical excision is potentially quite attractive.
radiation-induced spinal cord injury (among more than 100 malignant spinal neoplasm) suffered this complication in the midthoracic region. The literature indicates that the main factors associated with a risk of radiation-induced myelopathy are the total dose and fraction size, length of spinal cord irradiated and total duration of treatment (19, 40, 47). Delayed radiation myelopathy from conventional radiation therapy typically has a time course between 6 to 24 months (31, 40, 47). The traditional dose tolerance of the normal spinal cord to conventional fractionated external beam radiotherapy is often quoted to be 45 to 50 Gy delivered in 1.8 to 2 Gy fractions (19, 31, 40). However, other studies examining the incidental irradiation of the cervical spinal cord during radiotherapy for head and neck cancer suggest even greater radiation tolerance (31). Overall, the published literature suggests that a realistic estimate of a 5% risk of myelopathy at 5 years requires 57 to 61 Gy delivered in 2 Gy fractions (47). The present limited experience (with only one complication) is insufficient for determining the absolute threshold for developing spinal cord damage after multisession radiosurgery. Longer follow-up is also needed to assess the ultimate risk of spinal radiosurgery.
Response of Symptoms to Spinal Radiosurgery
The most common presenting symptom of spinal tumors was pain, and reasonable success at pain alleviation was achieved within the time frame of this study. Although tolerable doses of radiosurgery have been shown to be effective for managing pain secondary to spinal metastasis, the ultimate rate of tumor control remains to be defined (10, 14, 42). Interestingly, the specific pathophysiological mechanisms of pain relief after irradiation of all spinal tumors remain poorly defined. In the case of vertebral metastasis without compression fractures, stretching of periosteum by tumor expansion, mechanical stress of the weakened bone, activation of pain receptors by the release of chemical pain mediators/cytokines from the tumor and the inflammatory response to it, and nerve entrapment/nerve root infiltration by the tumor are all potential pain mechanisms (35). The analgesic action of radiotherapy for bone metastases is possibly mediated via tumor shrinkage and inhibition of the release of chemical pain mediators (20). The sometimes rapid initial pain relief observed after only a single-fraction may suggest an effect on chemical mediators of the inflammatory response (20). Because many patients in this study reported pain relief without radiographic evidence of tumor acquiescence, it seems reasonable that similar processes occur after radiosurgical ablation of benign histologies. In the present series, approximately 70 and 50% of patients with spinal meningioma or schwannoma, respectively, reported significant improvement and, in many cases, complete relief of their pain. In general, no correlation was observed between pain relief and the number of multisession treatments or the amount of radiation delivered. The time course of pain amelioration varied from a few weeks to months, although one patient reported complete pain abatement after only 6
One patient in the current series experienced a radiationinduced spinal cord injury. To the best of our knowledge, this seems to be the first published case of radiation-induced myelopathy after SRS. By the standards of the present study, this woman’s treatment was not especially aggressive. The volume of tumor, dose, and fractionation were unremarkable. The one treatment variable that may have contributed to her injury, however, was the volume of spinal cord irradiated. Approximately 1.7 cm3 of spinal cord was irradiated with slightly more than 6 Gy per fraction and 18 Gy over all three sessions. Although this did not seem unusual at the time of surgery (given our experience treating vertebral metastasis), this volume of irradiated spinal cord does represent an outlier in the current study. Although this certainly gives us pause, there were other patients who received more radiation to their spinal cord without sequela. It is also reasonable to speculate that the trauma from two prior surgical resections may have predisposed this woman’s spinal cord to subsequent radiation injury. Furthermore, it is worth noting that this complication did not occur in the watershed region of the midthoracic region where spinal cord injury of all kinds, especially radiation induced, is most frequent. The only other radiosurgery patients at Stanford who have developed
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days. Some patients reported a temporary increase in radicular symptoms 2 to 3 weeks after radiosurgery, which improved with corticosteroids and later resolved without additional analgesia. This phenomenon is hypothesized to be secondary to radiation-induced tumor swelling, which might correlate with the slight transient increase in tumor size occasionally observed at 6 to 8 months. Many patients first reported improved symptoms at their 12 month assessment, and no patient who achieved complete pain relief has reported recurrence. The pain response therefore appears durable. Not all patients experienced pain relief. Several patients, who in retrospect likely had postsurgical pain, not surprisingly did not improve. Patients with NF1 (unlike those who carry the diagnosis of NF2) also often failed to attain analgesic or other symptomatic relief, possibly because of nerve infiltration or our inability to accurately identify which of their tumors was responsible for symptoms. In addition, persistent pain was observed in NF cases where new lesions arose and in a small number of patients who had larger tumors that, after SRS, were less likely to shrink appreciably in the short term. This last limitation also applies to the use of radiosurgical ablation for larger intraspinal tumors that cause significant myelopathy. Slow-growing, benign, intradural extramedullary tumors presumably cause radicular and myelopathic symptoms of weakness and numbness from gradual nerve root and spinal cord compression. Interestingly, improvement in these symptoms was often observed without radiographic evidence of tumor shrinkage. Seven of the 16 patients with spinal schwannoma who initially presented with complaints of weakness or sensory loss reported some form of symptom improvement after radiosurgery. More interesting, only one of those seven was among the 25% of schwannomas that were reduced in size. Similarly, 8 of the 16 patients with spinal meningioma that exhibited clinical weakness or sensory loss described symptom improvement after CyberKnife treatment. Four of these patients had tumors that decreased in size after radiosurgery, whereas four patients had tumors that remained stable. The mechanism responsible for clinical improvement in these cases remains as enigmatic as the analgesic action of radiation. Importantly, no neurological symptoms developed as a result of treatment in any asymptomatic patient. Because, as described above, the growth of benign spinal tumors can take several years, the length of follow-up in the current study is insufficient to establish the long-term efficacy of spinal radiosurgery for these lesions (46). Nonetheless, long-term studies in patients with benign brain tumors who were treated with radiosurgery suggests that tumor control at 3 years is very likely to be durable (26). Ultimately, longer follow-up will be needed to definitively establish the safety, and even more so, the efficacy, of radiosurgery for benign spinal tumors.
were based on our own and published experience with intracranial ablation, which in hindsight may have been more conservative than needed. As we have gained experience and confidence in the overall safety of spinal radiosurgery, doses have been gradually escalated and the number of fractions decreased. Thus, the dose-fraction regimens described here should not be viewed as optimal but merely as useful starting points for future investigation. Nevertheless, this study demonstrates both the relative safety, and early evidence of efficacy, for spinal radiosurgery and provides a rough framework for treating patients going forward. Given the average length of follow-up to date, it is not possible to say anything definitive about long-term efficacy of spinal radiosurgery for benign tumors; this topic will remain the subject of ongoing investigation at our institution. Nevertheless, the present study does suggest that CyberKnife SRS could someday serve as a useful adjunct to the neurosurgical armamentarium for managing selected benign spinal tumors.
1. Adler JR Jr, Chang SD, Murphy MJ, Doty J, Geis P, Hancock SL: The Cyberknife: A frameless robotic system for radiosurgery. Stereotact Funct Neurosurg 69:124–128, 1997. 2. Asazuma T, Toyama Y, Maruiwa H, Fujimura Y, Hirabayashi K: Surgical strategy for cervical dumbbell tumors based on a three-dimensional classification. Spine 29:E10–E14, 2004. 3. Chang SD, Adler JR Jr: Treatment of cranial base meningiomas with linear accelerator radiosurgery. Neurosurgery 41:1019–1025, 1997. 4. Chang SD, Adler JR Jr: Current status and optimal use of radiosurgery. Oncology (Williston Park) 15:209–221, 2001. 5. Chang SD, Main W, Martin DP, Gibbs IC, Heilbrun MP: An analysis of the accuracy of the CyberKnife: A robotic frameless stereotactic radiosurgical system. Neurosurgery 52:140–147, 2003. 6. Deleted in proof. 7. Cohen-Gadol AA, Zikel OM, Koch CA, Scheithauer BW, Krauss WE: Spinal meningiomas in patients younger than 50 years of age: A 21-year experience. J Neurosurg Spine 98:258–263, 2003. 8. Conti P, Pansini G, Mouchaty H, Capuano C, Conti R: Spinal neurinomas: Retrospective analysis and long-term outcome of 179 consecutively operated cases and review of the literature. Surg Neurol 61:34–44, 2004. 9. De Salles AA, Pedroso AG, Medin P, Agazaryan N, Solberg T, CabatanAwang C, Espinosa DM, Ford J, Selch MT: Spinal lesions treated with Novalis shaped beam intensity-modulated radiosurgery and stereotactic radiotherapy. J Neurosurg 101 [Suppl 3]:435–440, 2004. 10. Degen JW, Gagnon GJ, Voyadzis JM, McRae DA, Lunsden M, Dieterich S, Molzahn I, Henderson FC: CyberKnife stereotactic radiosurgical treatment of spinal tumors for pain control and quality of life. J Neurosurg Spine 2:540–549, 2005. 11. Evans DG, Trueman L, Wallace A, Collins S, Strachan T: Genotype/ phenotype correlations in type 2 neurofibromatosis (NF2): Evidence for more severe disease associated with truncating mutations. J Med Genet 35:450–455, 1998. 12. Gambardella G, Gervasio O, Zaccone C: Approaches and surgical results in the treatment of ventral thoracic meningiomas. Review of our experience with a postero-lateral combined transpedicular-transarticular approach. Acta Neurochir (Wien) 145:385–392, 2003. 13. Deleted in proof. 14. Gerszten PC, Welch WC: Cyberknife radiosurgery for metastatic spine tumors. Neurosurg Clin North Am 15:491–501, 2004. 15. Gezen F, Kahraman S, Canakci Z, Beduk A: Review of 36 cases of spinal cord meningioma. Spine 25:727–731, 2000. 16. Deleted in proof.
At the start of this study, we harbored grave concerns that radiosurgical ablative doses could prove injurious to the adjacent spinal cord. Selection of doses and fraction number
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17. Halliday AL, Sobel RA, Martuza RL: Benign spinal nerve sheath tumors: Their occurrence sporadically and in neurofibromatosis types 1 and 2. J Neurosurg 74:248–253, 1991. 18. Helseth A, Mork SJ: Primary intraspinal neoplasms in Norway, 1955 to 1986. A population-based survey of 467 patients. J Neurosurg 71:842–845, 1989. 19. Isaacson SR: Radiation therapy and the management of intramedullary spinal cord tumors. J Neurooncol 47:231–238, 2000. 20. Jeremic B: Single fraction external beam radiation therapy in the treatment of localized metastatic bone pain. A review. J Pain Symptom Manage 22:1048–1058, 2001. 21. Kameyama S, Tanaka R, Honda Y, Hasegawa A, Yamazaki H, Kawaguchi T: The long-term growth rate of residual acoustic neurinomas. Acta Neurochir (Wien) 129:127–130, 1994. 22. Kasantikul V, Charuchaikul S, Shuangshoti S: Extramedullary subdural meningioma after trauma. Neurosurgery 29:930–931, 1991. 23. King AT, Sharr MM, Gullan RW, Bartlett JR: Spinal meningiomas: A 20-year review. Br J Neurosurg 12:521–526, 1998. 24. Klekamp J, Samii M: Surgery of spinal nerve sheath tumors with special reference to neurofibromatosis. Neurosurgery 42:279–290, 1998. 25. Kondziolka D, Lunsford LD, McLaughlin MR, Flickinger JC: Long-term outcomes after radiosurgery for acoustic neuromas. N Engl J Med 339:1426– 1433, 1998. 26. Kondziolka D, Nathoo N, Flickinger JC, Niranjan A, Maitz AH, Lunsford LD: Long-term results after radiosurgery for benign intracranial tumors. Neurosurgery 53:815–821, 2003. 27. Laasonen EM, Troupp H: Volume growth rate of acoustic neurinomas. Neuroradiology 28:203–207, 1986. 28. Leber KA, Bergloff J, Pendl G: Dose-response tolerance of the visual pathways and cranial nerves of the cavernous sinus to stereotactic radiosurgery. J Neurosurg 88:43–50, 1998. 29. Lee JY, Niranjan A, McInerney J, Kondziolka D, Flickinger JC, Lunsford LD: Stereotactic radiosurgery providing long-term tumor control of cavernous sinus meningiomas. J Neurosurg 97:65–72, 2002. 30. Lunsford LD, Kondziolka D, Flickinger JC: Stereotactic radiosurgery for benign intracranial tumors. Clin Neurosurg 40:475–497, 1993. 31. Marcus RB Jr, Million RR: The incidence of myelitis after irradiation of the cervical spinal cord. Int J Radiat Oncol Biol Phys 19:3–8, 1990. 32. Mautner VF, Tatagiba M, Lindenau M, Funsterer C, Pulst SM, Baser ME, Kluwe L, Zanella FE: Spinal tumors in patients with neurofibromatosis type 2: MR imaging study of frequency, multiplicity, and variety. AJR Am J Roentgenol 165:951–955, 1995. 33. McCormick PC: Surgical management of dumbbell and paraspinal tumors of the thoracic and lumbar spine. Neurosurgery 38:67–74, 1996. 34. McCormick PC: Surgical management of dumbbell tumors of the cervical spine. Neurosurgery 38:294–300, 1996. 35. Mercadante S: Malignant bone pain: Pathophysiology and treatment. Pain 69:1–18, 1997. 36. Murphy MJ: Tracking moving organs in real time. Semin Radiat Oncol 14:91–100, 2004. 37. Parsa AT, Lee J, Parney IF, Weinstein P, McCormick PC, Ames C: Spinal cord and intradural-extraparenchymal spinal tumors: Current best care practices and strategies. J Neurooncol 69:291–318, 2004. 38. Perry A, Gutmann DH, Reifenberger G: Molecular pathogenesis of meningiomas. J Neurooncol 70:183–202, 2004. 39. Prasad D, Steiner M, Steiner L: Gamma surgery for vestibular schwannoma. J Neurosurg 92:745–759, 2000. 40. Rampling R, Symonds P: Radiation myelopathy. Curr Opin Neurol 11:627– 632, 1998. 41. Rock JP, Ryu S, Yin FF: Novalis radiosurgery for metastatic spine tumors. Neurosurg Clin North Am 15:503–509, 2004. 42. Rock JP, Ryu S, Yin FF, Schreiber F, Abdulhak M: The evolving role of stereotactic radiosurgery and stereotactic radiation therapy for patients with spine tumors. J Neurooncol 69:319–334, 2004. 43. Ross DA, Edwards MS, Wilson CB: Intramedullary neurilemomas of the spinal cord: Report of two cases and review of the literature. Neurosurgery 19:458–464, 1986.
44. Roux FX, Nataf F, Pinaudeau M, Borne G, Devaux B, Meder JF: Intraspinal meningiomas: Review of 54 cases with discussion of poor prognosis factors and modern therapeutic management. Surg Neurol 46:458–463, 1996. 45. Ryu SI, Chang SD, Kim DH, Murphy MJ, Le QT, Martin DP, Adler JR Jr: Image-guided hypo-fractionated stereotactic radiosurgery to spinal lesions. Neurosurgery 49:838–846, 2001. 46. Schick U, Marquardt G, Lorenz R: Recurrence of benign spinal neoplasms. Neurosurg Rev 24:20–25, 2001. 47. Schultheiss TE, Kun LE, Ang KK, Stephens LC: Radiation response of the central nervous system. Int J Radiat Oncol Biol Phys 31:1093–1112, 1995. 48. Seppala MT, Haltia MJ, Sankila RJ, Jaaskelainen JE, Heiskanen O: Long-term outcome after removal of spinal neurofibroma. J Neurosurg 82:572–577, 1995. 49. Seppala MT, Haltia MJ, Sankila RJ, Jaaskelainen JE, Heiskanen O: Long-term outcome after removal of spinal schwannoma: A clinicopathological study of 187 cases. J Neurosurg 83:621–626, 1995. 50. Solero CL, Fornari M, Giombini S, Lasio G, Oliveri G, Cimino C, Pluchino F: Spinal meningiomas: Review of 174 operated cases. Neurosurgery 25:153– 160, 1989. 51. Sorensen SA, Mulvihill JJ, Nielsen A: Long-term follow-up of von Recklinghausen neurofibromatosis. Survival and malignant neoplasms. N Engl J Med 314:1010–1015, 1986. 52. Stafford SL, Pollock BE, Leavitt JA, Foote RL, Brown PD, Link MJ, Gorman DA, Schomberg PJ: A study on the radiation tolerance of the optic nerves and chiasm after stereotactic radiosurgery. Int J Radiat Oncol Biol Phys 55:1177–1181, 2003. 53. Thakkar SD, Feigen U, Mautner VF: Spinal tumours in neurofibromatosis type 1: An MRI study of frequency, multiplicity and variety. Neuroradiology 41:625–629, 1999. 54. Tishler RB, Loeffler JS, Lunsford LD, Duma C, Alexander E 3rd, Kooy HM, Flickinger JC: Tolerance of cranial nerves of the cavernous sinus to radiosurgery. Int J Radiat Oncol Biol Phys 27:215–221, 1993. 55. Wilkinson JM, McClelland MR, Battersby RD: Spinal cord schwannoma after vertebral trauma: A causal relation? J Neurol Neurosurg Psychiatry 59:358, 1995. 56. Yin FF, Ryu S, Ajlouni M, Zhu J, Yan H, Guan H, Faber K, Rock J, Abdalhak M, Rogers L, Rosenblum M, Kim JH: A technique of intensity-modulated radiosurgery (IMRS) for spinal tumors. Med Phys 29:2815–2822, 2002.
he authors not only provide clinical and radiosurgical details on the largest series of benign spinal tumors treated with radiosurgery to date, but they also thoroughly discuss the particularly relevant questions for this relatively new addition to the clinical armementarium. Although longer follow-up of this cohort will be necessary, the length of clinical and radiological follow-up in this series serves as a basis for compelling clinical information, especially in view of the low morbidity after significant cumulative doses of radiation to the spinal cord. The prospective manner of data collection allows for an optimal reliability in terms of clinical assessment, especially for complaints of pain. As is not uncommon in radiosurgical series, the diagnosis is not always pathologically confirmed. In the present series, the diagnosis was established based on magnetic resonance imaging in a certain percentage of patients, underscoring the need for careful clinical and radiological follow-up. Perhaps one of the most worrisome issues for practitioners relates to the extent of spinal cord compression that would limit this form of nonsurgical treatment. While it is stated in this report that very few patients had significant spinal cord compression, future reports focusing on this radiological parameter will be necessary. In this regard, it is interesting to note that many of the tumors in this series did not decrease in size. Attention should also be drawn to the data relative to the volume of spinal cord receiving significant doses of radiation; less than 0.4 cm2
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received 80% of the prescribed dose and less than 1.4 cm2 received 50% of the prescribed dose. These volumes represent a significant potential for neurological deterioration, yet the morbidity noted in this series remained low. Notably, while only one tumor (1/55) actually enlarged radiologically, surgery for persistence or worsening of symptoms was required in 3 patients from the entire cohort. Despite only 3 patients requiring subsequent surgery, a greater percentage of patients still reported increased symptoms, and this issue, while disappointing, has been addressed in the discussion. While only one convincing radiation-induced complication is reported in this series, it would seem reasonable to also consider as a possible radiation-induced complication the patient who was radiated for a C2 tumor and died 7 months after treatment with respiratory insufficiency. Overall, this report from one of the pioneering groups in the field is informative and the results are encouraging. Jack P. Rock Detroit, Michigan his paper represents an important landmark in the development of radiosurgery. This group of investigators should be commended for their courage in aggressively pursuing this new indication for radiosurgery. Prior investigations regarding spinal radiosurgery have concentrated primarily on treatment of metastasis disease to the spine. This report, by contrast, addresses treatment of benign intradural spinal disease. The long overall life expectancy of the subjects, as well as the technical constraints in regards to limiting spinal cord exposure to radiation, increases the potential for risk. Evaluation of outcomes for these patients is difficult due to the long follow-up periods required in order to determine disease control, neurological function, and radiation-induced side effects. This paper analyzes a sizeable number of patients with fairly heterogeneous pathology, including several different tumor types and sizes, varying degrees of cord compression, and varying histories of prior surgical resection. Such limitations do not, however, take away from the primary observations of technical feasibility and overall safety of the procedure. The median follow-up length in this report is sufficient to make some basic conclusion regarding early outcomes. As such, this paper serves as an important starting point for further investigations into the application of radiosurgery in the treatment of benign intradural spinal tumors. The present information in the literature, however, is deficient primarily in its description of the long-term tolerance of the spinal cord to specific dose and fractionation regimens. Groups interested in pursuing this form of treatment should understand the current lack of understanding in regards to the therapeutic window of efficacy and safety when treating for this indication. The authors have demonstrated that the early risk of complications from hypofractionated stereotactic radiotherapy is low, and the rate of tumor control is respectable. Nevertheless, the overall role of spinal conformal radiotherapy for benign intradural tumors in specific circumstances remains to be determined. Its utilization in the clinical setting should be tempered by the availability of highly safe and effective open surgical treatment. In the setting of a neurological deficit due to a compressive myelopathy, surgery should continue to be recommended as the first-line treatment of choice. Radiosurgery in such instances should be discouraged. While the use of spinal radiosurgery at present should be restricted to patients who are poor surgical risks or who refuse surgery in the setting of adequate and complete informed consent, continued accrual of clinical data may ultimately change
this recommendation. This has been the case for a variety of cranial indications where radiosurgery has assumed the role of treatment of first choice. Michael R. Girvigian Radiation Oncologist Joseph C.T. Chen Los Angeles, California
odd et al. have presented the outcomes of 51 patients with benign spinal tumors having CyberKnife treatment. These early results are encouraging, with less than 10% of patients requiring operative resection after the radiation treatments. This approach is especially attractive for patients with neurofibromatosis and for patients with recurrent tumors after prior surgery. Bruce E. Pollock Rochester, Minnesota
tereotactic radiosurgery is becoming an important new technique for the management of a variety of spinal tumors. While there is an increasing body of evidence supporting the role of radiosurgery for malignant spinal tumors, there is much less experience and more controversy regarding its use for benign tumors of the spine. Indeed, less than 15% of our total spinal radiosurgery experience has been for benign tumors, mostly neurofibromas, schwanommas, and meningiomas. This is somewhat different than the intracranial radiosurgery experience at most centers. In this study, the authors have attempted to carefully analyze their experience with radiosurgery for benign intradural extramedullary spinal tumors in what is the largest published series to date on this subject. The authors have organized their analysis based on tumor histology. While a relatively small clinical series, their results mirror radiographic tumor control rates for these histologies when treated within the cranium. As is often the case with such new technologies, patient selection is often due to the fact that they are not candidates for more conventional treatments, namely open surgical techniques. Many of these patients are referred for spinal radiosurgery either because they cannot or wish not to undergo open surgery. In other cases, radiosurgery is used as a “salvage” technique after post-surgical tumor recurrence. There are several limitations to this study. It represents a cohort of quite different patients with a wide variety of differently sized (0.136 to 24.6 cm3) and shaped tumors. There was also quite a difference in radiosurgical technique employed between patients. Total treatment doses range from 16 to 30 Gy delivered in one to five fractions. This makes it somewhat more difficult for the reader to extrapolate the best dose and fractionation scheme to use on his or her own patients. The authors did their best to explain their rationale for dose prescription. As the authors state, “the dose-fraction regimens described here should not be viewed as optimal but merely as useful starting points for future investigation.” I believe that the authors’ statement that the study demonstrates both the relative safety and early evidence of efficacy for spinal radiosurgery for benign intradural extramedullary spinal neoplasms has been validated by this manuscript. Our own experience with a comparable number of patients has also been equally encouraging. I would hope that future standardization of fractionation schemes, as well as doses, will allow for the more useful comparison between clinical series. I expect for spinal radiosurgery to be an exciting new development in the treatment of these potentially very challenging cases. Peter Gerszten Pittsburgh, Pennsylvania
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