Volume effects in the irradiated canine spinal cord: do they exist when the probability of injury is low?

PURPOSE The purpose of this study was to investigate volume effects in the irradiated canine spinal cord. MATERIALS AND METHODS Eighty-nine beagle dogs were given 44-84 Gy photons in 4 Gy fractions to 4 or 20 cm lengths of thoracic spinal cord. As controls, 36 dogs were given 60-84 Gy in 2 Gy fractions to a 20 cm length of spinal cord and six dogs were unirradiated. Dogs were evaluated for clinical signs, and after euthanasia, for occurrence of gross lesions, severe lesions of massive hemorrhage, white matter necrosis and/or parenchymal atrophy and mild lesions of focal fiber loss. White matter vacuoles, meningeal thickness and dorsal root ganglia lesions were quantified. Data were analyzed to test for an effect of volume on dose-response curves. RESULTS Significant volume effects were found between 4 and 20 cm lengths of irradiated spinal cord for gross lesions, severe lesions and mild lesions (8.3-15.0 Gy difference at the ED50 level). The ED50 in 4 Gy fractions for severe lesions was 56.9 Gy (95% CI 53.1-60.6) for 20 cm and 68.8 Gy (95% CI 64.5-75.1) for 4 cm fields. Significant improvements in the fit of data to dose-response curves resulted when using models with either parallel or non-parallel curves, but in either case an appreciable difference existed between curves at low probabilities of injury. Volume effects were present for meningeal thickness and slopes of dose-response curves were different. Clinical signs correlated well with severe lesions for 20 cm (ED50 = 54.0 Gy), but not for 4 cm fields (ED50 = 77.6 Gy). CONCLUSIONS Volume effects exist for the occurrence of pathologic lesions in irradiated canine spinal cord. Clinical compensation for pathologic lesions occur at small, but not large irradiated volumes. There is insufficient data to support a decreased slope of dose-response curves with decreased volume. Volume effects estimated at the 50% level of spinal cord injury could also hold at low probabilities of injury characteristic of the clinic.

[1]  T. Schultheiss.  Spinal cord radiation "tolerance": doctrine versus data. , 1990, International journal of radiation oncology, biology, physics.

[2]  M. Pfeffer,et al.  Radiation-induced changes in the profile of spinal cord serotonin, prostaglandin synthesis, and vascular permeability. , 1995, International journal of radiation oncology, biology, physics.

[3]  H R Withers,et al.  Critical volume model. , 1993, International journal of radiation oncology, biology, physics.

[4]  A. Niemierko,et al.  Modeling of normal tissue response to radiation: the critical volume model. , 1993, International journal of radiation oncology, biology, physics.

[5]  J. Hopewell,et al.  The radiation response of the cervical spinal cord of the pig: effects of changing the irradiated volume. , 1995, International journal of radiation oncology, biology, physics.

[6]  E. A. Wright,et al.  The effects of dose and field size on late radiation damage to the rat spinal cord. , 1975, International journal of radiation biology and related studies in physics, chemistry, and medicine.

[7]  J. Hopewell,et al.  The influence of field size on the late tolerance of the rat spinal cord to single doses of X rays. , 1987, The British journal of radiology.

[8]  L. Cohen,et al.  An iso-effect table for radiation tolerance of the human spinal cord. , 1981, International journal of radiation oncology, biology, physics.

[9]  S. Dische,et al.  Radiation myelopathy in patients treated for carcinoma of bronchus using a six fraction regime of radiotherapy. , 1981, The British journal of radiology.

[10]  P. McCullagh,et al.  Generalized Linear Models , 1984 .

[11]  J. Van Dyk,et al.  Radiation myelopathy following single courses of radiotherapy and retreatment. , 1994, International journal of radiation oncology, biology, physics.

[12]  A. Niemierko,et al.  Dose-volume effects in the spinal cord. , 1994, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[13]  T E Schultheiss,et al.  Models in radiotherapy: volume effects. , 1983, Medical physics.

[14]  T. Delozier,et al.  Radiation myelopathy of the cervical spinal cord: time, dose and volume factors. , 1978, International journal of radiation oncology, biology, physics.

[15]  S. Hornsey,et al.  Radiation damage to the rat spinal cord: the effect of single and fractionated doses of X rays. , 1978, The British journal of radiology.

[16]  H. Vinters,et al.  Blood-spinal cord barrier function and morphometry after single doses of x-rays in rat spinal cord. , 1995, International journal of radiation oncology, biology, physics.

[17]  J. Lyman,et al.  Normal tissue complication probabilities: variable dose per fraction. , 1992, International journal of radiation oncology, biology, physics.

[18]  van der Kogel Aj.  Radiation-induced damage in the central nervous system: an interpretation of target cell responses. , 1986 .

[19]  K. Ang,et al.  Radiation myelopathy in primates treated with conventional fractionation. , 1990, International journal of radiation oncology, biology, physics.

[20]  S. Leibel,et al.  Tolerance of the brain and spinal cord to conventional irradiation , 1991 .

[21]  R. Marcus,et al.  The incidence of myelitis after irradiation of the cervical spinal cord. , 1990, International journal of radiation oncology, biology, physics.

[22]  J. Hopewell,et al.  Boron neutron capture therapy: a guide to the understanding of the pathogenesis of late radiation damage to the rat spinal cord. , 1994, International journal of radiation oncology, biology, physics.

[23]  J. Hopewell,et al.  Boron neutron capture irradiation of the rat spinal cord: histopathological evidence of a vascular-mediated pathogenesis. , 1996, Radiation research.

[24]  Y Lo,et al.  The effect of fractionated doses of radiation on mouse spinal cord. , 1993, International journal of radiation oncology, biology, physics.

[25]  P. McCullagh,et al.  Generalized Linear Models , 1992 .

[26]  B. Powers,et al.  Pathology of radiation injury to the canine spinal cord. , 1992, International journal of radiation oncology, biology, physics.

[27]  K. Ang,et al.  Volume effects in rhesus monkey spinal cord. , 1994, International journal of radiation oncology, biology, physics.

[28]  K. Ang,et al.  Elevated levels of plasminogen activators in the pathogenesis of delayed radiation damage in rat cervical spinal cord in vivo. , 1994, Radiation research.

[29]  B. Jeremic,et al.  Incidence of radiation myelitis of the cervical spinal cord at doses of 5500 cGy or greater , 1991, Cancer.

[30]  J. Brown,et al.  The effects of single and multifraction radiation courses on the mouse spinal cord. , 1976, Radiology.

[31]  H. Reinhold,et al.  Radiation myelopathy of the thoracic spinal cord. , 1976, International journal of radiation oncology, biology, physics.

[32]  A. V. D. Kogel,et al.  Dose-volume effects in the spinal cord. , 1993 .

[33]  H. Withers,et al.  Treatment volume and tissue tolerance. , 1988, International journal of radiation oncology, biology, physics.

[34]  H. Withers,et al.  Dose Fractionation and Volume Effects in Normal Tissues and Tumors , 1988, American journal of clinical oncology.

[35]  G. Boden.  Radiation myelitis of the cervical spinal cord. , 1948, The British journal of radiology.