Delayed Radiation Induced Myelopathy After Spinal.11

SPINAL RADIOSURGERY

DELAYED RADIATION-INDUCED MYELOPATHY AFTER SPINAL RADIOSURGERY Iris C. Gibbs, M.D. Department of Radiation Oncology, Stanford University Medical Center, Stanford, California

Chirag Patil, M.D. Department of Neurosurgery, Stanford University Medical Center, Stanford, California

Peter C. Gerszten, M.D. Departments of Neurological Surgery and Radiation Oncology, University of Pittsburgh School of Medicine University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania

John R. Adler, Jr., M.D. Department of Neurosurgery, Stanford University Medical Center, Stanford, California

Steven A. Burton, M.D. Department of Radiation Oncology, University of Pittsburgh School of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania Reprint requests: Iris C. Gibbs, M.D., Department of Radiation Oncology, Stanford University Medical Center, 875 Blake Wilbur Drive, Stanford, CA 94305-5847. Email: [email protected] Received, June 2, 2008. Accepted, November 6, 2008. Copyright © 2009 by the Congress of Neurological Surgeons

OBJECTIVE: Spinal cord injury is arguably the most feared complication in radiotherapy and has historically limited the aggressiveness of spinal tumor treatment. We report a case series of 6 patients treated with radiosurgery who developed delayed myelopathy. METHODS: Between 1996 and 2005, 1075 patients with benign or malignant spinal tumors were treated by CyberKnife (Accuray, Inc., Sunnyvale, CA) robotic radiosurgery at Stanford University Medical Center and the University of Pittsburgh Medical Center. Patients were followed prospectively with clinical and radiographic assessments at 1- to 6-month intervals. A retrospective review identified patients who developed delayed radiation-induced myelopathy. Six patients (5 women, 1 man) with a mean age of 48 years (range, 25–61 years) developed delayed myelopathy at a mean of 6.3 months (range, 2–9 months) after spinal radiosurgery. Three tumors were metastatic; 3 were benign. The metastases were in the upper to midthoracic spine, whereas the benign tumors were partially in the cervical region. Three cases involved previous radiation therapy. RESULTS: Dose volume histograms were generated for target and critical structures. Clinical and dosimetric factors were analyzed for factors predictive of spinal cord injury. Specific dosimetric factors contributing to this complication could not be identified, but one-half of the patients with myelopathy received spinal cord biological equivalent doses exceeding 8 Gy. CONCLUSION: Delayed myelopathy after radiosurgery is uncommon with the dose schedules used in this case series. Radiation injury to the spinal cord occurred over a spectrum of dose parameters that prevented identification of specific dosimetric factors contributing to this complication. Primarily, biological equivalent dose estimates were not usable for defining spinal cord tolerance to hypofractionated dose schedules. We recommend limiting the volume of spinal cord treated above an 8-Gy equivalent dose, because half of the complications occurred beyond this level. KEY WORDS: Myelopathy, Radiation complications, Radiosurgery Neurosurgery 64:A67–A72, 2009

DOI: 10.1227/01.NEU.0000341628.98141.B6

S

ince the classic reports of cervical spinal cord radiation myelopathy by Ahlbom (1) in 1941 and Boden (3) in 1948, radiationinduced myelopathy has been a feared complication of conventional radiotherapy (13). Animal studies and clinical modeling derived from observational data provide the basis for our current understanding of the factors affecting the spinal cord’s tolerance to radiation. The most important of these appear to be the radiation dose schedule, which includes dose per fraction, total dose, and interfraction ABBREVIATIONS: BED, biological equivalent dose; MRI, magnetic resonance imaging

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interval. It is widely accepted that the therapeutic index of radiotherapy limits the radiation dose near the spinal cord to such an extent that the control of many tumors is compromised. With advances in technology, especially the development of image-guided radiosurgery, the ability to deliver a more aggressive radiation dose adjacent to the spine is now feasible. Nevertheless, the tolerance of the spinal cord to such single or hypofractionated radiation schedules is uncertain and may well differ markedly from conventional radiation therapy precedents. Combining 2 of the largest CyberKnife (Accuray, Inc., Sunnyvale, CA) spinal radiosurgery series, we report 6

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cases of radiation-induced myelopathy among more than 1000 patients treated with the CyberKnife for benign and metastatic spinal tumors.

PATIENTS AND METHODS Between 1996 and 2005, 1075 patients with benign or metastatic spinal tumors were enrolled prospectively onto Institutional Review Board-approved registry protocols and treated with CyberKnife radiosurgery at either Stanford University or the University of Pittsburgh. Patients with spinal instability, target tumors involving more than 2 vertebral levels, or spinal cord compression causing acute neurological deterioration were excluded from enrollment. The overall cohort of 1075 patients included 156 patients with benign extramedullary tumors and 919 patients with metastatic tumors. Of the metastatic tumors, the primary histologies were predominantly renal cell carcinoma (142 patients), breast cancer (134 patients), lung cancer (129 patients), melanoma (49 patients), gastrointestinal adenocarcinoma (57 patients), sarcoma (42 patients), and prostate (40 patients). A database of clinical and dosimetric factors was collected and used to identify patients who developed treatment-related spinal cord injury. Pretreatment setup and immobilization of cervical lesions used a simple, nonrigid Aquaplast face mask (WFR/Aquaplast Corp., Wyckoff, NJ). In the lumbothoracosacral region, a vacuum foam cradle was used. Treatment plans were generated using thin-section (1.25-mm slice thickness) contrast computed tomographic scans through the anatomic region of interest. As most metastatic vertebral body tumors were clearly visible by computed tomography, magnetic resonance imaging (MRI) with image fusion was used when necessary to define the extent of benign extramedullary tumors. In general, for treatment planning purposes, small metastatic tumors involving less than 25% of the vertebral body were contoured with an approximately 2- to 3-mm margin; all other vertebral body tumors encompassed the entire vertebra. Until 2004, spinal targeting in the lower cervical, thoracic, and lumbar spine required the preradiosurgical percutaneous insertion of either stainless steel bone screws (Stanford University Medical Center) or subperiosteal gold seeds (University of Pittsburgh Medical Center), which served as localizing fiducials. Treatment simulation techniques were similar at the 2 institutions and have been described previously (4, 6). In 2004, the availability of fiducial-less Xsight (Accuray, Inc.) hierarchical mesh tracking obviated the need for metallic markers; with this system, the imaging system correlates images of bony anatomy rather than implanted fiducials. On the basis of institutional preference, radiosurgery was generally administered in a single fraction at the University of Pittsburgh, whereas patients were treated in 2 to 5 sessions at Stanford University, depending on the tumor size or proximity to the spinal cord. A detailed description of the treatment planning used at both institutions has previously been published (6). For all patients, the total dose prescription varied between 12.5 and 25 Gy (12.5–20 Gy in 1 fraction, 18 to 22 Gy in 2 fractions, 18 to 24 Gy in 3 fractions, 14 to 24 Gy in 4 fractions, or 25 Gy in 5 fractions). The majority of patients (112 benign, 803 metastatic) were treated with a single fraction; 90 (22 benign, 68 metastatic) were treated in 2 fractions; and 70 (22 benign, 48 metastatic) were treated in 3 to 5 fractions. Care was taken to limit the maximum dose to the spinal cord or cauda equina to less than 8 to 10 Gy while aiming to optimize the coverage of the target lesion to at least 90%. However, this constraint was relaxed when the volume of spinal cord receiving greater than this dose was estimated to be only a few voxels. Dose volume histograms were generated for the target lesion and critical structures including the spinal cord. Conformality, homogeneity, and coverage indices were calculated and recorded using conven-

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tional measures (12, 16). Radiosurgery was performed as an outpatient procedure lasting 30 to 60 minutes. Subsequently, patients with metastatic lesions were followed both clinically and radiographically at 1- to 3-month intervals, and patients with benign lesions were followed at 6-month intervals. Late complications were scored according to the Common Toxicity Criteria, Versions 2.0 and 3.0 (17, 19). The dose volume effects on the spinal cord were analyzed for all patients in this series. Because of the variety of radiation schedules, each was converted to biological equivalent doses (BED3) using the following formula, with an assumed α/β ratio of 3 for spinal cord (7):

冢

BED  nd 1 

d α/β

冣

To determine which factors were predictive of spinal cord injury, multiple clinical and dosimetric factors including sex, age, histology, presenting symptoms, previous radiotherapy, anatomic level, prescribed dose, dose per fraction, tumor volume, and spinal cord dose were analyzed.

RESULTS The tumor volumes in all patients ranged from 0.025 to 685 mL. More than 55% of metastatic patients were previously irradiated. Although care was taken to limit the volume of spinal cord receiving 8 Gy or higher, the maximum spinal cord dose ranged from 3.6 to 29.9 Gy. In all but 2 patients treated in single fractions, the volume of spinal cord treated to a dose of more than 8 Gy was less than 1 mL. The average spinal cord volume treated to 8 Gy equivalent dose or more was also less than 1 mL. Our review identified 6 patients who developed radiationinduced delayed spinal cord myelopathy. The mean time to onset was 6.3 months (range, 2–10 months). Four patients were treated at Stanford University Medical Center and 2 at the University of Pittsburgh Medical Center. The characteristics of the 6 patients who developed radiation-induced myelopathy after spinal radiosurgery are shown in Tables 1 and 2. The mean age of the 5 women and 1 man was 48 years (range, 25–61 years). Three of the 6 spinal tumors were metastases, and 3 were benign tumors (meningioma, schwannoma, and neurofibroma). The three metastatic tumors were located entirely in the upper to midthoracic spine, whereas all 3 benign tumors were located predominantly in the cervical and cervicothoracic region. With regard to clinical symptoms of myelopathy, 5 of the 6 patients had motor and sensory deficits, 3 had bowel and bladder symptoms, and 4 had significant pain (Table 3). Myelopathic symptoms were initially managed by corticosteroids in all patients. Some patients also received a combination of vitamin E and pentoxifylline (Trental; Sanofi-Aventis, Bridgewater, NJ), hyberbaric oxygen, gabapentin (Neurontin; Pfizer, New York), and/or physical therapy. After an initial worsening, 3 of the 6 patients had improvement in their myelopathic symptoms after treatment, 2 reached a plateau, and 1 patient progressed to paraplegia. All 3 patients who showed clinical improvement had complete radiographic resolution of their spinal cord edema on MRI. The earliest radiographic findings were edema within the spinal cord, signified by hyperintensity on the T2-weighted MRI sequence above and below the region of injury. In most patients, clinical symptoms shortly

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SPINAL MYELOPATHY AFTER RADIOSURGERY

TABLE 1. Patient characteristics and tumor location Patient no.

Age (y)/ sex

Tumor type

Location

Onset of myelopathy (mo)

Previous radiation and interval between courses (mo)

Previous surgery

Previous chemotherapy

No

Yes

1

59/F

Renal cell carcinoma

T6

9

No

2

55/F

Breast cancer

T5

6

Yes (80.8)

No

Yes

3

59/F

Breast cancer

T1

4

Yes (70.0)

Yes

Yes

4

29/F

Meningioma

C7–T2

9

No

Yes

No

5

61/F

Schwannoma

C6

2

No

Yes

No

6

25/M

Neurofibroma

C–C7

5

No

No

No

TABLE 2. Tumor and radiosurgery treatment plan characteristicsa Patient no.

a

Tumor type

Location

Treatment Total No. of volume prescription treatments 3 (cm ) dose (Gy)

Maximum dose to spinal cord (Gy)

Maximum Volume of cord spinal cord receiving  BED3 BED3 (Gy) (8 Gy) (cm3)

1

Renal cell carcinoma

T6 vertebral body and spinal canal

13.7

25

2

26.2

140.6

3.4

2

Breast cancer

T5 vertebral body

10.5

20

2

19.2

80.6

2.6

3

Breast cancer

T1 posterior elements

18.9

21

2

13.9

46.1

0.3

4

Meningioma

Right C7–T2 spinal canal

7.6

24

3

29.9

129.2

4.0

5

Schwannoma

Right C6 spinal canal

4.5

20

1

8.5

32.6

0.1

6

Neurofibroma

Right C7 spinal canal

1.2

20

1

43.3

0.2

10

BED3 (8 Gy)  biological equivalent dose of 8 Gy in 1 fraction  29 Gy.

preceded or were coincident with these findings. Within 6 to 8 months, an area of contrast enhancement at the level of injury developed. By 12 to 18 months from onset, a region of myelomalacia was seen within the spinal cord at the area of injury. Figure 1 shows these characteristic radiographic findings of radiation- induced myelopathy. Two of the patients had received irradiation before radiosurgery at doses of 50.4 and 39.6 Gy in 1.8-Gy fractions, at 70 and 81 months, respectively. The estimated maximum spinal cord doses in these previous courses were 25.2 and 40 Gy, respectively. Also of interest is that 2 of the 6 patients who developed these injuries received an antiangiogenic or epidermal growth factor inhibitor-targeted therapy within 2 months of developing clinical myelopathy. One patient died of systemic disease progression 17 months after treatment and 7 months after the onset of myelopathy. Of note, the treated lesion in this patient appeared radiographically stable at the last follow-up examination. An analysis of the cohort of myelopathic patients shows that the mean prescribed dose to the tumor margin was 21.6 Gy. The mean treatment volume was 9.4 mL. The mean maximum BED3 for the spinal cord dose was 78.7 Gy (range, 32.6–140.3 Gy; standard deviation, 46.4 Gy) (Table 2). Three of the 6 patients received a maximum spinal cord dose of less than the average dose received among all patients. One patient received a dose

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A

B

FIGURE 1. Characteristic radiographic findings of delayed radiation- induced myelopathy. A, spinal cord edema at the onset of symptoms (brackets) and vertebral level of the T1 spinous process initially treated (arrow). B, spinal cord enhancement (brackets) at 6 to 8 months after onset. C, myelomalacia (brackets) 12 to 18 months after onset of symptoms.

C

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TABLE 3. Myelopathy symptoms and response to treatment Patient no.

Pain

Sensory symptoms

Motor weakness

Bowel or bladder symptoms

1

Yes

No

Yes

Yes

Corticosteroids, vitamin E, pentoxifylline, hyperbaric oxygen, physical therapy

Stable

2

Yes

Yes

Yes

Yes

Corticosteroids, vitamin E, pentoxifylline, hyperbaric oxygen, physical therapy

Progressive myelopathy

3

Yes

Yes

Yes

Yes

Corticosteroids, physical therapy, gabapentin

Improved

4

No

Yes

Yes

No

Physical therapy, corticoteroids

Stable

5

No

Yes

No

No

Corticosteroids, vitamin E, pentoxifylline

6

Yes

Yes

Yes

No

Corticosteroids, gabapentin, vitamin E, pentoxifylline, hyperbaric oxygen, physical therapy

Treatments

above 1 standard deviation, and another received a maximum dose nearly 2 standard deviations of the mean within this cohort. Among these 6 patients, the mean volume of the spinal cord receiving the biological equivalent of 8 Gy in 1 fraction (i.e., BED3  29 Gy) was 1.77 mL (range, 0.1–4.0 mL; standard deviation, 1.77 mL). Three of the myelopathic patients had a spinal cord volume of more than 1 mL treated above this dose level. Owing to the low incidence of myelopathy among our patients, logistic regression failed to show age, sex, primary site, anatomic location, anatomic level, previous treatment, total dose, dose per fraction, maximum dose, maximum spinal cord dose, and tumor volume as predictive of spinal injury.

DISCUSSION Although multiple publications now describe the technique for and outcome from spinal radiosurgery, the complication of radiation-induced myelopathy has never been analyzed and characterized in detail. In this study, we report 6 patients treated with spinal stereotactic radiosurgery who developed delayed radiation-induced myelopathy. Similar to radiation therapyinduced spinal cord injury, the pathogenesis of myelopathy after radiosurgery is likely to be multifactorial, with no single target cell and no single pathway. Injury is likely mediated by damage to both white matter tracts and the local vasculature. This asser-

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Neurological status after intervention

Current disability

Mortality status

Walker-dependent ambulation

Dead

Progression to T4 paraplegia

Alive

Walker-dependent ambulation

Alive

Intermittent use of cane

Alive

Improved

Mild left lowerextremity numbness

Alive

Improved

Gradual improvement in numbness, weakness, and ambulation

Alive

tion is supported by the pathological observation of demyelination, necrosis, increased vascularity, telangiectasis, hyaline degeneration, vasculitis, fibrin exudation, thrombosis, and edema in cases of spinal cord injury from radiation (16). By virtue of lying within a vascular watershed region, the lower cervical and upper thoracic spinal cord have a more tenuous blood supply and may be more susceptible to radiation injury. Early symptoms of spinal cord radiation damage include sensory deficit, clumsiness, leg weakness, and Lhermitte’s syndrome. These symptoms occur within weeks of therapy and are often reversible. However, delayed radiation-induced myelopathy typically occurs more than 6 months after irradiation and is characterized by more profound weakness, numbness, spasticity, paresthesias, pain, and hyper-reflexia. In the current series, the latency between radiosurgery and the onset of spinal cord symptoms averaged 6.3 months and is similar to what has been described for delayed myelopathy after conventional radiotherapy. Because the presentation of radiation myelopathy mirrors myelopathy from other causes, alternative etiologies (such as tumor progression) must be excluded. MRI is of greatest help in distinguishing between these etiologies. For each patient reported here, the initial radiographic sign of radiation injury was an intramedullary increase in signal intensity on T2weighted MRI sequences, which is thought to correlate with spinal cord edema.

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Data from numerous studies shape our current understanding of the radiation dose tolerance for the spinal cord. Current estimates are that 45 Gy in 22 to 25 fractions yields an incidence of myelopathy of less than 0.2%. It is also suggested that a 5% incidence rate of radiation myelopathy lies between 57 and 61 Gy (2). Marcus and Million (10) have demonstrated that conventionally fractionated 45 Gy is on the flat part of the doseresponse curve such that any decrease in dose leads to a minimal decrement in the incidence of myelopathy. Unlike conventional radiotherapy, during which a full dose is delivered to both the spine and the spinal cord, the CyberKnife can deliver higher-dose hypofractionated radiation to the target region while relatively sparing the adjacent spinal cord. Thus, only portions of the spinal cord, rather than the entire spinal cord, were subjected to the prescription dose at the targeted spinal level. This reinforces the concept that there may be a partial volume effect, which has also been suggested using other LINAC-based radiosurgery techniques (14). The spinal cord dose limit using conventional radiotherapy fractions of 1.8 to 2 Gy and a total dose of 45 Gy is generally observed. This dose corresponds to a BED3 equal to 76 Gy. Even though the BED formula predicts this rather high spinal cord dose limit of 76 Gy, our fear of possible catastrophic spinal cord injury led us to observe a more conservative limit. Thus, we observed a single-session spinal cord dose limit of 8 to 10 Gy, or the equivalent of a BED3 of 29 Gy, if multifractions were delivered. On the basis of clinical experience with other neural structures such as the optic chiasm and optic nerve, this dose limit is widely believed to be safe. In an ad hoc and nonrandomized fashion, this constraint was gradually relaxed over the course of our several years of experience. With respect to the maximal spinal cord BED3, 3 of the 6 injured patients in this series were, in hindsight, clear outliers and regretfully treated with much larger than average doses. However, inexplicably, spinal injury occurred in the remaining 3 patients, even though only a small volume of spinal cord received the equivalent of 8 Gy in a single fraction and virtually no portion was treated to more than 10 Gy. Although genetic mutations were not tested in this study, it is possible that potential predisposing genetic factors may have been present that could explain these toxicities. For example, it has been suggested that germ line alterations in genes such as transforming growth factor β 1(TGβ1) and ataxia telangiectasia (ATM) may predict radiation-induced late effects (18). Animal studies support the notion of a dose volume, i.e., dose length, radiation effect in spinal cord (9). Available clinical data after radiation therapy, however, fail to support such a phenomenon. This fact may be attributable to the relatively large volume (or length) of spinal cord irradiated in conventional radiotherapy. Nevertheless, in a summary of dose volume effects, Emami et al. (5) determined that when one-third or the entire spinal cord was irradiated, the spinal cord radiation tolerance varied narrowly between 50 and 47 Gy, respectively. Despite the lack of evidence supporting a significant dose volume effect for the spinal cord, we

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attempted to minimize the amount of spinal cord treated above a BED of 29 Gy. In assessing the risk of radiation-induced myelopathy, other factors to consider are the effects of re-irradiation and systemic therapy. Particularly among patients treated for metastatic tumors, more than one- half of our current patients have received such previous irradiation. In the current series, the 2 previously irradiated patients had been treated more than 6 years before undergoing radiosurgery. In a recent review of 40 re-irradiated patients, myelopathy did not occur when BED2 for either course was 102 Gy or less (which approximates a BED3 of 85 Gy) or when the interval between courses was more than 2 months (11). In contrast, the 2 previously irradiated patients in the present series who developed spinal complications had received a BED3 of only 46 and 81 Gy, and the interval between courses of radiation was 70 to 80 months. Because some chemotherapy agents can potentiate the effects of radiation, we are cautious about concurrent chemotherapy. In the past few years, targeted antibody and antireceptor therapies have emerged. Two of the patients in this series had received vascular endothelial growth factor and epidermal growth factor receptor inhibitors within 3 months of the onset of myelopathy. These same patients were also among the more aggressively treated dose volume outliers. Therefore, the extent to which dose volume effects versus radiosensitization by these agents contributed to myelopathy remains unknown. Given the experience presented here with more than 1000 patients, among whom 6 (0.6%) developed injury, we conclude that radiation-induced myelopathy is an uncommon complication of spinal radiosurgery and that the key variables underlying this phenomenon remain, at best, partially elucidated. Similar to other efforts to understand the risks of myelopathy using hypofractionated dose strategies, we were unable to define clear factors (8). Although we attempted to use radiobiological estimates of the BED to guide us, it is unlikely that these formulae will ultimately prove to be useful in establishing the limits of spinal cord tolerance to hypofractionated radiation courses. Delayed myelopathy after radiosurgery is uncommon with the dose schedules used in this case series. Specific dosimetric factors contributing to this complication could not be identified in this small series. BED estimates did not clearly predict spinal cord tolerance to hypofractionated dose schedules. We recommend limiting the volume of spinal cord treated above an 8-Gy equivalent dose, because half of the complications occurred beyond this level.

CONCLUSION Hypofractionated radiosurgery is safe. On the basis of the data presented here, we suggest that caution be used when considering radiosurgery plans that expose more than approximately 1 cm3 of the spinal cord to a 8-Gy or higher dose equivalent. With a better understanding and future refinements in radiosurgical technique, it may be possible to reduce the risk of this dreaded complication.

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Disclosures Iris C. Gibbs, M.D., is a member of the Clinical Advisory Board of Accuray, Inc., the manufacturer of CyberKnife. John R. Adler, Jr., M.D., is a stockholder of Accuray, Inc. The other authors have no personal financial or institutional interest in any of the drugs, materials, or devices described in this article.

REFERENCES 1. Ahlbom HE: The results of radiotherapy of hypopharyngeal cancer at the Radiumhemmet, Stockholm. Acta Radiol 22:155–171, 1941. 2. Baumann M, Budach V, Appold S: Radiation tolerance of the human spinal cord [in German]. Strahlenther Onkol 170:131–139, 1994. 3. Boden G: Radiation myelitis of the cervical spinal cord. Br J Radiol 21:464– 469, 1948. 4. Dodd RL, Ryu MR, Kamnerdsupaphon P, Gibbs IC, Chang SD Jr, Adler JR Jr: CyberKnife radiosurgery for benign intradural extramedullary spinal tumors. Neurosurgery 58:674–685, 2006. 5. Emami B, Lyman J, Brown A, Coia L, Goitein M, Munzenrider JE, Shank B, Solin LJ, Wesson M: Tolerance of normal tissue to therapeutic irradiation. Int J Radiat Oncol Biol Phys 21:109–122, 1991. 6. Gerszten PC, Ozhasoglu C, Burton SA, Vogel WJ, Atkins BA, Kalnicki S, Welch WC: CyberKnife frameless stereotactic radiosurgery for spinal lesions: Clinical experience in 125 cases. Neurosurgery 55:89–99, 2004. 7. Hall EJ, Brenner DJ: The radiobiology of radiosurgery: Rationale for different treatment regimes for AVMs and malignancies. Int J Radiat Oncol Biol Phys 25:381–385, 1993. 8. Hatlevoll R, Høst H, Kaalhus O: Myelopathy following radiotherapy of bronchial carcinoma with large single fractions: A retrospective study. Int J Radiat Oncol Biol Phys 9:41–44, 1983.

9. Hopewell JW, Morris AD, Dixon-Brown A: The influence of field size on the late tolerance of the rat spinal cord to single doses of x rays. Br J Radiol 60:1099–1108, 1987. 10. 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. 11. Nieder C, Grosu AL, Andratschke NH, Molls M: Proposal of human spinal cord reirradiation dose based on collection of data from 40 patients. Int J Radiat Oncol Biol Phys 61:851–855, 2005. 12. Paddick I: A simple scoring ratio to index the conformity of radiosurgical treatment plans. Technical note. J Neurosurg 93 [Suppl 3]:219–222, 2000. 13. Rampling R, Symonds P: Radiation myelopathy. Curr Opin Neurol 11:627– 632, 1998. 14. Ryu S, Jin JY, Jin R, Rock J, Ajlouni M, Movsas B, Roseblum M, Kim JH: Partial volume tolerance of the spinal cord and complication of single-dose radiosurgery. Cancer 109:628–636, 2007. 15. 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. 16. Shaw E, Kline R, Gillin M, Souhami L, Hirschfeld A, Dinapoli R, Martin L; Radiation Therapy Oncology Group: Radiosurgery quality assurance guidelines. Int J Radiat Oncol Biol Phys 27:1231–1239, 1993. 17. Shimizu T, Saijo N: Common toxicity criteria: Version 2.0, an improved reference for grading the adverse reaction of cancer treatment [in Japanese]. Nippon Rinsho 61:937–942, 2003. 18. Travis EL: Genetic susceptibility to late normal tissue injury. Semin Radiat Oncol 17:149–155, 2007. 19. Trotti A, Colevas AD, Setser A, Rusch V, Jaques D, Budach V, Langer C, Murphy B, Cumberlin R, Coleman CN, Rubin P: CTCAE v3.0: Development of a comprehensive grading system for the adverse effects of cancer treatment. Semin Radiat Oncol 13:176–181, 2003.

IN-TRAINING LIAISONS The Congress of Neurological Surgeons exists for the purpose of promoting public welfare through the advancement of neurosurgery by a commitment to excellence in education and by a dedication to research and scientific knowledge. —Mission Statement Congress of Neurological Surgeons Inherent in this commitment is a critical charge to serve the needs of the in-training individuals. Considering the importance of this vital group within the neurosurgical community, the Journal has established a position within its board structure termed In-training Liaison. The individuals holding this position will act as spokespersons especially addressing the needs and concerns of individuals in in-training positions globally, as they relate to journal content and perspective. The current individuals holding this position are: Michael L. DiLuna, M.D., Ian F. Dunn, M.D., James B. Elder, M.D., and Daniel Hoh, M.D. Issues attendant to in-training matters should be conveyed to: Michael L. DiLuna, M.D. Department of Neurosurgery Yale University School of Medicine TMP 404 333 Cedar Street New Haven, CT 06510 Email: [email protected]

Ian F. Dunn, M.D. Department of Neurosurgery Brigham and Women’s Hospital/Children’s Hospital 75 Francis Street Boston, MA 02115 Email: [email protected]

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James B. Elder, M.D. Department of Neurological Surgery University of Southern California Keck School of Medicine 1200 N. State Street, Ste. 5046 Los Angeles, CA 90033 Email: [email protected]

Daniel Hoh, M.D. Department of Neurological Surgery University of Southern California Keck School of Medicine 1200 N. State Street, Ste. 5046 Los Angeles, CA 90033 Email: [email protected]

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