Fractionation Concepts

Part of the Medical Radiology book series (MEDRAD)


This chapter summarizes the principles of fractionated radiotherapy and altered fractionation approaches. Clinical reirradiation examples and isoeffect calculations are provided. The vast majority of published reirradiation series consist of retrospective data or small prospective studies with limited statistical power. In addition, the typical patient populations are more heterogeneous than in first-line radiotherapy studies. For example, patients with local relapse, regional relapse, or second primary tumors might be included. Therefore, the level of evidence is not comparable to that of first-line radiotherapy, where many treatment recommendations and guidelines are based on large and well-designed prospective randomized trials or meta-analyses of several trials. Reirradiation is often used for palliative symptoms but occasionally curative approaches, which require high total radiation doses, might be possible. Hyperfractionated reirradiation might theoretically improve the therapeutic ratio, but prospective trials are required to confirm this hypothesis.


Rectal Cancer Stereotactic Body Radiotherapy Late Toxicity Biologically Effective Dose Fractionation Regimen 
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  1. Abdel-Wahab MM, Wolfson AH, Raub W et al (1997) The role of hyperfractionated re-irradiation in metastatic brain disease: a single institutional trial. Am J Clin Oncol 20:158–160PubMedCrossRefGoogle Scholar
  2. Bauman GS, Sneed PK, Wara WM et al (1996) Reirradiation of primary CNS tumors. Int J Radiat Oncol Biol Phys 36:433–441PubMedCrossRefGoogle Scholar
  3. Baumann M, Beck-Bornholdt HP (1999) Hyperfractionated radiotherapy: tops or flops. Med Pediatr Oncol 33:399–402PubMedCrossRefGoogle Scholar
  4. Baumann M, Gregoire V (2009) Modified fractionation. In: Joiner M, van der Kogel A (eds) Basic clinical radiobiology. Hodder Arnold, London, pp 135–148Google Scholar
  5. Baumann M, Bentzen S, Ang KK (1998) Hyperfractionated radiotherapy in head and neck cancer: a second look at the clinical data. Radiother Oncol 46:127–130PubMedCrossRefGoogle Scholar
  6. Beck-Bornholdt HP, Dubben HH, Liertz-Petersen C, Willers H (1997) Hyperfractionation: where do we stand? Radiother Oncol 43:1–21PubMedCrossRefGoogle Scholar
  7. Benchalal M, Bachaud JM, François P et al (1995) Hyperfractionation in the reirradiation of head and neck cancers. Result of a pilot study. Radiother Oncol 36:203–210PubMedCrossRefGoogle Scholar
  8. Bentzen SM, Saunders MI, Dische S (1999) Repair halftimes estimated from observations of treatment-related morbidity after CHART or conventional radiotherapy in head and neck cancer. Radiother Oncol 53:219–226PubMedCrossRefGoogle Scholar
  9. Bourhis J, Overgaard J, Audry H et al (2006) Hyperfractionated or accelerated radiotherapy in head and neck cancer: a meta-analysis. Lancet 368:843–854PubMedCrossRefGoogle Scholar
  10. Brown JM, Probert JC (1975) Early and late radiation changes following a second course of irradiation. Radiology 115:711–716PubMedGoogle Scholar
  11. Burri RJ, Stone NN, Unger P et al (2010) Long-term outcome and toxicity of salvage brachytherapy for local failure after initial radiotherapy for prostate cancer. Int J Radiat Oncol Biol Phys 77:1338–1344PubMedCrossRefGoogle Scholar
  12. 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 78:499–506Google Scholar
  13. Cox JD, Pajak TF, Herskovic A et al (1991) Five-year survival after hyperfractionated radiation therapy for non-small-cell carcinoma of the lung (NSCCL): results of RTOG protocol 81-08. Am J Clin Oncol 14:280–284PubMedCrossRefGoogle Scholar
  14. Das P, Delclos ME, Skibber JM et al (2010) Hyperfractionated accelerated radiotherapy for rectal cancer in patients with prior pelvic irradiation. Int J Radiat Oncol Biol Phys 77:60–65Google Scholar
  15. Dritschilo A, Bruckman JE, Cassady JR, Belli JA (1981) Tolerance of brain to multiple courses of radiation therapy. Br J Radiol 54:782–786PubMedCrossRefGoogle Scholar
  16. Dunkel IJ, Gardner SL, Garvin JH Jr et al (2010) High-dose carboplatin, thiotepa, and etoposide with autologous stem cell rescue for patients with previously irradiated recurrent medulloblastoma. Neurooncology 12:297–303Google Scholar
  17. Edsmyr F, Andersson L, Esposti PL et al (1985) Irradiation therapy with multiple small fractions per day in urinary bladder cancer. Radiother Oncol 4:197–203PubMedCrossRefGoogle Scholar
  18. Fallai C, Olmi P (1997) Hyperfractionated and accelerated radiation therapy in central nervous system tumours (malignant gliomas, pediatric tumours, and brain metastases). Radiother Oncol 43:235–246PubMedCrossRefGoogle Scholar
  19. 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
  20. Fu KK, Newman H, Phillips TL (1975) Treatment of locally recurrent carcinoma of the nasopharynx. Radiology 117:425–431PubMedGoogle Scholar
  21. Fu KK, Pajak TF, Trotti A et al (2000) A Radiation Therapy Oncology Group (RTOG) phase III randomized study to compare hyperfractionation and two variants of accelerated fractionation to standard fractionation radiotherapy for head and neck squamous cell carcinomas: first report of RTOG 9003. Int J Radiat Oncol Biol Phys 48:7–16PubMedCrossRefGoogle Scholar
  22. Greenberg M, Eisert DR, Cox JD (1976) Initial evaluation of reduced fractionation in the irradiation of malignant epithelial tumors. AJR Am J Roentgenol 126:268–278PubMedGoogle Scholar
  23. Grosu AL, Weber WA, Franz M et al (2005) Reirradiation of recurrent high-grade gliomas using amino acid PET (SPECT)/CT/MRI image fusion to determine gross tumor volume for stereotactic fractionated radiotherapy. Int J Radiat Oncol Biol Phys 63:511–519PubMedCrossRefGoogle Scholar
  24. Haddock MG, Gunderson LL, Nelson H et al (2001) Intraoperative irradiation for locally recurrent colorectal cancer in previously irradiated patients. Int J Radiat Oncol Biol Phys 49:1267–1274PubMedCrossRefGoogle Scholar
  25. Haque W, Crane CH, Krishnan S et al (2009) Reirradiation to the abdomen for gastrointestinal malignancies. Radiat Oncol 4:55PubMedCrossRefGoogle Scholar
  26. Hellman S (1975) Cell kinetics, models, and cancer treatment—some principles for the radiation oncologist. Radiology 114:219–223PubMedGoogle Scholar
  27. Heron DE, Rwigema JC, Gibson MK et al (2010) Concurrent cetuximab with stereotactic body radiotherapy for recurrent squamous cell carcinoma of the head and neck: a single institution matched case-control study. Am J Clin Oncol. Epub ahead of print. Accessed 3 Aug 2010Google Scholar
  28. Holsti LR, Salmo M, Elkind MM (1978) Unconventional fractionation in clinical radiotherapy. Br J Cancer Suppl 3:307–310PubMedGoogle Scholar
  29. Horiot JC, Le Fur R, N’Guyen T et al (1992) Hyperfractionation versus conventional fractionation in oropharyngeal carcinoma: final analysis of a randomized trial of the EORTC cooperative group of radiotherapy. Radiother Oncol 25:231–241PubMedCrossRefGoogle Scholar
  30. Hunter RD, Stewart JG (1977) The tolerance of re-irradiation of heavily irradiated human skin. Br J Radiol 50:573–575PubMedCrossRefGoogle Scholar
  31. Jereczek-Fossa BA, Kowalczyk A, D’Onofrio A et al (2008) Three-dimensional conformal or stereotactic reirradiation of recurrent, metastatic or new primary tumors. Analysis of 108 patients. Strahlenther Onkol 184:36–40PubMedCrossRefGoogle Scholar
  32. Jeremić B, Milicić B (2008) From conventionally fractionated radiation therapy to hyperfractionated radiation therapy alone and with concurrent chemotherapy in patients with early-stage nonsmall cell lung cancer. Cancer 112:876–884PubMedCrossRefGoogle Scholar
  33. Jeremic B, Shibamoto Y, Acimovic l, Milisavlijvic S (1997) Hyperfractionated radiotherapy alone for clinical stage I non small cell lung cancer. Int J Radiat On col Biol Phys. 38:521–525 CrossRefGoogle Scholar
  34. Joiner MC (1993) Hyperfractionation and accelerated radiotherapy. In: Steel GG (ed) Basic clinical radiobiology. Arnold Publishers, London, pp 65–71Google Scholar
  35. Joiner MC, Marples B, Lambin P et al (2001) Low-dose hypersensitivity: current status and possible mechanisms. Int J Radiat Oncol Biol Phys 49:379–389PubMedCrossRefGoogle Scholar
  36. Joseph KJ, Al-Mandhari Z, Pervez N et al (2008) Reirradiation after radical radiation therapy: a survey of patterns of practice among Canadian radiation oncologists. Int J Radiat Oncol Biol Phys 72:1523–1529PubMedCrossRefGoogle Scholar
  37. Krause M, Hessel F, Wohlfarth J et al (2003) Ultrafractionation in A7 human malignant glioma in nude mice. Int J Radiat Biol 79:377–383PubMedCrossRefGoogle Scholar
  38. Krause M, Prager J, Wohlfarth J et al (2005a) Ultrafractionation dose not improve the results of radiotherapy in radioresistant murine DDL1 lymphoma. Strahlenther Onkol 181:440–444CrossRefGoogle Scholar
  39. Krause M, Wohlfarth J, Georgi B et al (2005b) Low-dose hyperradiosensitivity of human glioblastoma cell lines in vitro does not translate into improved outcome of ultrafractionated radiotherapy in vivo. Int J Radiat Biol 81:751–758PubMedCrossRefGoogle Scholar
  40. Laramore GE, Griffin TW, Parker RG et al (1978) The use of electron beams in treating local recurrence of breast cancer in previously irradiated fields. Cancer 41:991–995PubMedCrossRefGoogle Scholar
  41. Lingareddy V, Ahmad NR, Mohiuddin M (1997) Palliative reirradiation for recurrent rectal cancer. Int J Radiat Oncol Biol Phys 38:785–790PubMedCrossRefGoogle Scholar
  42. Meoz RT, Fletcher GH, Peters LJ et al (1984) Twice-daily fractionation schemes for advanced head and neck cancer. Int J Radiat Oncol Biol Phys 10:831–836PubMedCrossRefGoogle Scholar
  43. Messahel B, Ashley S, Saran F et al (2009) Relapsed intracranial ependymoma in children in the UK: patterns of relapse, survival and therapeutic outcome. Eur J Cancer 45:1815–1823PubMedCrossRefGoogle Scholar
  44. Mohiuddin M, Marks GM, Lingareddy V, Marks J (1997) Curative surgical resection following reirradiation for recurrent rectal cancer. Int J Radiat Oncol Biol Phys 39:643–649PubMedCrossRefGoogle Scholar
  45. Monroe AT, Bhandare N, Morris CG, Mendenhall WM (2005) Preventing radiation retinopathy with hyperfractionation. Int J Radiat Oncol Biol Phys 61:856–864PubMedCrossRefGoogle Scholar
  46. Näslund I, Nilsson B, Littbrand B (1994) Hyperfractionated radiotherapy of bladder cancer. A ten-year follow-up of a randomized clinical trial. Acta Oncol 33:397–402PubMedCrossRefGoogle Scholar
  47. Nieder C, Nestle U, Niewald M et al (1999) Hyperfractionated reirradiation for malignant glioma. Front Radiat Ther Oncol 33:150–157CrossRefGoogle Scholar
  48. Nieder C, Milas L, Ang KK (2000) Tissue tolerance to reirradiation. Semin Radiat Oncol 10:200–209PubMedCrossRefGoogle Scholar
  49. Nieder C, Andratschke N, Wiedenmann N et al (2004) Radiotherapy for high-grade gliomas. Does altered fractionation improve the outcome? Strahlenther Onkol 180:401–407PubMedCrossRefGoogle Scholar
  50. Nieder C, Grosu AL, Andratschke NH, Molls M (2006) Update of human spinal cord reirradiation tolerance based on additional data from 38 patients. Int J Radiat Oncol Biol Phys 66:1446–1449PubMedCrossRefGoogle Scholar
  51. 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
  52. Niewald M, Feldmann U, Feiden W et al (1998) Multivariate logistic analysis of dose–effect relationship and latency of radiomyelopathy after hyperfractionated and conventionally fractionated radiotherapy in animal experiments. Int J Radiat Oncol Biol Phys 41:681–688PubMedCrossRefGoogle Scholar
  53. Notter G, Turesson I (1984) Multiple small fractions per day versus conventional fractionation. Comparison of normal tissue reactions and effect on breast carcinoma. Radiother Oncol 1:299–308PubMedCrossRefGoogle Scholar
  54. Popovtzer A, Gluck I, Chepeha DB et al (2009) The pattern of failure after reirradiation of recurrent squamous cell head and neck cancer: implications for defining the targets. Int J Radiat Oncol Biol Phys 74:1342–1347PubMedCrossRefGoogle Scholar
  55. Pulkkanen K, Lahtinen T, Lehtimäki A et al (2007) Effective palliation without normal tissue toxicity using low-dose ultrafractionated re-irradiation for tumor recurrence after radical or adjuvant radiotherapy. Acta Oncol 46:1037–1041PubMedCrossRefGoogle Scholar
  56. Ruifrok AC, Kleiboer BJ, van der Kogel AJ (1992) Fractionation sensitivity of the rat cervical spinal cord during radiation retreatment. Radiother Oncol 25:295–300PubMedCrossRefGoogle Scholar
  57. Sause WT, Scott C, Taylor S et al (1995) Radiation Therapy Oncology Group (RTOG) 88-08 and Eastern Cooperative Oncology Group (ECOG) 4588: preliminary results of a phase III trial in regionally advanced, unresectable non-small-cell lung cancer. J Natl Cancer Inst 87:198–205PubMedCrossRefGoogle Scholar
  58. Sause W, Kolesar P, Taylor S IV et al (2000) Final results of phase III trial in regionally advanced unresectable non-small cell lung cancer: Radiation Therapy Oncology Group, Eastern Cooperative Oncology Group, and Southwest Oncology Group. Chest 117:358–364PubMedCrossRefGoogle Scholar
  59. Schoenthaler R, Albright NW, Wara WM et al (1992) Reirradiation of pituitary adenoma. Int J Radiat Oncol Biol Phys 24:307–314PubMedCrossRefGoogle Scholar
  60. Seydel HG, Diener-West M, Urtasun R et al (1985) Hyperfractionation in the radiation therapy of unresectable non-oat cell carcinoma of the lung: preliminary report of a RTOG Pilot Study. Int J Radiat Oncol Biol Phys 11:1841–1847PubMedCrossRefGoogle Scholar
  61. Shehata WM, Hendrickson FR, Hindo WA (1974) Rapid fractionation technique and re-treatment of cerebral metastases by irradiation. Cancer 34:257–261PubMedCrossRefGoogle Scholar
  62. Short SC, Kelly J, Mayes CR et al (2001) Low-dose hypersensitivity after fractionated low-dose irradiation in vitro. Int J Radiat Biol 77:655–664PubMedCrossRefGoogle Scholar
  63. Simmonds RH, Hopewell JW, Robbins ME (1989) Residual radiation-induced injury in dermal tissue: implications for retreatment. Br J Radiol 62:915–920PubMedCrossRefGoogle Scholar
  64. Simonsson M, Qvarnström F, Nyman J et al (2008) Low-dose hypersensitive gammaH2AX response and infrequent apoptosis in epidermis from radiotherapy patients. Radiother Oncol 88:388–397PubMedCrossRefGoogle Scholar
  65. Spencer SA, Harris J, Wheeler RH et al (2008) Final report of RTOG 9610, a multi-institutional trial of reirradiation and chemotherapy for unresectable recurrent squamous cell carcinoma of the head and neck. Head Neck 30:281–288PubMedCrossRefGoogle Scholar
  66. Stewart FA (1999) Re-treatment after full-course radiotherapy: is it a viable option? Acta Oncol 38:855–862PubMedCrossRefGoogle Scholar
  67. Stewart FA, Soranson JA, Alpen EL et al (1984) Radiation-induced renal damage: the effects of hyperfractionation. Radiat Res 98:407–420PubMedCrossRefGoogle Scholar
  68. Tomé WA, Howard SP (2007) On the possible increase in local tumour control probability for gliomas exhibiting low dose hyper-radiosensitivity using a pulsed schedule. Br J Radiol 80:32–37PubMedCrossRefGoogle Scholar
  69. Valentini V, Morganti AG, Gambacorta MA et al (2006) Preoperative hyperfractionated chemoradiation for locally recurrent rectal cancer in patients previously irradiated to the pelvis: a multicentric phase II study. Int J Radiat Oncol Biol Phys 64:1129–1139PubMedCrossRefGoogle Scholar
  70. Watkins JM, Shirai KS, Wahlquist AE et al (2009) Toxicity and survival outcomes of hyperfractionated split-course reirradiation and daily concurrent chemotherapy in locoregionally recurrent, previously irradiated head and neck cancers. Head Neck 31:493–502PubMedCrossRefGoogle Scholar
  71. Withers HR (1985) Biological basis for altered fractionation schemes. Cancer 55:2086–2095PubMedCrossRefGoogle Scholar
  72. Withers HR, Peters LJ, Thames HD, Fletcher GH (1982) Hyperfractionation. Int J Radiat Oncol Biol Phys 8:1807–1809PubMedCrossRefGoogle Scholar
  73. Yomo S, Arkha Y, Delsanti C et al (2009) Repeat gamma knife surgery for regrowth of vestibular schwannomas. Neurosurgery 64:48–54PubMedCrossRefGoogle 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 Hospital Carl Gustav CarusDresdenGermany

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