Fractionation Concepts

  • Carsten Nieder
  • Michael Baumann
Part of the Medical Radiology book series (MEDRAD)


This chapter summarizes the principles of fractionated radiotherapy and altered fractionation approaches. We also provide clinical reirradiation examples and isoeffect calculations. 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 rely on large and well-designed prospective randomized trials or meta-analyses of several trials. Reirradiation is often used to palliative symptoms, but occasionally a curative approach, which requires high cumulative radiation doses, is possible and should be offered. A key consideration is to apply high precision radiotherapy techniques. Hyperfractionated reirradiation might theoretically improve the therapeutic ratio, but prospective trials are required to confirm this hypothesis. Many recent studies actually relied on more convenient hypofractionated regimens.


Rectal Cancer Late Toxicity Biologically Effective Dose Fractionation Regimen Hyperfractionated Radiotherapy 
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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 20:158–160CrossRefPubMedGoogle Scholar
  2. Aupérin A, Le Péchoux C, Rolland E et al (2010) Meta-analysis of concomitant versus sequential radiochemotherapy in locally advanced non-small-cell lung cancer. J Clin Oncol 28:2181–2190CrossRefPubMedGoogle Scholar
  3. Bauman GS, Sneed PK, Wara WM et al (1996) Reirradiation of primary CNS tumors. Int J Radiat Oncol Biol Phys 36:433–441CrossRefPubMedGoogle Scholar
  4. Baumann M, Beck-Bornholdt HP (1999) Hyperfractionated radiotherapy: tops or flops. Med Pediat Oncol 33:399–402CrossRefGoogle Scholar
  5. Baumann M, Gregoire V (2009) Modified fractionation. In: Joiner M, van der Kogel A (eds) Basic clinical radiobiology. London, Hodder Arnold, pp 135–148CrossRefGoogle Scholar
  6. Baumann M, Krause M (2009) Linear-quadratisches Modell und Fraktionierung. In: Bamberg M, Molls M, Sack H (eds) Radioonkologie Band 1 Grundlagen, 2nd edn. W. Zuckschwerdt Verlag GmbH, München, pp 251–267Google Scholar
  7. Baumann M, Bentzen S, Ang KK (1998) Hyperfractionated radiotherapy in head and neck cancer: a second look at the clinical data. Radiother Oncol 46:127–130CrossRefPubMedGoogle Scholar
  8. Beck-Bornholdt HP, Dubben HH, Liertz-Petersen C, Willers H (1997) Hyperfractionation: where do we stand? Radiother Oncol 43:1–21CrossRefPubMedGoogle Scholar
  9. 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 36:203–210CrossRefPubMedGoogle Scholar
  10. Bentzen SM, Joiner MC (2009) The linear-quadratic approach in clinical practice. In: Joiner M, van der Kogel A (eds) Basic clinical radiobiology, 4th edn. Hodder Education, London, pp 120–134CrossRefGoogle Scholar
  11. 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 53:219–226CrossRefPubMedGoogle Scholar
  12. Bourhis J, Overgaard J, Audry H et al (2006) Hyperfractionated or accelerated radiotherapy in head and neck cancer: a meta-analysis. Lancet 368:843–854CrossRefPubMedGoogle Scholar
  13. Brown JM, Probert JC (1975) Early and late radiation changes following a second course of irradiation. Radiology 115:711–716CrossRefPubMedGoogle Scholar
  14. 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 77:1338–1344CrossRefPubMedGoogle Scholar
  15. 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 78:499–506CrossRefPubMedGoogle Scholar
  16. Chow E, van der Linden YM, Roos D et al (2014) Single versus multiple fractions of repeat radiation for painful bone metastases: a randomised, controlled, non-inferiority trial. Lancet Oncol 15:164–171CrossRefPubMedGoogle Scholar
  17. 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 14:280–284CrossRefPubMedGoogle Scholar
  18. 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 77:60–65CrossRefPubMedGoogle Scholar
  19. Dörr W, Baumann M, Herrmann T (1996) Nomenclature of modified fractionation protocols in radiotherapy. Strahlenther Onkol 172:353–355PubMedGoogle Scholar
  20. Dritschilo A, Bruckman JE, Cassady JR, Belli JA (1981) Tolerance of brain to multiple courses of radiation therapy. Br J Radiol 54:782–786CrossRefPubMedGoogle Scholar
  21. 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. Neuro Oncol 12:297–303CrossRefPubMedPubMedCentralGoogle Scholar
  22. Edsmyr F, Andersson L, Esposti PL et al (1985) Irradiation therapy with multiple small fractions per day in urinary bladder cancer. Radiother Oncol 4:197–203CrossRefPubMedGoogle Scholar
  23. Fogh SE, Andrews DW, Glass J et al (2010) Hypofrationated stereotactic radiation therapy: an effective therapy for recurrent high-grade gliomas. J Clin Oncol 28:3048–3053CrossRefPubMedPubMedCentralGoogle Scholar
  24. Fu KK, Newman H, Phillips TL (1975) Treatment of locally recurrent carcinoma of the nasopharynx. Radiology 117:425–431CrossRefPubMedGoogle Scholar
  25. 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 48:7–16CrossRefPubMedGoogle Scholar
  26. Greenberg M, Eisert DR, Cox JD (1976) Initial evaluation of reduced fractionation in the irradiation of malignant epithelial tumors. AJR Am J Roentgenol 126:268–278CrossRefPubMedGoogle Scholar
  27. 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 63:511–519CrossRefPubMedGoogle Scholar
  28. 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 49:1267–1274CrossRefPubMedGoogle Scholar
  29. Haque W, Crane CH, Krishnan S et al (2009) Reirradiation to the abdomen for gastrointestinal malignancies. Radiat Oncol 4:55CrossRefPubMedPubMedCentralGoogle Scholar
  30. Hellman S (1975) Cell kinetics, models, and cancer treatment – some principles for the radiation oncologist. Radiology 114:219–223CrossRefPubMedGoogle Scholar
  31. Hermann T, Baumann M, Dörr W (2006) Klinische Strahlenbiologie: kurz und bündig, 4th edn. Elsevier GmbH/Urban & Fischer Verlag, MünchenGoogle Scholar
  32. Heron DE, Rwigema JC, Gibson MK et al (2011) 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 34:165–172PubMedGoogle Scholar
  33. Holsti LR, Salmo M, Elkind MM (1978) Unconventional fractionation in clinical radiotherapy. Br J Cancer Suppl 3:307–310PubMedPubMedCentralGoogle Scholar
  34. 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 25:231–241CrossRefPubMedGoogle Scholar
  35. Hunter RD, Stewart JG (1977) The tolerance of re-irradiation of heavily irradiated human skin. Br J Radiol 50:573–575CrossRefPubMedGoogle Scholar
  36. Janot F, de Raucourt D, Benhamou E et al (2008) Radomized trial of postoperative reirradiation combined with chemotherapy after salvage surgery compared with salvage surgery alone in head and neck carcinoma. J Clin Oncol 26:5518–5523CrossRefPubMedGoogle Scholar
  37. Jereczek-Fossa BA, Kowalczyk A, D’Onofrio A (2008) Three-dimensional conformal or stereotactic reirradiation of recurrent, metastatic or new primary tumors. Analysis of 108 patients. Strahlenther Onkol 184:36–40CrossRefPubMedGoogle Scholar
  38. 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 112:876–884CrossRefPubMedGoogle Scholar
  39. Jeremic B, Shibamoto Y, Acimovic L et al (1997) Hyperfractionated radiotherapy alone for clinical stage I nonsmall cell lung cancer. Int J Radiat Oncol Biol Phys 38(3):521–525Google Scholar
  40. Joiner MC (1993) Hyperfractionation and accelerated radiotherapy. In: Steel GG (ed) Basic clinical radiobiology. London, Arnold Publishers, pp 65–71Google Scholar
  41. Joiner MC, Bentzen SM (2009) Fractionation: the linear-quadratic approach. In: Joiner M, van der Kogel A (eds) Basic clinical radiobiology, 4th edn. Hodder Education, London, pp 102–119CrossRefGoogle Scholar
  42. Joiner MC, Marples B, Lambin P et al (2001) Low-dose hypersensitivity: current status and possible mechanisms. Int J Radiat Oncol Biol Phys 49:379–389CrossRefPubMedGoogle Scholar
  43. 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 72:1523–1529CrossRefPubMedGoogle Scholar
  44. Karam I, Huang SH, McNiven A et al (2015) Outcomes after reirradiation for recurrent nasopharyngeal carcinoma: North American experience. Head Neck doi:  10.1002/hed.24166
  45. Kilburn JM, Kuremsky JG, Blackstock AW et al (2014) Thoracic re-irradiation using stereotactic body radiotherapy (SBRT) techniques as first or second course of treatment. Radiother Oncol 110:505–510CrossRefPubMedPubMedCentralGoogle Scholar
  46. Krause M, Hessel F, Wohlfarth J et al (2003) Ultrafractionation in A7 human malignant glioma in nude mice. Int J Radiat Biol 79:377–383CrossRefPubMedGoogle Scholar
  47. 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
  48. 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 81:751–758CrossRefPubMedGoogle Scholar
  49. 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 41:991–995CrossRefPubMedGoogle Scholar
  50. Lingareddy V, Ahmad NR, Mohiuddin M (1997) Palliative reirradiation for recurrent rectal cancer. Int J Radiat Oncol Biol Phys 38:785–790CrossRefPubMedGoogle Scholar
  51. Lohaus F, Appold S, Krause M, Baumann M (2013) Local recurrence rate and toxicities after curative reirradiation of HNSCC. Strahlenther Onkol Suppl 1:P24Google Scholar
  52. Magnuson W, Ian Robins H, Mohindra P, Howard S (2014) Large volume reirradiation as salvage therapy for glioblastoma after progression on bevacizumab. J Neurooncol 117:133–139CrossRefPubMedGoogle Scholar
  53. Maranzano E, Trippa F, Casale M et al (2012) Reirradiation of brain metatases with radiosurgery. Radiother Oncol 102:192–197CrossRefPubMedGoogle Scholar
  54. Mauguen A, Péchoux L, Saunders MI et al (2012) Hyperfractionated or accelerated radiotherapy in lung cancer: an individual patient data meta-analysis. J Clin Oncol 30:2788–2797CrossRefPubMedPubMedCentralGoogle Scholar
  55. McDonald MW, Moore MG, Johnstone PA (2012) Risk of carotid blowout after reirradiation of the head and neck: a systematic review. Int J Radiat Oncol Biol Phys 82:1083–1089CrossRefPubMedGoogle Scholar
  56. Meijneke TR, Petit SF, Wentzler D, Hoogeman M, Nuyttens JJ (2013) Reirradiation and stereotactic radiotherapy for tumors in the lung: dose summation and toxicity. Radiother Oncol 107:423–427CrossRefPubMedGoogle Scholar
  57. 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 10:831–836CrossRefPubMedGoogle Scholar
  58. 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 45:1815–1823CrossRefPubMedGoogle Scholar
  59. Mohiuddin M, Marks GM, Lingareddy V, Marks J (1997) Curative surgical resection following reirradiation for recurrent rectal cancer. Int J Radiat Oncol Biol Phys 39:643–649CrossRefPubMedGoogle Scholar
  60. Monroe AT, Bhandare N, Morris CG, Mendenhall WM (2005) Preventing radiation retinopathy with hyperfractionation. Int J Radiat Oncol Biol Phys 61:856–864CrossRefPubMedGoogle Scholar
  61. Näslund I, Nilsson B, Littbrand B (1994) Hyperfractionated radiotherapy of bladder cancer. A ten-year follow-up of a randomized clinical trial. Acta Oncol 33:397–402CrossRefPubMedGoogle Scholar
  62. Nieder C, Nestle U, Niewald M et al (1999) Hyperfractionated reirradiation for malignant glioma. Front Radiat Ther Oncol 33:150–157CrossRefGoogle Scholar
  63. Nieder C, Milas L, Ang KK (2000) Tissue tolerance to reirradiation. Semin Radiat Oncol 10:200–209CrossRefPubMedGoogle Scholar
  64. Nieder C, Andratschke N, Wiedenmann N et al (2004) Radiotherapy for high-grade gliomas. Does altered fractionation improve the outcome? Strahlenther Onkol 180:401–407CrossRefPubMedGoogle Scholar
  65. 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 66:1446–1449CrossRefPubMedGoogle Scholar
  66. 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 31:300–305CrossRefPubMedGoogle Scholar
  67. 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 41:681–688CrossRefPubMedGoogle Scholar
  68. 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 1:299–308CrossRefPubMedGoogle Scholar
  69. Peulen H, Karlsson K, Lindberg K et al (2011) Toxicity after reirradiation of pulmonary tumours with stereotactic body radiotherapy. Radiother Oncol 101:260–266CrossRefPubMedGoogle Scholar
  70. 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 74:1342–1347CrossRefPubMedPubMedCentralGoogle Scholar
  71. 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 46:1037–1041CrossRefPubMedGoogle Scholar
  72. Rudžianskas V, Inčiūra A, Vaitkus S et al (2014) Reirradiation for patients with recurrence head and neck squamous cell carcinoma: a single-institution comparative study. Medicina (Kaunas) 50:92–99CrossRefGoogle Scholar
  73. Ruifrok AC, Kleiboer BJ, van der Kogel AJ (1992) Fractionation sensitivity of the rat cervical spinal cord during radiation retreatment. Radiother Oncol 25:295–300CrossRefPubMedGoogle Scholar
  74. 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 87:198–205CrossRefPubMedGoogle Scholar
  75. 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 117:358–364CrossRefPubMedGoogle Scholar
  76. Schoenthaler R, Albright NW, Wara WM et al (1992) Reirradiation of pituitary adenoma. Int J Radiat Oncol Biol Phys 24:307–314CrossRefPubMedGoogle Scholar
  77. 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 11:1841–1847CrossRefPubMedGoogle Scholar
  78. Shehata WM, Hendrickson FR, Hindo WA (1974) Rapid fractionation technique and re-treatment of cerebral metastases by irradiation. Cancer 34:257–261CrossRefPubMedGoogle Scholar
  79. Short SC, Kelly J, Mayes CR et al (2001) Low-dose hypersensitivity after fractionated low-dose irradiation in vitro. Int J Radiat Biol 77:655–664CrossRefPubMedGoogle Scholar
  80. Simmonds RH, Hopewell JW, Robbins ME (1989) Residual radiation-induced injury in dermal tissue: implications for retreatment. Br J Radiol 62:915–920CrossRefPubMedGoogle Scholar
  81. Simonsson M, Qvarnström F, Nyman J et al (2008) Low-dose hypersensitive gammaH2AX response and infrequent apoptosis in epidermis from radiotherapy patients. Radiother Oncol 88:388–397CrossRefPubMedGoogle Scholar
  82. 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 30:281–288CrossRefPubMedGoogle Scholar
  83. Stewart FA (1999) Re-treatment after full-course radiotherapy: is it a viable option? Acta Oncol 38:855–862CrossRefPubMedGoogle Scholar
  84. Stewart FA, Soranson JA, Alpen EL et al (1984) Radiation-induced renal damage: the effects of hyperfractionation. Radiat Res 98:407–420CrossRefPubMedGoogle Scholar
  85. Tian YM, Zhao C, Guo Y et al (2014) Effect of total dose and fraction size on survival of patients with locally recurrent nasopharyngeal carcinoma treated with intensity-modulated radiotherapy: a phase 2, single-center, randomized controlled trial. Cancer 120:3502–3509CrossRefPubMedGoogle Scholar
  86. 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 80:32–37CrossRefPubMedGoogle Scholar
  87. 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 64:1129–1139CrossRefPubMedGoogle Scholar
  88. 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 31:493–502CrossRefPubMedGoogle Scholar
  89. Withers HR (1985) Biological basis for altered fractionation schemes. Cancer 55:2086–2095CrossRefPubMedGoogle Scholar
  90. Withers HR, Peters LJ, Thames HD, Fletcher GH (1982) Hyperfractionation. Int J Radiat Oncol Biol Phys 8:1807–1809CrossRefPubMedGoogle Scholar
  91. Yomo S, Arkha Y, Delsanti C et al (2009) Repeat gamma knife surgery for regrowth of vestibular schwannomas. Neurosurgery 64:48–54CrossRefPubMedGoogle Scholar
  92. Zhang B, Zhu F, Ma X et al (2014) Matched-pair comparisons of stereotactic body radiotherapy (SBRT) versus surgery for the treatment of early stage non-small cell lung cancer: a systematic review and meta-analysis. Radiother Oncol 112:250–255CrossRefPubMedGoogle Scholar

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© Springer International Publishing Switzerland 2016

Authors and Affiliations

  1. 1.Department of Oncology and Palliative MedicineNordland HospitalBodøNorway
  2. 2.Department of Radiation Oncology, Faculty of Medicine and University Hospital Carl Gustav CarusTechnische Universität DresdenDresdenGermany
  3. 3.OncoRay – National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav CarusTechnische Universität Dresden, Helmholtz-Zentrum Dresden – RossendorfDresdenGermany
  4. 4.Helmholtz-Zentrum Dresden – Rossendorf, Institute od RadiooncologyDresdenGermany
  5. 5.Deutsches Konsortium für Translationale Krebsforschung (DKTK)Dresden und Deutsches Krebsforschungszentrum (DKFZ)HeidelbergGermany
  6. 6.National Center for Tumor Diseases (NCT)Partner Site DresdenDresdenGermany

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