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Radiation Dose–Volume Effects in the Spinal Cord

2010; Elsevier BV; Volume: 76; Issue: 3 Linguagem: Inglês

10.1016/j.ijrobp.2009.04.095

1879-355X

John P. Kirkpatrick, Albert J. van der Kogel, Timothy E. Schultheiss,

Spine and Intervertebral Disc Pathology

Dose–volume data for myelopathy in humans treated with radiotherapy (RT) to the spine is reviewed, along with pertinent preclinical data. Using conventional fractionation of 1.8–2 Gy/fraction to the full-thickness cord, the estimated risk of myelopathy is <1% and <10% at 54 Gy and 61 Gy, respectively, with a calculated strong dependence on dose/fraction (α/β = 0.87 Gy.) Reirradiation data in animals and humans suggest partial repair of RT-induced subclinical damage becoming evident about 6 months post-RT and increasing over the next 2 years. Reports of myelopathy from stereotactic radiosurgery to spinal lesions appear rare (<1%) when the maximum spinal cord dose is limited to the equivalent of 13 Gy in a single fraction or 20 Gy in three fractions. However, long-term data are insufficient to calculate a dose–volume relationship for myelopathy when the partial cord is treated with a hypofractionated regimen. Dose–volume data for myelopathy in humans treated with radiotherapy (RT) to the spine is reviewed, along with pertinent preclinical data. Using conventional fractionation of 1.8–2 Gy/fraction to the full-thickness cord, the estimated risk of myelopathy is <1% and <10% at 54 Gy and 61 Gy, respectively, with a calculated strong dependence on dose/fraction (α/β = 0.87 Gy.) Reirradiation data in animals and humans suggest partial repair of RT-induced subclinical damage becoming evident about 6 months post-RT and increasing over the next 2 years. Reports of myelopathy from stereotactic radiosurgery to spinal lesions appear rare (<1%) when the maximum spinal cord dose is limited to the equivalent of 13 Gy in a single fraction or 20 Gy in three fractions. However, long-term data are insufficient to calculate a dose–volume relationship for myelopathy when the partial cord is treated with a hypofractionated regimen. The spinal cord consists of bundles of motor and sensory tracts, surrounded by the thecal sac, which is, in turn, encased by the spinal canal (1Goetz C. Textbook of clinical neurology.2nd ed. Saunders, Chicago, IL2003Google Scholar). Although the cord proper extends from the base of skull through the top of the lumbar spine, individual nerves continue down the spinal canal to the level of the pelvis. Portions of the spinal cord are often included in radiotherapy (RT) fields for treatment of malignancies involving the neck, thorax, abdomen, and pelvis. In addition, metastatic disease to the bony spine, often requiring RT, is encountered in ∼40% of all cancer patients (2Klimo Jr., P. Thompson C.J. Kestle J.R. et al.A meta-analysis of surgery versus conventional radiotherapy for the treatment of metastatic spinal epidural disease.Neuro Oncol. 2005; 7: 64-76Crossref PubMed Scopus (263) Google Scholar). Though rare, RT-induced spinal cord injury (i.e., myelopathy) can be severe, resulting in pain, paresthesias, sensory deficits, paralysis, Brown-Sequard syndrome, and bowel/bladder incontinence (3Schultheiss T.E. Kun L.E. Ang K.K. et al.Radiation response of the central nervous system.Int J Radiat Oncol Biol Phys. 1995; 31: 1093-1112Abstract Full Text PDF PubMed Scopus (365) Google Scholar). In this analysis, we consider three clinical scenarios for the development of myelopathy following: (1) de novo irradiation of the complete spinal cord cross-section via conventionally fractionated external beam RT, (2) reirradiation of the complete spinal cord cross-section after a previous course of conventional external beam RT, and (3) irradiation of a partial cross-section of the cord using high-dose/fraction stereotactic radiosurgery. Herein, myelopathy is defined as a Grade 2 or higher myelitis, per Common Terminology Criteria for Adverse Events v3.0 (4Cancer Therapy Evaluation Program, Common Terminology Criteria for Adverse Events, Version 3.0, DCTD, NCI, NIH, DHHS, March 31, 2003. Available online at: http://ctep.cancer.gov. Accessed August 31, 2008.Google Scholar). Asymptomatic changes in the cord detected radiographically or mild signs/symptoms such as Babinski's sign or L'Hermitte syndrome are not classified as myelopathy for purpose of this analysis. Thus, a diagnosis of myelopathy is based on the appearance of signs/symptoms of sensory or motor deficits, loss of function or pain, now frequently confirmed by magnetic resonance imaging. Radiation myelopathy rarely occurs less than 6 months after completion of radiotherapy and most cases appear within 3 years (5Abbatucci J.S. DeLozier T. Quint R. et al.Radiation myelopathy of the cervical spinal cord. Time, dose, and volume factors.Int J Radiat Oncol Biol Phys. 1978; 4: 239-248Abstract Full Text PDF PubMed Scopus (115) Google Scholar). In some situations, the question of recurrent tumor can confound the diagnosis of RT-induced myelopathy. Magnetic resonance imaging is useful in this regard with surgical resection/biopsy as indicated for diagnosis and, potentially, therapy. In conventional external beam RT, the field generally encompasses the entire circumference of the cord, vertebral body, and spinal nerve roots at the treated levels. Thus, precise organ definition is not critical in conventional RT apart from appropriately identifying the level of the involved cord. Delineation of the cord in body radiosurgery is unsettled (6Saghal A. Larson D. Chang E.L. Stereotactic body radiosurgery for spinal metastases: A critical review.Int J Radiat Oncol Biol Phys. 2008; 71: 652-665Abstract Full Text Full Text PDF PubMed Scopus (245) Google Scholar) with various studies contouring the critical organ in the axial plane as the spinal cord, the spinal cord +2–3 mm, the thecal sac and its contents, or the spinal canal. As the high-dose regions may extend superiorly and inferiorly to the target, several studies extend the critical organ volume above and below the target volume (e.g., 6 mm inferiorly and superiorly in the case of Henry Ford Hospital) (7Ryu S. Jin J.Y. Jin R. et al.Partial volume tolerance of the spinal cord and complications of single-dose radiosurgery.Cancer. 2007; 109: 628-636Crossref PubMed Scopus (195) Google Scholar). A large number of small-animal studies have explored spinal cord tolerance to de novo radiation and reirradiation, including time-dependent repair of such damage. Several reports suggest regional differences in radiosensitivity across the spinal cord (8Philippens M.E. Pop L.A. Visser A.G. et al.Dose-volume effects in rat thoracolumbar spinal cord: The effects of nonuniform dose distribution.Int J Radiat Oncol Biol Phys. 2007; 69: 204-213Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar, 9Coderre J.A. Morris G.M. Micca P.L. et al.Late effects of radiation on the central nervous system: Role of vascular endothelial damage and glial stem cell survival.Radiat Res. 2006; 166: 495-503Crossref PubMed Scopus (133) Google Scholar). The clinical endpoint in most studies is paralysis, with the spinal cord showing nonspecific white matter necrosis. The pathogenesis of injury is generally believed to be primarily from vascular/endothelial damage, glial cell injury, or both (3Schultheiss T.E. Kun L.E. Ang K.K. et al.Radiation response of the central nervous system.Int J Radiat Oncol Biol Phys. 1995; 31: 1093-1112Abstract Full Text PDF PubMed Scopus (365) Google Scholar, 9Coderre J.A. Morris G.M. Micca P.L. et al.Late effects of radiation on the central nervous system: Role of vascular endothelial damage and glial stem cell survival.Radiat Res. 2006; 166: 495-503Crossref PubMed Scopus (133) Google Scholar). Using focused protons, Bijl demonstrated large regional differences in rat spinal cord radiosensitivity (10Bijl H.P. van Luijk P. Coppes R.P. et al.Dose-volume effects in the rat cervical spinal cord after proton irradiation.Int J Radiat Oncol Biol Phys. 2002; 52: 205-211Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar, 11Bijl H.P. van Luijk P. Coppes R.P. et al.Regional differences in radiosensitivity across the rat cervical spinal cord.Int J Radiat Oncol Biol Phys. 2005; 61: 543-551Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar). There was a rightward shift in the dose–response curve from 21 Gy (ED50) with full thickness irradiation vs. 29–33 Gy for lateral cord treatment (wide and narrow geometry, respectively), and 72 Gy when only the central portion of the cord was treated. White matter necrosis was observed in all paralyzed rats, with none seen in animals not exhibiting paralysis. No damage was observed in central grey matter for doses up to 80 Gy. The differences in central vs. peripheral response were attributed to vascular density differences in these regions, with a potential role for differential oligodendrocyte progenitor cell distribution. However, an alternative explanation may be functional differences in the cord white matter regions irradiated, especially given the clinical endpoint of paralysis, which would not be expected if sensory tracts were preferentially irradiated. No similar published reports are available in higher order species, making application of these findings to highly conformal radiotherapy techniques, such as stereotactic body RT (SBRT) or intensity-modulated proton therapy, difficult. Animal studies support a time-dependent model of repair for radiation damage to the spinal cord (12Ang K.K. van der Kogel A.J. van der Schueren E. et al.The effect of small radiation doses on the rat spinal cord: The concept of partial tolerance.Int J Radiat Oncol Biol Phys. 1983; 9: 1487-1491Abstract Full Text PDF PubMed Scopus (36) Google Scholar, 13Ang K.K. Price R.E. Stephens L.C. et al.The tolerance of primate spinal cord to re-irradiation.Int J Radiat Oncol Biol Phys. 1993; 25: 459-464Abstract Full Text PDF PubMed Scopus (126) Google Scholar, 14Ang K.K. Jiang G.L. Feng Y. et al.Extent and kinetics of recovery of occult spinal cord injury.Int J Radiat Oncol Biol Phys. 2001; 50: 1013-1020Abstract Full Text Full Text PDF PubMed Scopus (156) Google Scholar, 15Knowles J.F. The radiosensitivity of the guinea-pig spinal cord to X-rays: The effect of retreatment at one year and the effect of age at the time of irradiation.Int J Radiat Biol Relat Stud Phys Chem Med. 1983; 44: 433-442Crossref PubMed Scopus (43) Google Scholar, 16Ruifrok A.C. Kleiboer B.J. van der Kogel A.J. Repair kinetics of radiation damage in the developing rat cervical spinal cord.Int J Radiat Biol. 1993; 63: 501-508Crossref PubMed Scopus (12) Google Scholar, 17Wong C.S. Hao Y. Long-term recovery kinetics of radiation damage in rat spinal cord.Int J Radiat Oncol Biol Phys. 1997; 37: 171-179Abstract Full Text PDF PubMed Scopus (46) Google Scholar). For example, Ang (13Ang K.K. Price R.E. Stephens L.C. et al.The tolerance of primate spinal cord to re-irradiation.Int J Radiat Oncol Biol Phys. 1993; 25: 459-464Abstract Full Text PDF PubMed Scopus (126) Google Scholar) treated the thoracic and cervical spines of Rhesus monkeys to 44 Gy, and then reirradiated these animals with an additional 57 Gy at 1–2 years, or 66 Gy at 2–3 years, yielding aggregate doses of 101 and 110 Gy, respectively. The study endpoint was lower extremity weakness or balance disturbances at 2.5 years after reirradiation. Of 45 animals evaluated at the end of the observation period, 4 developed endpoint symptoms. A reirradiation tolerance model developed by combining these data with those of a prior study of single-dose tolerance in the same animal model (14Ang K.K. Jiang G.L. Feng Y. et al.Extent and kinetics of recovery of occult spinal cord injury.Int J Radiat Oncol Biol Phys. 2001; 50: 1013-1020Abstract Full Text Full Text PDF PubMed Scopus (156) Google Scholar) resulted in an estimated recovery of 34 Gy (76%), 38 Gy (85%), and 45 Gy (101%) at 1, 2, and 3 years, respectively. Under conservative assumptions, an estimated overall recovery of 26 Gy (61%) was calculated. A recent analysis used published reports of radiation myelopathy in 335 and 1,946 patients receiving radiotherapy to their cervical and thoracic spines, respectively (18Schultheiss T.E. The radiation dose-response of the human spinal cord.Int J Radiat Oncol Biol Phys. 2008; 71: 1455-1459Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar). Although a few of these patients received relatively high doses/fraction, none were treated using stereotactic techniques to exclude a portion of the circumference of the cord. These data are summarized in Table 1, Table 2. Note that the dose to the cord is the prescribed dose reported in those studies; typically, dosimetric data were not available to calculate the true cord dose. An α/β ratio of 0.87 Gy was estimated from the data and used to calculate the 2-Gy dose per fraction equivalent total dose for each regimen, as described in the following section. Note that this α/β ratio is less than the values of 2–4 Gy frequently encountered in the literature and predicts a more severe effect at larger doses per fraction.Table 1Summary of published reports of cervical spinal cord myelopathy in patients receiving conventional radiotherapy 18Schultheiss T.E. The radiation dose-response of the human spinal cord.Int J Radiat Oncol Biol Phys. 2008; 71: 1455-1459Abstract Full Text Full Text PDF PubMed Scopus (116) Google ScholarInstitutionDose (Gy)Dose/fraction (Gy)Cases of myelopathy/ total number of patientsProbability of myelopathy∗Calculated using the percentage of patients experiencing myelopathy corrected for overall survival as a function of time by the method in (18).2-Gy dose equivalent†Calculated using α/β = 0.87 Gy (18).Wake Forest 19McCunniff A.J. Lliang M.J. Radiation tolerance of the cervical spinal cord.Int J Radiat Oncol Biol Phys. 1989; 16: 675-678Abstract Full Text PDF PubMed Scopus (87) Google Scholar6021/120.09060.0651.630/240.00056.6Caen 5Abbatucci J.S. DeLozier T. Quint R. et al.Radiation myelopathy of the cervical spinal cord. Time, dose, and volume factors.Int J Radiat Oncol Biol Phys. 1978; 4: 239-248Abstract Full Text PDF PubMed Scopus (115) Google Scholar5437/150.62272.8Brookhaven 20Atkins H.L. Tretter P. Time-dose considerations in radiation myelopathy.Acta Radiol Ther Phys Biol Gy. 1966; 5: 79-94Crossref PubMed Scopus (49) Google Scholar199.54/130.43768.6Florida 21Marcus Jr., R.B. Million R.R. The incidence of myelitis after irradiation of the cervical spinal cord.Int J Radiat Oncol Biol Phys. 1990; 93: 3-8Abstract Full Text PDF Scopus (187) Google Scholar47.51.90/2110.00045.052.51.90/220.00049.86022/190.11860.0Yugoslavia 22Jeremic B.J. Djuric L. Mijatovic L. Incidence of radiation myelitis of the cervical spinal cord at doses of 5500 cGy or greater.Cancer. 1991; 68: 2138-2141Crossref PubMed Scopus (49) Google Scholar651.630/190.00056.6∗ Calculated using the percentage of patients experiencing myelopathy corrected for overall survival as a function of time by the method in 18Schultheiss T.E. The radiation dose-response of the human spinal cord.Int J Radiat Oncol Biol Phys. 2008; 71: 1455-1459Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar.† Calculated using α/β = 0.87 Gy 18Schultheiss T.E. The radiation dose-response of the human spinal cord.Int J Radiat Oncol Biol Phys. 2008; 71: 1455-1459Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar. Open table in a new tab Table 2Summary of published reports of thoracic spinal cord myelopathy in patients receiving conventional radiotherapy 18Schultheiss T.E. The radiation dose-response of the human spinal cord.Int J Radiat Oncol Biol Phys. 2008; 71: 1455-1459Abstract Full Text Full Text PDF PubMed Scopus (116) Google ScholarInstitutionDose (Gy)Dose/fraction (Gy)Cases of myelopathy/total number of patientsProbability of myelopathy∗Calculated using the percentage of patients experiencing myelopathy corrected for overall survival as a function of time by the method in (18).2-Gy dose equivalent†Calculated using α/β = 0.87 Gy (18).MCV 23Hazra T.A. Chandrasekaran M.S. Colman M. et al.Survival in carcinoma of the lung after a split course of radiotherapy.Br J Radiol. 1974; 47: 464-466Crossref PubMed Scopus (23) Google Scholar4531/160.09360.7MGH 24Choi N.C.H. Grillo H.C. Gardiello M. et al.Basis for new strategies in postoperative radiotherapy of bronchogenic carcinoma.Int J Radiat Oncol Biol Phys. 1980; 6: 31-35Abstract Full Text PDF PubMed Scopus (119) Google Scholar4530/750.00060.7Abramson 25Abramson N. Cavanaugh P.J. Short-course radiation therapy in carcinoma of the lung.Radiology. 1973; 108: 685-687PubMed Google Scholar4044/2710.06367.9MUSC 26Fitzgerald R.H. Marks R.D. Wallace K.M. Chronic radiation myelitis.Radiology. 1982; 144: 609-612PubMed Google Scholar4046/450.33267.9Leicester 27Madden F.J.F. English J.S.C. Moore A.K. et al.Split course radiation in inoperable carcinoma of the bronchus.Eur J Cancer. 1979; 15: 1175-1177Abstract Full Text PDF PubMed Scopus (7) Google Scholar4041/430.28467.9Iowa 28Guthrie R.T. Ptacek J.J. Hjass A.C. Comparative analysis of two regimens of split course radiation in carcinoma of the lung.Am J Roentgenol. 1973; 117: 605-608Crossref Scopus (25) Google Scholar4040/420.00067.9Mt. Vernon 29Dische S. Warburton M.F. Sanders M.I. Radiation myelitis and survival in the radiotherapy of lung cancer.Int J Radiat Oncol Biol Phys. 1988; 15: 75-81Abstract Full Text PDF PubMed Scopus (38) Google Scholar34.45.713/1450.27878.9Norway 30Hatlevoll R. Host H. Kaalhus O. Myelopathy following radiotherapy of bronchial carcinoma with large single fractions: A retrospective study.Int J Radiat Oncol Biol Phys. 1983; 9: 41-44Abstract Full Text PDF PubMed Scopus (50) Google Scholar383×6 Gy +5×4 Gy8/1570.19677.0383×6 Gy +3×4 Gy +2×2 Gy9/2300.15167.4Berlin 31Eichhorn H.J. Lessel A. Rotte K.H. Einfuss verschiedener Bestrahlungsrhythmen auf Tumor-und Normalgewebe in vivo.Strahlentheraphie. 1972; 146: 614-629Google Scholar66.22.458/1420.25676.5Virginia 32Scruggs H. El-Mahdi A. Marks Jr., R.D. et al.The results of split-course radiation therapy in cancer of the lung.Am J Roentgenol Radium Ther Nucl Med. 1974; 121: 754-760Crossref PubMed Scopus (15) Google Scholar405 x 4 Gy +8 x 2.5 Gy2/2480.02857.4UK NIRC 33Macbeth F.R. Bolger J.J. Hopwood P. et al.Randomized trial of palliative two-fraction versus more intensive 13-fraction radiotherapy for patients with inoperable non-small cell lung cancer and good performance status. Medical Research Council Lung Cancer Working Party.Clin Oncol (R Coll Radiol). 1996; 8 ([see comment]): 167-175Abstract Full Text PDF PubMed Scopus (192) Google Scholar, 34Macbeth F.R. Wheldon T.E. Girling D.J. et al.Radiation myelopathy: Estimates of risk in 1048 patients in three randomized trials of palliative radiotherapy for non-small cell lung cancer. The Medical Research Council Lung Cancer Working Party.Clin Oncol (R Coll Radiol). 1996; 8: 176-181Abstract Full Text PDF PubMed Scopus (94) Google Scholar18.49.23/5240.03264.539.83.062/1530.06254.5∗ Calculated using the percentage of patients experiencing myelopathy corrected for overall survival as a function of time by the method in 18Schultheiss T.E. The radiation dose-response of the human spinal cord.Int J Radiat Oncol Biol Phys. 2008; 71: 1455-1459Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar.† Calculated using α/β = 0.87 Gy 18Schultheiss T.E. The radiation dose-response of the human spinal cord.Int J Radiat Oncol Biol Phys. 2008; 71: 1455-1459Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar. Open table in a new tab In evaluating reirradiation of the spinal cord, one must not only consider the dose regimen for each course and the volume and region (re)irradiated but also the time interval between the courses of RT (35Nieder C. Grosu A.L. Andratschke N.H. et al.Proposal of human spinal cord reirradiation dose based on collection of data from 40 patients.Int J Radiat Oncol Biol Phys. 2005; 61: 851-855Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar). Table 3 summarizes published reports involving reirradiation of the spinal cord using both conventional, full-circumference external beam RT and SBRT. For purposes of comparing different regimens, an α/β of 3 Gy was used to calculate the biologically equivalent dose in Gy3 and both α/β values of 1 and 3 Gy were employed to calculate the 2-Gy per fraction equivalent dose. In all of these studies, the median interval between courses was at least 6 months and only a small number of cases were treated at intervals less than 6 months. Note that few cases of myelopathy are reported despite large cumulative doses, with essentially no cases of myelopathy observed for cumulative doses ≤60 Gy in 2-Gy equivalent doses. These data are consistent with the observations of post-RT repair observed in the animal models.Table 3Summary of published reports involving reirradiation of the spinal cordInstitutionCases of myelopathy/total patientsMedian F/U (months)BED, initial course, (Gy3) Median (Range)BED, reirradiation (Gy3) Median (range)Interval between courses (months) Median (range)Total BED (Gy3) Median (range)2- Gy dose equivalent, α/β = 3 Gy Median (range)2- Gy dose equivalent, α/β = 1 Gy Median (range)MSK 36Wright J.L. Lovelock D.M. Bilsky M.H. et al.Clinical outcomes after reirradiation of paraspinal tumors.Am J Clin Oncol. 2006; 29: 495-502Crossref PubMed Scopus (25) Google Scholar0/37860 (10–101)16 5–5019 (2–125)79 (21–117)47 (13–70)51 (8–100)VU 37Langendijk J.A. Kasperts N. Leemans C.R. et al.A phase II study of primary reirradiation in squamous cell carcinoma of head and neck.Radiother Oncol. 2006; 78: 306-312Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar0/34———<100<60 3–9(40–56)(18–35)(8–20)(58–91)(35–57)(28–51)VU 44Sminia P. Oldenburger F. Slotman B.J. et al.Re-irradiation of the human spinal cord.Strahlenther Onkol. 2002; 178: 453-456Crossref PubMed Scopus (26) Google Scholar0/856 (29–78)42 (36–83)30 (4–152)106 (65–159)64 (39–96)69 (48–93)Brescia 45Magrini S.M. Biti G.P. de Scisciolo G. et al.Neurological damage in patients irradiated twice on the spinal cord: A morphologic and electrophysiological study.Radiother Oncol. 1990; 17: 209-218Abstract Full Text PDF PubMed Scopus (15) Google Scholar0/516847 (32–47)55 (33–67)24 (12–36)94 (80–113)57 (48–68)56 (47–67)Hamburg 46Rades D. Stalpers L.J.A. Veninga T. et al.Evaluation of five radiation schedules and prognostic factors for metastatic spinal cord compression.J Clin Oncol. 2005; 23: 3366-3375Crossref PubMed Scopus (270) Google Scholar0/621229 (29–47)29 (29–47)6 (2–40)69 (59–77)41 (35–46)53 (48–57)Melbourne 47Jackson M.A. Ball D.L. Palliative retreatment of locally recurrent lung cancer after radical radiotherapy.Med J Aust. 1987; 147: 391-394PubMed Google Scholar0/615All 7336 (32–39)15106 (103–109)63 (62–65)66 (64–68)Princess Margaret 48Wong C.S. Van Dyk J. Milosevic M. et al.Radiation myelopathy following single courses of radiotherapy and retreatment.Int J Radiat Oncol Biol Phys. 1994; 30: 575-581Abstract Full Text PDF PubMed Scopus (117) Google Scholar Cases with myelopathy11/–1172 (28–96)42 (14–86)11 (2–71)115 (100–138)69 (60–83)80 (65–94)Stereotactic body radiotherapyKorea 49Gwak H.-S. Yoo H.-J. Youn S.-M. et al.Hypofractionated stereotactic radiotherapy for skull base and upper cervical chordoma and chondrosarcoma: Preliminary results.Stereotact Funct Neurosurg. 2005; 83: 233-243Crossref PubMed Scopus (43) Google Scholar Case with myelopathy No myelopathy1/31224(60–81)8160, 81(64–154)15464, 90(18–120)1854, 120(145–235)235145, 150(87–141)14187, 90(98–179)17998,114∗ Overall survival.† One patient received two courses of reirradiation, 1 received three courses. Open table in a new tab Published reports of radiation myelopathy from SBRT to the spine are summarized in Table 4. These studies include de novo RT alone, reirradiation alone, and combination of the two (mixed series.)Table 4Summary of 9 published reports of spinal cord doses and myelopathy in patients receiving stereotactic radiosurgeryInstitution (ref.)Cases of myelopathy/total patientsTotal dose (Gy)Dose/fraction (Gy)Dose to cord (Gy)BED to cord (Gy3)Proportion of patients previously irradiated to involved segment of spineStanford and Pittsburgh 50Gibbs I.C. Patil I. Gerszten P.C. et al.Delayed radiation-induced myelopathy after spinal radiosurgery.Neurosurg. 2009; 64: A67-A72Crossref PubMed Scopus (117) Google Scholar6/107512.5–255–25Dmax: 3.6–30Range: 24–141 Gy3>55%2512.5Dmax: 26.2Dmax: 1412010Dmax: 19.2Dmax: 812110.5Dmax: 13.9Dmax: 46248Dmax: 29.9Dmax: 129202Dmax: 8.5Dmax: 332020Dmax: 10Dmax: 43Henry Ford 7Ryu S. Jin J.Y. Jin R. et al.Partial volume tolerance of the spinal cord and complications of single-dose radiosurgery.Cancer. 2007; 109: 628-636Crossref PubMed Scopus (195) Google Scholar1/86∗Patients surviving at least 1 year.<10–18<10–18Mean ± SDDmax: 12.2 ± 2.5D1: 10.7 ± 2.3D10: 8.6 2.1MaximumDmax: 19.2D1: 15.8D10: 13Mean ± SDDmax: 62 ± 4.6D1: 49 ± 4.1D10: 33 ± 3.6MaximumDmax: 142D1: 99D10: 690%18†Results for subset of 39 lesions treated at Henry Ford Hospital with a single 18-Gy fraction.18Mean ± SDDmax: 13.8 ± 2.2D1: 12.1 ± 1.9D10: 9.8 ± 1.5Mean ± SDDmax: 77 ± 3.8D1: 61 ± 3.1D10: 42 ± 2.31616Dmax:14.8D1: 13.0D10: 9.6Dmax:88D1:69D10: 40Korea 49Gwak H.-S. Yoo H.-J. Youn S.-M. et al.Hypofractionated stereotactic radiotherapy for skull base and upper cervical chordoma and chondrosarcoma: Preliminary results.Stereotact Funct Neurosurg. 2005; 83: 233-243Crossref PubMed Scopus (43) Google Scholar2/921–443–5MedianDmax:32.9D25:11.0RangeDmax: 11–37D25: 1.2–24MedianDmax:106D25:21RangeDmax: 19–172D25: 1–8833%3010Dmax: 35.2D25: 15.5Dmax:172D25: 423311Dmax: 32.9 D25: 24.015388NYMC 51Benzil D.L. Saboori M. Mogilner A.Y. et al.Safety and efficacy of stereotactic radiosurgery for tumors of the spine.J Neurosurg. 2004; 101: 413-418PubMed Google Scholar‡For the NYMC data (51), the cord dose was calculated assuming that the total dose was delivered in two fractions. Although the cord dose for the patients developing myelopathy were not given in the paper, the total BED to the tumor for the 3 patients experiencing myelopathy was 53.3, 60, and ∼167 Gy3 vs. <50 Gy3 for patients without myelopathy.3/31Median: 10Median: 5Median: 6.012Unknown100501212205UCSF 52Sahgal A. Choua D. Amesa C. et al.Proximity of spinous/paraspinous radiosurgery metastatic targets to the spinal cord versus risk of local failure.Int J Radiat Oncol Biol Phys. 2007; 69: S243Abstract Full Text Full Text PDF Google Scholar0/38248MedianD0.1cc: 10.5D1cc: 7.4MedianD0.1cc: 23D1cc: 1462%UCSF 53Sahgal A. Chou D. Ames C. et al.Image-guided robotic stereotactic body radiotherapy for benign spinal tumors: The University of California San Francisco preliminary experience.Technol Cancer Res Treat. 2007; 6: 595-604PubMed Google Scholar0/16217MedianDmax: 20.9D0.1cc: 16.6D1cc: 13.8RangeDmax: 4.3–23D0.1cc: 3.4–22D1cc: 2.8–19MedianD0.1cc: 61D1cc: 22RangeD0.1cc: 7–76D1cc: 6–546%MDACC 54Chang E.L. Shiu A.S. Mendel E. et al.Phase I/II study of stereotactic body radiotherapy for spinal metastasis and its pattern of failure.J Neurosurg Spine. 2007; 7: 151-160Crossref PubMed Scopus (344) Google Scholar0/6330 patients: 3033 patients: 2730 patients: 633 patients: 930 patients: <1033 patients:<930 patients: <16.733 patients: <1856%Pittsburgh 55Gerszten P.C. Burton S.A. Welch W.C. et al.Single-fraction radiosurgery for the treatment of spinal breast metastases.Cancer. 2005; 104: 2244-2254Crossref PubMed Scopus (101) Google Scholar0/501919MeanDmax: 10RangeDmax: 6.5–13MeanDmax: 21RangeDmax: 11–3296%Duke 56Nelson J.W. Yoo D.S. Wang Z. et al.Stereotactic body radiotherapy for lesions of the spine and paraspinal regions.Int J Radiat Oncol Biol Phys. 2009; 73: 1369-1375Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar0/32Median:18Median: 7Mean ± SDDmax: 14.4±2.3D1: 13.1±2.2D10: 11.5±2.1MaximumDmax: 19.2D1: 17.4D10: 15.2Mean ± SDDmax: 46.0±13.2D1: 39.0±10.8D10: 31.2±8.1MaximumDmax: 78.3D1: 59.1D10: 46.558%All patients within that institutional series are shown in normal font; myelopathy cases shown in bold italics.∗ Patients surviving at least 1 year.† Results for subset of 39 lesions treated at Henry Ford Hospital with a single 18-Gy fraction.‡ For the NYMC data 51Benzil D.L. Saboori M.