Normal Tissue Tolerance to Reirradiation

  • Carsten Nieder
  • Johannes A. Langendijk
Part of the Medical Radiology book series (MEDRAD)


As a result of longer survival times, even among patients with incurable malignancies, the probability of developing second primary tumours and/or locoregional recurrences in previously irradiated areas might increase. Consequently, the need for additional therapeutic measures providing local control and/or symptom palliation along different lines of treatment has emerged. This has resulted in increasing requests for delivering a second course of radiation to target volumes within or close to previously irradiated anatomical areas. On the one hand, improved imaging and delivery techniques including image-guided and intensity-modulated radiotherapy might facilitate reirradiation of previously exposed regions of the body. On the other hand, late toxicity in several recently reported studies is considerable and may have a devastating impact on health-related quality of life. Therefore, knowledge about long-term recovery of occult radiation injury is of utmost importance. This chapter summarizes available experimental and clinical data on the effects of reirradiation to various organs.


Late Toxicity Radiation Therapy Oncology Group Radiation Pneumonitis Biologically Effective Dose Priming Dose 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. Alsner J, Andreassen CN, Overgaard J (2008) Genetic markers for prediction of normal tissue toxicity after radiotherapy. Semin Radiat Oncol 18:126–135PubMedCrossRefGoogle Scholar
  2. Ang KK, Price RE, Stephens LC et al (1995) The tolerance of primate spinal cord to re-irradiation. Int J Radiat Oncol Biol Phys 25:459–464CrossRefGoogle Scholar
  3. Ang KK, Jiang GL, Feng Y et al (2001) Extent and kinetics of recovery of occult spinal cord injury. Int J Radiat Oncol Biol Phys 50:1013–1020PubMedCrossRefGoogle Scholar
  4. Biagioli MC, Harvey M, Roman E et al (2007) Intensity-modulated radiotherapy with concurrent chemotherapy for previously irradiated, recurrent head and neck cancer. Int J Radiat Oncol Biol Phys 69:1067–1073PubMedCrossRefGoogle Scholar
  5. Choi CY, Adler JR, Gibbs IC et al (2010) Stereotactic radiosurgery for treatment of spinal metastases recurring in close proximity to previously irradiated spinal cord. Int J Radiat Oncol Biol Phys 78:499–506PubMedCrossRefGoogle Scholar
  6. Combs SE, Thilmann C, Edler L et al (2005) Efficacy of fractionated stereotactic reirradiation in recurrent gliomas: long-term results in 172 patients treated in a single institution. J Clin Oncol 23:8863–8869PubMedCrossRefGoogle Scholar
  7. Combs SE, Burkholder I, Edler L et al (2010) Randomised phase I/II study to evaluate carbon ion radiotherapy versus fractionated stereotactic radiotherapy in patients with recurrent or progressive gliomas: the CINDERELLA trial. BMC Cancer 10:533PubMedCrossRefGoogle Scholar
  8. Damast S, Wright J, Bilsky M et al (2010) Impact of dose on local failure rates after image-guided reirradiation of recurrent paraspinal metastases. Int J Radiat Oncol Biol Phys (in press)Google Scholar
  9. De Crevoisier R, Bourhis J, Domenge C et al (1998) Full-dose reirradiation for unresectable head and neck carcinoma: experience at the Gustave-Roussy Institute in a series of 169 patients. J Clin Oncol 16:3556–3562PubMedGoogle Scholar
  10. Dritschilo A, Bruckman JE, Cassady JR, Belli JA (1981) Tolerance of brain to multiple courses of radiation therapy. I. Clinical experiences. Br J Radiol 54:782–786PubMedCrossRefGoogle Scholar
  11. Duprez F, Madani I, Bonte K et al (2009) Intensity-modulated radiotherapy for recurrent and second primary head and neck cancer in previously irradiated territory. Radiother Oncol 93:563–569PubMedCrossRefGoogle Scholar
  12. Flickinger JC, Deutsch M, Lunsford LD (1989) Repeat megavoltage irradiation of pituitary and suprasellar tumours. Int J Radiat Oncol Biol Phys 17:171–175PubMedCrossRefGoogle Scholar
  13. Fogh SE, Andrews DW, Glass J et al (2010) Hypofractionated stereotactic radiation therapy: an effective therapy for recurrent high-grade gliomas. J Clin Oncol 28:3048–3053PubMedCrossRefGoogle Scholar
  14. Greenberger JS (2009) Radioprotection. In Vivo 23:323–336PubMedGoogle Scholar
  15. Grosu AL, Andratschke N, Nieder C, Molls M (2002) Retreatment of the spinal cord with palliative radiotherapy. Int J Radiat Oncol Biol Phys 52:1288–1292PubMedCrossRefGoogle Scholar
  16. Haque W, Crane CH, Krishnan S et al (2009) Reirradiation to the abdomen for gastrointestinal malignancies. Radiat Oncol 4:55PubMedCrossRefGoogle Scholar
  17. Harms W, Krempien R, Grehn C et al (2004) Reirradiation of chest wall local recurrences from breast cancer. Zentralbl Gynakol 126:19–23PubMedCrossRefGoogle Scholar
  18. Hauswald H, Stoiber E, Rochet N et al (2010) Treatment of recurrent bronchial carcinoma: the role of high-dose-rate endoluminal brachytherapy. Int J Radiat Oncol Biol Phys 77:373–377PubMedCrossRefGoogle Scholar
  19. Heinzelmann F, Ottinger H, Engelhard M et al (2010) Advanced-stage III/IV follicular lymphoma: treatment strategies for individual patients. Strahlenther Onkol 186:247–254PubMedCrossRefGoogle Scholar
  20. Hornsey S, Myers R, Warren P (1982) Residual injury in the spinal cord after treatment with X-rays or neutrons. Br J Radiol 55:516–519PubMedCrossRefGoogle Scholar
  21. Jackson MA, Ball DL (1987) Palliative retreatment of locally recurrent lung cancer after radical radiotherapy. Med J Aust 147:391–394PubMedGoogle Scholar
  22. Kim TH, Kim DY, Jung KH et al (2010) The role of omental flap transposition in patients with locoregional recurrent rectal cancer treated with reirradiation. J Surg Oncol 102:789–795PubMedCrossRefGoogle Scholar
  23. Kirkpatrick JP, van der Kogel AJ, Schultheiss TE (2010) Radiation dose-volume effects in the spinal cord. Int J Radiat Oncol Biol Phys 76:S42–S49PubMedCrossRefGoogle Scholar
  24. Kishi K, Sonomura T, Shirai S et al (2009) Critical organ preservation in reirradiation brachytherapy by injectable spacer. Int J Radiat Oncol Biol Phys 75:587–594PubMedCrossRefGoogle Scholar
  25. Knowles JW (1983) 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 44:433–442CrossRefGoogle Scholar
  26. Kong FM, Ao X, Wang L, Lawrence TS (2008) The use of blood biomarkers to predict radiation lung toxicity: a potential strategy to individualize thoracic radiation therapy. Cancer Control 15:140–150PubMedGoogle Scholar
  27. Kosaka Y, Okuno Y, Tagawa Y et al (2010) Osteoradionecrosis of the cervical vertebrae in patients irradiated for head and neck cancers. Jpn J Radiol 28:388–394PubMedCrossRefGoogle Scholar
  28. Kruse JJ, Stewart FA (2007) Gene expression arrays as a tool to unravel mechanisms of normal tissue radiation injury and prediction of response. World J Gastroenterol 13:2669–2674PubMedGoogle Scholar
  29. Landuyt W, van der Kogel AJ, de Roo M et al (1988) Unilateral kidney irradiation and late retreatment with cis-dichlorodiamineplatinum (II): functional measurements with 99m technetium-dimercaptosuccinic acid. Int J Radiat Oncol Biol Phys 14:95–101PubMedCrossRefGoogle Scholar
  30. Langendijk JA, Kasperts N, Leemans CR et al (2006) A phase II study of primary reirradiation in squamous cell carcinoma of head and neck. Radiother Oncol 78:306–312PubMedCrossRefGoogle Scholar
  31. Langer CJ, Harris J, Horwitz EM et al (2007) Phase II study of low-dose paclitaxel and cisplatin in combination with split-course concomitant twice-daily reirradiation in recurrent squamous cell carcinoma of the head and neck: results of Radiation Therapy Oncology Group Protocol 9911. J Clin Oncol 25:4800–4805PubMedCrossRefGoogle Scholar
  32. Lavey RS, Taylor J, Tward JD et al (1994) The extent, time course, and fraction size dependence of mouse spinal cord recovery from radiation injury. Int J Radiat Oncol Biol Phys 30:609–617PubMedCrossRefGoogle Scholar
  33. Lee AW, Law SC, Ng SH et al (1992) Retrospective analysis of nasopharyngeal carcinoma treated during 1976–1985: late complications following megavoltage irradiation. Br J Radiol 65:918–928PubMedCrossRefGoogle Scholar
  34. Lee AW, Foo W, Law SC (1997) Reirradiation for recurrent nasopharyngeal carcinoma: factors affecting the therapeutic ratio and ways for improvement. Int J Radiat Oncol Biol Phys 38:43–52PubMedCrossRefGoogle Scholar
  35. Lee AW, Foo W, Law SC et al (2000) Total biological effect on late reactive tissues following reirradiation for recurrent nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys 46:865–872PubMedCrossRefGoogle Scholar
  36. Lingareddy V, Ahmad NR, Mohiuddin M (1997) Palliative reirradiation for recurrent rectal cancer. Int J Radiat Oncol Biol Phys 38:785–790PubMedCrossRefGoogle Scholar
  37. Machtay M, Rosenthal DI, Chalian AA et al (2004) Pilot study of postoperative reirradiation, chemotherapy, and amifostine after surgical salvage for recurrent head-and-neck cancer. Int J Radiat Oncol Biol Phys 59:72–77PubMedCrossRefGoogle Scholar
  38. Magrini SM, Biti GP, de Scisciolo G et al (1990) Neurological damage in patients irradiated twice on the spinal cord: a morphologic and electrophysiological study. Radiother Oncol 17:209–218PubMedCrossRefGoogle Scholar
  39. Mason KA, Withers HR, Chiang CS (1993) Late effects of radiation on the lumbar spinal cord of guinea pigs: re-treatment tolerance. Int J Radiat Oncol Biol Phys 26:643–648PubMedCrossRefGoogle Scholar
  40. Mayer R, Sminia P (2008) Reirradiation tolerance of the human brain. Int J Radiat Oncol Biol Phys 70:1350–1360PubMedCrossRefGoogle Scholar
  41. Mohiuddin M, Marks G, Marks J (2002) Long-term results of reirradiation for patients with recurrent rectal carcinoma. Cancer 95:1144–1150PubMedCrossRefGoogle Scholar
  42. Moman MR, Van der Poel HG, Battermann JJ et al (2009) Treatment outcome and toxicity after salvage 125-I implantation for prostate cancer recurrences after primary 125-I implantation and external beam radiotherapy. Brachytherapy 9:119–125PubMedCrossRefGoogle Scholar
  43. Montebello JF, Aron BS, Manatunga AK et al (1993) The reirradiation of recurrent bronchogenic carcinoma with external beam irradiation. Am J Clin Oncol 16:482–488PubMedCrossRefGoogle Scholar
  44. Nieder C, Price RE, Rivera B et al (2005a) Effects of insulin-like growth factor-1 (IGF-1) and amifostine in spinal cord reirradiation. Strahlenther Onkol 181:691–695PubMedCrossRefGoogle Scholar
  45. Nieder C, Grosu AL, Andratschke NH, Molls M (2005b) Proposal of human spinal cord reirradiation dose based on collection of data from 40 patients. Int J Radiat Oncol Biol Phys 61:851–855PubMedCrossRefGoogle Scholar
  46. Nieder C, Grosu AL, Andratschke NH, Molls M (2006a) Update of human spinal cord reirradiation tolerance based on additional data from 38 patients. Int J Radiat Oncol Biol Phys 66:1446–1449PubMedCrossRefGoogle Scholar
  47. Nieder C, Adam M, Molls M, Grosu AL (2006b) Therapeutic options for recurrent high-grade glioma in adult patients: recent advances. Crit Rev Oncol Hematol 60:181–193PubMedCrossRefGoogle Scholar
  48. Nieder C, Astner ST, Mehta MP et al (2008) Improvement, clinical course, and quality of life after palliative radiotherapy for recurrent glioblastoma. Am J Clin Oncol 31:300–305PubMedCrossRefGoogle Scholar
  49. Nuyten DS, van de Vijver MJ (2008) Using microarray analysis as a prognostic and predictive tool in oncology: focus on breast cancer and normal tissue toxicity. Semin Radiat Oncol 18:105–114PubMedCrossRefGoogle Scholar
  50. Paulino AC, Mai WY, Chintagumpala M et al (2008) Radiation-induced malignant gliomas: is there a role for reirradiation? Int J Radiat Oncol Biol Phys 71:1381–1387PubMedCrossRefGoogle Scholar
  51. Raza SM, Jabbour S, Thai QA et al (2007) Repeat stereotactic radiosurgery for high-grade and large intracranial arteriovenous malformations. Surg Neurol 68:24–34PubMedCrossRefGoogle Scholar
  52. Reynaud A, Travis EL (1984) Late effects of irradiation in mouse jejunum. Int J Radiat Biol 46:125–134CrossRefGoogle Scholar
  53. Robbins ME, Bywaters T, Rezvani M et al (1991) Residual radiation-induced damage to the kidney of the pig as assayed by retreatment. Int J Radiat Biol 60:917–928PubMedGoogle Scholar
  54. Ruifrok ACC, Kleiboer BJ, van der Kogel AJ (1992a) Fractionation sensitivity of the rat cervical spinal cord during radiation retreatment. Radiother Oncol 25:295–300PubMedCrossRefGoogle Scholar
  55. Ruifrok ACC, Kleiboer BJ, van der Kogel AJ (1992b) Reirradiation tolerance of the immature rat spinal cord. Radiother Oncol 23:249–256PubMedCrossRefGoogle Scholar
  56. Russell AH, Koh WJ, Markette K et al (1987) Radical reirradiation for recurrent or second primary carcinoma of the female reproductive tract. Gynecol Oncol 27:226–232PubMedCrossRefGoogle Scholar
  57. Sahgal A, Ma L, Weinberg V et al (2010) Reirradiation human spinal cord tolerance for stereotactic body radiotherapy. Int J Radiat Oncol Biol Phys (in press)Google Scholar
  58. Schiff D, Shaw E, Cascino TL (1995) Outcome after spinal reirradiation for malignant epidural spinal cord compression. Ann Neurol 37:583–589PubMedCrossRefGoogle Scholar
  59. Shaw E, Scott C, Souhami L et al (1996) Radiosurgery for the treatment of previously irradiated recurrent primary brain tumours and brain metastases: initial report of radiation therapy oncology group protocol (90-05). Int J Radiat Oncol Biol Phys 34:647–654PubMedCrossRefGoogle Scholar
  60. Shaw E, Scott C, Souhami L et al (2000) Single dose radiosurgical treatment of recurrent previously irradiated primary brain tumours and brain metastases: final report of RTOG protocol 90-05. Int J Radiat Oncol Biol Phys 47:291–298PubMedCrossRefGoogle Scholar
  61. Shepherd SF, Laing RW, Cosgrove VP et al (1997) Hypofractionated stereotactic radiotherapy in the management of recurrent glioma. Int J Radiat Oncol Biol Phys 37:393–398PubMedCrossRefGoogle Scholar
  62. Simmonds RH, Hopewell JW, Robbins MEC (1989) Residual radiation-induced injury in dermal tissue: implications for retreatment. Br J Radiol 62:915–920PubMedCrossRefGoogle Scholar
  63. Sterzing F, Hauswald H, Uhl M et al (2010) Spinal cord sparing reirradiation with helical tomotherapy. Cancer 116:3961–3968PubMedCrossRefGoogle Scholar
  64. Stewart FA, Oussoren Y, Luts A (1990) Long-term recovery and reirradiation tolerance of mouse bladder. Int J Radiat Oncol Biol Phys 18:1399–1406PubMedCrossRefGoogle Scholar
  65. Stewart FA, Oussoren Y, van Tinteren H et al (1994) Loss of reirradiation tolerance in the kidney with increasing time after single or fractionated partial tolerance doses. Int J Radiat Biol 66:169–179PubMedCrossRefGoogle Scholar
  66. Sulman EP, Schwartz DL, Le TT et al (2009) IMRT reirradiation of head and neck cancer-disease control and morbidity outcomes. Int J Radiat Oncol Biol Phys 73:399–409PubMedCrossRefGoogle Scholar
  67. Tada T, Fukuda H, Matsui K et al (2005) Non-small-cell lung cancer: reirradiation for loco-regional relapse previously treated with radiation therapy. Int J Clin Oncol 10:247–250PubMedCrossRefGoogle Scholar
  68. Terry NHA, Tucker SL, Travis EL (1988) Residual radiation damage in murine lung assessed by pneumonitis. Int J Radiat Oncol Biol Phys 14:929–938PubMedCrossRefGoogle Scholar
  69. Terry NHA, Tucker SL, Travis EL (1989) Time course of loss of residual radiation damage in murine skin assessed by retreatment. Int J Radiat Biol 55:271–283PubMedCrossRefGoogle Scholar
  70. Valdagni R, Rancati T, Fiorino C (2009) Predictive models of toxicity with external radiotherapy for prostate cancer: clinical issues. Cancer 115:3141–3149PubMedCrossRefGoogle Scholar
  71. Van der Kogel AJ (1979) Late effects of radiation on the spinal cord. PhD thesis, University of Amsterdam, AmsterdamGoogle Scholar
  72. Veninga T, Langendijk HA, Slotman BJ et al (2001) Reirradiation of primary brain tumours: survival, clinical response and prognostic factors. Radiother Oncol 59:127–137PubMedCrossRefGoogle Scholar
  73. Wondergem J, van Ravels FJ, Reijnart IW et al (1996) Reirradiation tolerance of the rat heart. Int J Radiat Oncol Biol Phys 36:811–819PubMedCrossRefGoogle Scholar
  74. Wong CS, Han Y (1997) Long-term recovery kinetics of radiation damage in rat spinal cord. Int J Radiat Oncol Biol Phys 37:171–179PubMedCrossRefGoogle Scholar
  75. Wong CS, Minkin S, Hill RP (1993) Re-irradiation tolerance of rat spinal cord to fractionated X-ray doses. Radiother Oncol 28:197–202PubMedCrossRefGoogle Scholar
  76. Wong CS, van Dyk J, Milosevic M et al (1994) Radiation myelopathy following single courses of radiotherapy and retreatment. Int J Radiat Oncol Biol Phys 30:575–581PubMedCrossRefGoogle Scholar
  77. Würschmidt F, Dahle J, Petersen C et al (2008) Reirradiation of recurrent breast cancer with and without concurrent chemotherapy. Radiat Oncol 3:28PubMedCrossRefGoogle Scholar
  78. Ysebaert L, Truc G, Dalac S et al (2004) Ultimate results of radiation therapy for T1–T2 mycosis fungoides (including reirradiation). Int J Radiat Oncol Biol Phys 58:1128–1134PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2010

Authors and Affiliations

  1. 1.Department of Oncology and Palliative MedicineNordland HospitalBodøNorway
  2. 2.Department of Radiation OncologyUniversity Medical Center Groningen/University of GroningenGroningenThe Netherlands

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