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Radiation Dose–Volume Effects in the Spinal Cord

      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.

      Clinical Significance

      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 (
      • Goetz C.
      Textbook of clinical neurology.
      ). 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 (
      • Klimo 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.
      ). 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 (
      • Schultheiss T.E.
      • Kun L.E.
      • Ang K.K.
      • et al.
      Radiation response of the central nervous system.
      ).
      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.

      Endpoints

      Herein, myelopathy is defined as a Grade 2 or higher myelitis, per Common Terminology Criteria for Adverse Events v3.0 (

      Cancer 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.

      ). 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 (
      • Abbatucci J.S.
      • DeLozier T.
      • Quint R.
      • et al.
      Radiation myelopathy of the cervical spinal cord. Time, dose, and volume factors.
      ).
      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.

      Challenges Defining Volumes

      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 (
      • Saghal A.
      • Larson D.
      • Chang E.L.
      Stereotactic body radiosurgery for spinal metastases: A critical review.
      ) 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) (
      • Ryu S.
      • Jin J.Y.
      • Jin R.
      • et al.
      Partial volume tolerance of the spinal cord and complications of single-dose radiosurgery.
      ).

      Review of Dose–Volume Data

       Preclinical studies

      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 (
      • Philippens M.E.
      • Pop L.A.
      • Visser A.G.
      • et al.
      Dose-volume effects in rat thoracolumbar spinal cord: The effects of nonuniform dose distribution.
      ,
      • Coderre 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.
      ). 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 (
      • Schultheiss T.E.
      • Kun L.E.
      • Ang K.K.
      • et al.
      Radiation response of the central nervous system.
      ,
      • Coderre 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.
      ). Using focused protons, Bijl demonstrated large regional differences in rat spinal cord radiosensitivity (
      • Bijl H.P.
      • van Luijk P.
      • Coppes R.P.
      • et al.
      Dose-volume effects in the rat cervical spinal cord after proton irradiation.
      ,
      • Bijl H.P.
      • van Luijk P.
      • Coppes R.P.
      • et al.
      Regional differences in radiosensitivity across the rat cervical spinal cord.
      ). 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 (
      • Ang 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.
      ,
      • Ang K.K.
      • Price R.E.
      • Stephens L.C.
      • et al.
      The tolerance of primate spinal cord to re-irradiation.
      ,
      • Ang K.K.
      • Jiang G.L.
      • Feng Y.
      • et al.
      Extent and kinetics of recovery of occult spinal cord injury.
      ,
      • Knowles 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.
      ,
      • Ruifrok A.C.
      • Kleiboer B.J.
      • van der Kogel A.J.
      Repair kinetics of radiation damage in the developing rat cervical spinal cord.
      ,
      • Wong C.S.
      • Hao Y.
      Long-term recovery kinetics of radiation damage in rat spinal cord.
      ). For example, Ang (
      • Ang K.K.
      • Price R.E.
      • Stephens L.C.
      • et al.
      The tolerance of primate spinal cord to re-irradiation.
      ) 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 (
      • Ang K.K.
      • Jiang G.L.
      • Feng Y.
      • et al.
      Extent and kinetics of recovery of occult spinal cord injury.
      ) 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.

       De novo irradiation—conventional radiotherapy in humans

      A recent analysis used published reports of radiation myelopathy in 335 and 1,946 patients receiving radiotherapy to their cervical and thoracic spines, respectively (
      • Schultheiss T.E.
      The radiation dose-response of the human spinal cord.
      ). 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
      • Schultheiss T.E.
      The radiation dose-response of the human spinal cord.
      InstitutionDose (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
      • McCunniff A.J.
      • Lliang M.J.
      Radiation tolerance of the cervical spinal cord.
      6021/120.09060.0
      651.630/240.00056.6
      Caen
      • Abbatucci J.S.
      • DeLozier T.
      • Quint R.
      • et al.
      Radiation myelopathy of the cervical spinal cord. Time, dose, and volume factors.
      5437/150.62272.8
      Brookhaven
      • Atkins H.L.
      • Tretter P.
      Time-dose considerations in radiation myelopathy.
      199.54/130.43768.6
      Florida
      • Marcus Jr., R.B.
      • Million R.R.
      The incidence of myelitis after irradiation of the cervical spinal cord.
      47.51.90/2110.00045.0
      52.51.90/220.00049.8
      6022/190.11860.0
      Yugoslavia
      • Jeremic B.J.
      • Djuric L.
      • Mijatovic L.
      Incidence of radiation myelitis of the cervical spinal cord at doses of 5500 cGy or greater.
      651.630/190.00056.6
      Calculated using the percentage of patients experiencing myelopathy corrected for overall survival as a function of time by the method in
      • Schultheiss T.E.
      The radiation dose-response of the human spinal cord.
      .
      Calculated using α/β = 0.87 Gy
      • Schultheiss T.E.
      The radiation dose-response of the human spinal cord.
      .
      Table 2Summary of published reports of thoracic spinal cord myelopathy in patients receiving conventional radiotherapy
      • Schultheiss T.E.
      The radiation dose-response of the human spinal cord.
      InstitutionDose (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
      • Hazra T.A.
      • Chandrasekaran M.S.
      • Colman M.
      • et al.
      Survival in carcinoma of the lung after a split course of radiotherapy.
      4531/160.09360.7
      MGH
      • Choi N.C.H.
      • Grillo H.C.
      • Gardiello M.
      • et al.
      Basis for new strategies in postoperative radiotherapy of bronchogenic carcinoma.
      4530/750.00060.7
      Abramson
      • Abramson N.
      • Cavanaugh P.J.
      Short-course radiation therapy in carcinoma of the lung.
      4044/2710.06367.9
      MUSC
      • Fitzgerald R.H.
      • Marks R.D.
      • Wallace K.M.
      Chronic radiation myelitis.
      4046/450.33267.9
      Leicester
      • Madden F.J.F.
      • English J.S.C.
      • Moore A.K.
      • et al.
      Split course radiation in inoperable carcinoma of the bronchus.
      4041/430.28467.9
      Iowa
      • Guthrie R.T.
      • Ptacek J.J.
      • Hjass A.C.
      Comparative analysis of two regimens of split course radiation in carcinoma of the lung.
      4040/420.00067.9
      Mt. Vernon
      • Dische S.
      • Warburton M.F.
      • Sanders M.I.
      Radiation myelitis and survival in the radiotherapy of lung cancer.
      34.45.713/1450.27878.9
      Norway
      • Hatlevoll R.
      • Host H.
      • Kaalhus O.
      Myelopathy following radiotherapy of bronchial carcinoma with large single fractions: A retrospective study.
      383×6 Gy +

      5×4 Gy
      8/1570.19677.0
      383×6 Gy +

      3×4 Gy +

      2×2 Gy
      9/2300.15167.4
      Berlin
      • Eichhorn H.J.
      • Lessel A.
      • Rotte K.H.
      Einfuss verschiedener Bestrahlungsrhythmen auf Tumor-und Normalgewebe in vivo.
      66.22.458/1420.25676.5
      Virginia
      • Scruggs H.
      • El-Mahdi A.
      • Marks Jr., R.D.
      • et al.
      The results of split-course radiation therapy in cancer of the lung.
      405 x 4 Gy +

      8 x 2.5 Gy
      2/2480.02857.4
      UK NIRC
      • Macbeth 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.
      ,
      • Macbeth 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.
      18.49.23/5240.03264.5
      39.83.062/1530.06254.5
      Calculated using the percentage of patients experiencing myelopathy corrected for overall survival as a function of time by the method in
      • Schultheiss T.E.
      The radiation dose-response of the human spinal cord.
      .
      Calculated using α/β = 0.87 Gy
      • Schultheiss T.E.
      The radiation dose-response of the human spinal cord.
      .

       Reirradiation of the spinal cord

      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 (
      • Nieder C.
      • Grosu A.L.
      • Andratschke N.H.
      • et al.
      Proposal of human spinal cord reirradiation dose based on collection of data from 40 patients.
      ). 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 cord
      InstitutionCases 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
      • Wright J.L.
      • Lovelock D.M.
      • Bilsky M.H.
      • et al.
      Clinical outcomes after reirradiation of paraspinal tumors.
      0/37860 (10–101)16 5–5019 (2–125)79 (21–117)47 (13–70)51 (8–100)
      VU
      • Langendijk J.A.
      • Kasperts N.
      • Leemans C.R.
      • et al.
      A phase II study of primary reirradiation in squamous cell carcinoma of head and neck.
      0/34<100<60<60
      Munich
      • Grosu A.L.
      • Andratschke N.
      • Nieder C.
      • et al.
      Retreatment of the spinal cord with palliative radiotherapy.
      ,
      • Nieder C.
      • Grosu A.L.
      • Andratschke N.H.
      • et al.
      Update of human spinal cord reirradiation tolerance based on additional data from 38 patients.
      0/153070 (34–83)50 (38–83)30 (6–96)115 (91–166)69 (54–100)70 (48–107)
      Mayo
      • Schiff D.
      • Shaw E.G.
      • Cascino T.L.
      Outcome after spinal reirradiation for malignant epidural spinal cord compression.


       Cases with myelopathy
      4/54

      4
      4
      Overall survival.
      60

      All 60
      37

      73
      One patient received two courses of reirradiation, 1 received three courses.
      (29–115)
      10 (1–51)

      9 (5–21)
      97

      133 (109–175)
      58

      80 (65–105)
      62

      83 (69–89)
      Henry Ford
      • Ryu S.
      • Gorty S.
      • Kazee A.M.
      • et al.
      Reirradiation of human cervical spinal cord.
      0/16075721441478886
      UCI
      • Kuo J.V.
      • Cabebe E.
      • Al-Ghazi M.
      • et al.
      Intensity-modulated radiation therapy for the spine at the University of California, Irvine.
      0/187542371177067
      Ontario
      • Bauman G.S.
      • Sneed P.K.
      • Wara W.M.
      • et al.
      Reirradiation of primary CNS tumors.
      0/2>3–9(40–56)(18–35)(8–20)(58–91)(35–57)(28–51)
      VU
      • Sminia P.
      • Oldenburger F.
      • Slotman B.J.
      • et al.
      Re-irradiation of the human spinal cord.
      0/856 (29–78)42 (36–83)30 (4–152)106 (65–159)64 (39–96)69 (48–93)
      Brescia
      • Magrini 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.
      0/516847 (32–47)55 (33–67)24 (12–36)94 (80–113)57 (48–68)56 (47–67)
      Hamburg
      • Rades D.
      • Stalpers L.J.A.
      • Veninga T.
      • et al.
      Evaluation of five radiation schedules and prognostic factors for metastatic spinal cord compression.
      0/621229 (29–47)29 (29–47)6 (2–40)69 (59–77)41 (35–46)53 (48–57)
      Melbourne
      • Jackson M.A.
      • Ball D.L.
      Palliative retreatment of locally recurrent lung cancer after radical radiotherapy.
      0/615All 7336 (32–39)15106 (103–109)63 (62–65)66 (64–68)
      Princess Margaret
      • Wong C.S.
      • Van Dyk J.
      • Milosevic M.
      • et al.
      Radiation myelopathy following single courses of radiotherapy and retreatment.


       Cases with myelopathy
      11/–1172 (28–96)42 (14–86)11 (2–71)115 (100–138)69 (60–83)80 (65–94)
      Stereotactic body radiotherapy
      Korea
      • Gwak H.-S.
      • Yoo H.-J.
      • Youn S.-M.
      • et al.
      Hypofractionated stereotactic radiotherapy for skull base and upper cervical chordoma and chondrosarcoma: Preliminary results.


       Case with myelopathy No myelopathy
      1/3

      1

      2
      24(60–81)

      81

      60, 81
      (64–154)

      154

      64, 90
      (18–120)

      18

      54, 120
      (145–235)

      235

      145, 150
      (87–141)

      141

      87, 90
      (98–179)

      179

      98,114
      Overall survival.
      One patient received two courses of reirradiation, 1 received three courses.

       SBRT of the spine in humans

      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 radiosurgery
      Institution (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 spine
      Stanford and Pittsburgh
      • Gibbs I.C.
      • Patil I.
      • Gerszten P.C.
      • et al.
      Delayed radiation-induced myelopathy after spinal radiosurgery.
      6/107512.5–255–25Dmax: 3.6–30Range: 24–141 Gy3>55%
      2512.5Dmax: 26.2Dmax: 141
      2010Dmax: 19.2Dmax: 81
      2110.5Dmax: 13.9Dmax: 46
      248Dmax: 29.9Dmax: 129
      202Dmax: 8.5Dmax: 33
      2020Dmax: 10Dmax: 43
      Henry Ford
      • Ryu S.
      • Jin J.Y.
      • Jin R.
      • et al.
      Partial volume tolerance of the spinal cord and complications of single-dose radiosurgery.
      1/86
      Patients surviving at least 1 year.
      <10–18<10–18Mean ± SD

      Dmax: 12.2 ± 2.5

      D1: 10.7 ± 2.3

      D10: 8.6 2.1

      Maximum

      Dmax: 19.2

      D1: 15.8

      D10: 13
      Mean ± SD

      Dmax: 62 ± 4.6

      D1: 49 ± 4.1

      D10: 33 ± 3.6

      Maximum

      Dmax: 142

      D1: 99

      D10: 69
      0%
      18
      Results for subset of 39 lesions treated at Henry Ford Hospital with a single 18-Gy fraction.
      18Mean ± SD

      Dmax: 13.8 ± 2.2

      D1: 12.1 ± 1.9

      D10: 9.8 ± 1.5
      Mean ± SD

      Dmax: 77 ± 3.8

      D1: 61 ± 3.1

      D10: 42 ± 2.3
      1616Dmax:14.8

      D1: 13.0

      D10: 9.6
      Dmax:88

      D1:69

      D10: 40
      Korea
      • Gwak H.-S.
      • Yoo H.-J.
      • Youn S.-M.
      • et al.
      Hypofractionated stereotactic radiotherapy for skull base and upper cervical chordoma and chondrosarcoma: Preliminary results.
      2/921–443–5Median

      Dmax:32.9

      D25:11.0

      Range

      Dmax: 11–37

      D25: 1.2–24
      Median

      Dmax:106

      D25:21

      Range

      Dmax: 19–172

      D25: 1–88
      33%
      3010Dmax: 35.2

      D25: 15.5
      Dmax:172

      D25: 42
      3311Dmax: 32.9 D25: 24.0153

      88
      NYMC
      • Benzil D.L.
      • Saboori M.
      • Mogilner A.Y.
      • et al.
      Safety and efficacy of stereotactic radiosurgery for tumors of the spine.
      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: 6.012Unknown
      10050
      1212
      205
      UCSF
      • Sahgal A.
      • Choua D.
      • Amesa C.
      • et al.
      Proximity of spinous/paraspinous radiosurgery metastatic targets to the spinal cord versus risk of local failure.
      0/38248Median

      D0.1cc: 10.5

      D1cc: 7.4
      Median

      D0.1cc: 23

      D1cc: 14
      62%
      UCSF
      • Sahgal 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.
      0/16217Median

      Dmax: 20.9

      D0.1cc: 16.6

      D1cc: 13.8

      Range

      Dmax: 4.3–23

      D0.1cc: 3.4–22

      D1cc: 2.8–19
      Median

      D0.1cc: 61

      D1cc: 22

      Range

      D0.1cc: 7–76

      D1cc: 6–54
      6%
      MDACC
      • Chang 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.
      0/6330 patients: 30

      33 patients: 27
      30 patients: 6

      33 patients: 9
      30 patients: <10

      33 patients:<9
      30 patients: <16.7

      33 patients: <18
      56%
      Pittsburgh
      • Gerszten P.C.
      • Burton S.A.
      • Welch W.C.
      • et al.
      Single-fraction radiosurgery for the treatment of spinal breast metastases.
      0/501919Mean

      Dmax: 10

      Range

      Dmax: 6.5–13
      Mean

      Dmax: 21

      Range

      Dmax: 11–32
      96%
      Duke
      • Nelson J.W.
      • Yoo D.S.
      • Wang Z.
      • et al.
      Stereotactic body radiotherapy for lesions of the spine and paraspinal regions.
      0/32Median:18Median: 7Mean ± SD

      Dmax: 14.4±2.3

      D1: 13.1±2.2

      D10: 11.5±2.1

      Maximum

      Dmax: 19.2

      D1: 17.4

      D10: 15.2
      Mean ± SD

      Dmax: 46.0±13.2

      D1: 39.0±10.8

      D10: 31.2±8.1

      Maximum

      Dmax: 78.3

      D1: 59.1

      D10: 46.5
      58%
      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
      • Benzil D.L.
      • Saboori M.
      • Mogilner A.Y.
      • et al.
      Safety and efficacy of stereotactic radiosurgery for tumors of the spine.
      , 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.

      Factors Affecting Risk

      Animal studies suggest that the immature spine is slightly more susceptible to radiation-induced complications and the latent period is shorter (
      • Ang K.K.
      • Price R.E.
      • Stephens L.C.
      • et al.
      The tolerance of primate spinal cord to re-irradiation.
      ,
      • Ruifrok A.C.
      • Kleiboer B.J.
      • van der Kogel A.J.
      Radiation tolerance of the immature rat spinal cord.
      ,
      • Ruifrok A.C.
      • Kleiboer B.J.
      • van der Kogel A.J.
      Radiation tolerance and fractionation sensitivity of the developing rat cervical spinal cord.
      ,
      • Ruifrok A.C.
      • Stephens L.C.
      • van der Kogel A.J.
      Radiation response of the rat cervical spinal cord after irradiation at different ages: Tolerance, latency and pathology.
      ). For example, Ruifrok (
      • Ruifrok A.C.
      • Kleiboer B.J.
      • van der Kogel A.J.
      Radiation tolerance of the immature rat spinal cord.
      ) found that the 50% effect dose in 1-week-old rats was 19.5 Gy vs. 21.5 Gy in adult animals (p < 0.05). The latency to complications increased from about 2 weeks after irradiation in the 1-week-old rats to 6–8 months in the adults (
      • Ruifrok A.C.
      • Stephens L.C.
      • van der Kogel A.J.
      Radiation response of the rat cervical spinal cord after irradiation at different ages: Tolerance, latency and pathology.
      ). Although the ultimate white matter changes were the same in animals independent of age, vasculopathy increased with increasing age at irradiation (
      • Ruifrok A.C.
      • Stephens L.C.
      • van der Kogel A.J.
      Radiation response of the rat cervical spinal cord after irradiation at different ages: Tolerance, latency and pathology.
      ) Though the literature on radiation-induced myelopathy is sparse, care should be exercised in irradiating the pediatric spine because of the increased sensitivity of the child's developing central nervous system and bone to ionizing radiation (
      • Friedman D.L.
      • Constine L.S.
      Late effects of cancer treatment.
      )
      In rats, the use of various chemotherapy agents during radiotherapy has been shown to increase the radiosensitivity of the spinal cord. Administration of intrathecal ara-C (
      • Ruifrok A.C.
      • van der Kogel A.J.
      The effect of intraspinal cytosine arabinoside on the re-irradiation tolerance of the cervical spinal cord of young and adult rats.
      ) or intraperitoneal fludarabine (
      • Grégoire V.
      • Ruifrok A.C.
      • Price R.E.
      • et al.
      Effect of intra-peritoneal fludarabine on rat spinal cord tolerance to fractionated irradiation.
      ) immediately before irradiation of the spinal cord showed an enhanced effect on radiation-induced injury, yielding a dose modifying factor of 1.2–1.3. There are rare reports of radiation myelopathy at relatively low doses in human patients post chemotherapy (
      • Ruckdeschel J.C.
      • Baxter D.H.
      • McKneally M.F.
      • et al.
      Sequential radiotherapy and Adriamycin in the management of bronchogenic carcinoma: The question of additive toxicity.
      ,
      • Bloss J.D.
      • DiSaia P.J.
      • Mannel R.S.
      • et al.
      Radiation myelitis: A complication of concurrent cisplatin and 5-fluorouracil chemotherapy with extended field radiotherapy for carcinoma of the uterine cervix.
      ,
      • Chao M.W.
      • Wirth A.
      • Ryan G.
      • et al.
      Radiation myelopathy following transplantation and radiotherapy for non-Hodgkin's lymphoma.
      ,
      • Seddon B.M.
      • Cassoni A.M.
      • Galloway M.J.
      • et al.
      Fatal radiation myelopathy after high-dose busulfan and melphalan chemotherapy and radiotherapy for Ewing's sarcoma: A review of the literature and implications for practice.
      ). Dosimetry data are limited for this small number of cases and it is difficult to draw any absolute conclusions. Note that many chemotherapeutic agents are neurotoxic in their own right (
      • Lee Y.Y.
      • Nauert C.
      • Glass J.P.
      Treatment-related white matter changes in cancer patients.
      ) and caution is advised in their concurrent use during irradiation of the central nervous system (
      • Schultheiss T.E.
      • Kun L.E.
      • Ang K.K.
      • et al.
      Radiation response of the central nervous system.
      ).

      Models

       Conventionally fractionated, full-circumference irradiation

      Using the data in Table 1, Table 2, Schultheiss (
      • Schultheiss T.E.
      The radiation dose-response of the human spinal cord.
      ,
      • Schultheiss T.E.
      • Thames H.D.
      • Peters L.J.
      • et al.
      Effect of latency on calculated complication rates.
      ) estimated the risk of myelopathy as a function of dose using a probability distribution model. In this model, the probability of myelopathy was derived from the data in Table 1, Table 2 adjusted for estimated overall survival (
      • Schultheiss T.E.
      The radiation dose-response of the human spinal cord.
      ). A good fit to the combined cervical and thoracic cord data was not possible and separate analyses were performed. For the cervical cord data, values of D50 = 69.4 Gy and α/β = 0.87 Gy were obtained with a Pearson χ2 statistic of 2.1 for 5 degrees of freedom, providing a reasonable fit of the model as shown in Figure 1. The 95% confidence interval was 66.4 to 72.6 Gy for D50 and 0.54 to 1.19 Gy for α/β. At 2- Gy per fraction, the probability of myelopathy is 0.03% at 45 Gy and 0.2% at 50 Gy. However, the further one gets in the tail of the dose–response function, the more dependent the estimates become on the statistical distribution used to model this function.
      Figure thumbnail gr1
      Fig. 1The dose–response function for the myelopathy of the cervical spinal cord and data points (□) derived from . The probability of myelopathy was calculated from the data in , adjusted for estimated overall survival per
      (
      • Schultheiss T.E.
      The radiation dose-response of the human spinal cord.
      )
      .
      Because of the dispersion in thoracic data, it is not possible to obtain a good fit to the data. As shown in Figure 2, thoracic cord data points generally lie to the right of the dose–response curve for the cervical cord. This suggests that the thoracic cord is less radiation sensitive than the cervical cord.
      Figure thumbnail gr2
      Fig. 2The dose–response function for myelopathy of the cervical cord (solid line) and data points for the thoracic spinal cord (◊) derived from . The probability of myelopathy was calculated from the data in Table 1, Table 2, adjusted for estimated overall survival per
      (
      • Schultheiss T.E.
      The radiation dose-response of the human spinal cord.
      )
      .
      The applicability of the linear-quadratic model at high dose per fraction encountered in radiosurgery is controversial and the biologically equivalent doses calculated using α/β = 3 Gy in Table 4 are intended solely for roughly comparing regimens. In particular, it is not appropriate to extrapolate cord tolerance data obtained at a low dose per fraction to regimens using 10 Gy or more/fraction (
      • Kirkpatrick J.P.
      • Meyer J.J.
      • Marks L.B.
      The linear-quadratic model is inappropriate to model high-dose per fraction effects.
      ).

      Special Situations

      As discussed in detail previously, hypofractionation via radiosurgery is increasingly employed in the treatment of spinal lesions. Though reports of toxicity are rare, the follow-up time is short and patient numbers small. Caution should be observed in specifying the dose, taking special care to limit the dose to the cord by precise immobilization and image guidance. Predictions based on conventional fractionation should not be applied to such treatments without further careful study. The effect of concurrent chemotherapy is essentially unknown in that situation.

      Recommended Dose–Volume Limits

      With conventional fractionation of 2 Gy per day including the full cord cross-section, a total dose of 50 Gy, 60 Gy, and ∼69 Gy are associated with a 0.2, 6, and 50% rate of myelopathy. For reirradiation of the full cord cross-section at 2 Gy per day after prior conventionally fractionated treatment, cord tolerance appears to increase at least 25% 6 months after the initial course of RT based on animal and human studies. For partial cord irradiation as part of spine radiosurgery, a maximum cord dose of 13 Gy in a single fraction or 20 Gy in three fractions appears associated with a <1% risk of injury.

      Future Toxicity Studies

      In cases where it is appropriate to irradiate only a partial circumference of the cord (as in irradiation of vertebral body lesions) or spare the interior of the cord (epidural disease), dose tolerance may be increased. SBRT, particularly using intensity-modulated RT techniques, appears well suited for that purpose, as it can be used to deliver concave-shaped RT dose distributions around organs at risk (
      • Nelson J.W.
      • Yoo D.S.
      • Wang Z.
      • et al.
      Stereotactic body radiotherapy for lesions of the spine and paraspinal regions.
      ). Studies to better understand the importance of the spatial distribution of dose (and, hence, the utility of partial circumferential sparing) would be useful.
      For SBRT of spinal lesions, multi-institutional data need to be carefully collected over several years' time to better estimate the risk of acute and long-term toxicity. At a minimum, participating institutions should report detailed demographics, current treatment factors (anatomic location of the target lesion, cord volume, number of vertebral segments involved, number of fractions, Dmax, D1, D10, D50, D0.1cc, and D1cc,), history of concurrent and prior therapies (including the time interval from, dose and fractionation of previous radiotherapy to the involved levels), and treatment-related toxicity, particularly neurologic deficits.
      Given the low frequency of neurologic deficits in patients receiving spinal radiotherapy, further animal studies designed to understand the relationship between dose, fractionation dose distributions, and time between treatment courses would be useful.

      Toxicity Scoring

      We recommend that the Common Terminology Criteria for Adverse Events (version 3) be used to score both acute and late spinal cord injury.

      Acknowledgment

      Dr. Kirkpatrick has a research grant from Varian Medical Systems , Palo Alto, Ca.

      References

        • Goetz C.
        Textbook of clinical neurology.
        2nd ed. Saunders, Chicago, IL2003
        • Klimo 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: 64-76
        • Schultheiss 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: 1093-1112
      1. Cancer 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.

        • Abbatucci 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: 239-248
        • Saghal A.
        • Larson D.
        • Chang E.L.
        Stereotactic body radiosurgery for spinal metastases: A critical review.
        Int J Radiat Oncol Biol Phys. 2008; 71: 652-665
        • Ryu S.
        • Jin J.Y.
        • Jin R.
        • et al.
        Partial volume tolerance of the spinal cord and complications of single-dose radiosurgery.
        Cancer. 2007; 109: 628-636
        • Philippens 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: 204-213
        • Coderre 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: 495-503
        • Bijl 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: 205-211
        • Bijl 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: 543-551
        • Ang 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: 1487-1491
        • Ang 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: 459-464
        • Ang 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: 1013-1020
        • Knowles 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: 433-442
        • Ruifrok 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: 501-508
        • Wong C.S.
        • Hao Y.
        Long-term recovery kinetics of radiation damage in rat spinal cord.
        Int J Radiat Oncol Biol Phys. 1997; 37: 171-179
        • Schultheiss T.E.
        The radiation dose-response of the human spinal cord.
        Int J Radiat Oncol Biol Phys. 2008; 71: 1455-1459
        • McCunniff A.J.
        • Lliang M.J.
        Radiation tolerance of the cervical spinal cord.
        Int J Radiat Oncol Biol Phys. 1989; 16: 675-678
        • Atkins H.L.
        • Tretter P.
        Time-dose considerations in radiation myelopathy.
        Acta Radiol Ther Phys Biol Gy. 1966; 5: 79-94
        • Marcus 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: 3-8
        • Jeremic 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: 2138-2141
        • Hazra 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: 464-466
        • Choi 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: 31-35
        • Abramson N.
        • Cavanaugh P.J.
        Short-course radiation therapy in carcinoma of the lung.
        Radiology. 1973; 108: 685-687
        • Fitzgerald R.H.
        • Marks R.D.
        • Wallace K.M.
        Chronic radiation myelitis.
        Radiology. 1982; 144: 609-612
        • Madden 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: 1175-1177
        • Guthrie 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: 605-608
        • Dische 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: 75-81
        • Hatlevoll 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: 41-44
        • Eichhorn H.J.
        • Lessel A.
        • Rotte K.H.
        Einfuss verschiedener Bestrahlungsrhythmen auf Tumor-und Normalgewebe in vivo.
        Strahlentheraphie. 1972; 146: 614-629
        • Scruggs 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: 754-760
        • Macbeth 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]): 167-175
        • Macbeth 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: 176-181
        • Nieder 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: 851-855
        • Wright J.L.
        • Lovelock D.M.
        • Bilsky M.H.
        • et al.
        Clinical outcomes after reirradiation of paraspinal tumors.
        Am J Clin Oncol. 2006; 29: 495-502
        • Langendijk 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: 306-312
        • Grosu A.L.
        • Andratschke N.
        • Nieder C.
        • et al.
        Retreatment of the spinal cord with palliative radiotherapy.
        Int J Radiat Oncol Biol Phys. 2002; 52: 1288-1292
        • Nieder C.
        • Grosu A.L.
        • Andratschke N.H.
        • et al.
        Update of human spinal cord reirradiation tolerance based on additional data from 38 patients.
        Int J Radiat Oncol Biol Phys. 2006; 66: 1446-1449
        • Schiff D.
        • Shaw E.G.
        • Cascino T.L.
        Outcome after spinal reirradiation for malignant epidural spinal cord compression.
        Ann Neurol. 1995; 37: 583-5899
        • Ryu S.
        • Gorty S.
        • Kazee A.M.
        • et al.
        Reirradiation of human cervical spinal cord.
        Am J Clin Oncol. 2000; 23: 29-31
        • Kuo J.V.
        • Cabebe E.
        • Al-Ghazi M.
        • et al.
        Intensity-modulated radiation therapy for the spine at the University of California, Irvine.
        Med Dosim. 2002; 27: 137-145
        • Bauman G.S.
        • Sneed P.K.
        • Wara W.M.
        • et al.
        Reirradiation of primary CNS tumors.
        Int J Radiat Oncol Biol Phys. 1996; 36: 433-441
        • Sminia P.
        • Oldenburger F.
        • Slotman B.J.
        • et al.
        Re-irradiation of the human spinal cord.
        Strahlenther Onkol. 2002; 178: 453-456
        • Magrini 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: 209-218
        • Rades 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: 3366-3375
        • Jackson M.A.
        • Ball D.L.
        Palliative retreatment of locally recurrent lung cancer after radical radiotherapy.
        Med J Aust. 1987; 147: 391-394
        • Wong 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: 575-581
        • Gwak 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: 233-243
        • Gibbs I.C.
        • Patil I.
        • Gerszten P.C.
        • et al.
        Delayed radiation-induced myelopathy after spinal radiosurgery.
        Neurosurg. 2009; 64: A67-A72
        • Benzil D.L.
        • Saboori M.
        • Mogilner A.Y.
        • et al.
        Safety and efficacy of stereotactic radiosurgery for tumors of the spine.
        J Neurosurg. 2004; 101: 413-418
        • Sahgal 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: S243
        • Sahgal 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: 595-604
        • Chang 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: 151-160
        • Gerszten P.C.
        • Burton S.A.
        • Welch W.C.
        • et al.
        Single-fraction radiosurgery for the treatment of spinal breast metastases.
        Cancer. 2005; 104: 2244-2254
        • Nelson 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: 1369-1375
        • Ruifrok A.C.
        • Kleiboer B.J.
        • van der Kogel A.J.
        Radiation tolerance of the immature rat spinal cord.
        Radiother Oncol. 1992; 23: 249-256
        • Ruifrok A.C.
        • Kleiboer B.J.
        • van der Kogel A.J.
        Radiation tolerance and fractionation sensitivity of the developing rat cervical spinal cord.
        Int J Radiat Oncol Biol Phys. 1992; 24: 505-510
        • Ruifrok A.C.
        • Stephens L.C.
        • van der Kogel A.J.
        Radiation response of the rat cervical spinal cord after irradiation at different ages: Tolerance, latency and pathology.
        Int J Radiat Oncol Biol Phys. 1994; 29: 73-79
        • Friedman D.L.
        • Constine L.S.
        Late effects of cancer treatment.
        in: Halperin E.C. Constine L.S. Tarbell N.J. Kun L.E. Pediatric radiation oncology. Lippincott, Williams & Wilkins, Philadelphia2005
        • Ruifrok A.C.
        • van der Kogel A.J.
        The effect of intraspinal cytosine arabinoside on the re-irradiation tolerance of the cervical spinal cord of young and adult rats.
        Eur J Cancer. 1993; 29A: 1766-1770
        • Grégoire V.
        • Ruifrok A.C.
        • Price R.E.
        • et al.
        Effect of intra-peritoneal fludarabine on rat spinal cord tolerance to fractionated irradiation.
        Radiother Oncol. 1995; 36: 50-55
        • Ruckdeschel J.C.
        • Baxter D.H.
        • McKneally M.F.
        • et al.
        Sequential radiotherapy and Adriamycin in the management of bronchogenic carcinoma: The question of additive toxicity.
        Int J Radiat Oncol Biol Phys. 1979; 5: 1323-1328
        • Bloss J.D.
        • DiSaia P.J.
        • Mannel R.S.
        • et al.
        Radiation myelitis: A complication of concurrent cisplatin and 5-fluorouracil chemotherapy with extended field radiotherapy for carcinoma of the uterine cervix.
        Gynecol Oncol. 1991; 43: 305-308
        • Chao M.W.
        • Wirth A.
        • Ryan G.
        • et al.
        Radiation myelopathy following transplantation and radiotherapy for non-Hodgkin's lymphoma.
        Int J Radiat Oncol Biol Phys. 1998; 41: 1057-1061
        • Seddon B.M.
        • Cassoni A.M.
        • Galloway M.J.
        • et al.
        Fatal radiation myelopathy after high-dose busulfan and melphalan chemotherapy and radiotherapy for Ewing's sarcoma: A review of the literature and implications for practice.
        Clin Oncol (R Coll Radiol). 2005; 17: 385-390
        • Lee Y.Y.
        • Nauert C.
        • Glass J.P.
        Treatment-related white matter changes in cancer patients.
        Cancer. 1986; 57: 1473-1482
        • Schultheiss 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: 1093-1112
        • Schultheiss T.E.
        • Thames H.D.
        • Peters L.J.
        • et al.
        Effect of latency on calculated complication rates.
        Int J Radiat Oncol Biol Phys. 1986; 12: 1861-1865
        • Kirkpatrick J.P.
        • Meyer J.J.
        • Marks L.B.
        The linear-quadratic model is inappropriate to model high-dose per fraction effects.
        Semin Radiat Oncol. 2008; 18: 240-243

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