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Radiobiology of High Dose Fractions

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Stereotactic Body Radiotherapy

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Abstract

Advances in the technology of radiotherapy delivery have resulted in deliberate radiation fluence and dose displacement away from designated normal tissues, and with improved conformity of tumour dose. This applies to normal tissues outside the planning target volume (PTV) in most cases. The prospects for hypofractionation improve in these circumstances provided that loss of function of the normal tissue included in the PTV is not considered harmful or deleterious to the subsequent health and well-being of the patient.

The radiobiology of large fractions is considered in the context of the linear quadratic (LQ) model of radiation effect and the concept of the biological effective dose (BED). One feature of the model is that it might overestimate high fractional dose effects especially in tumours or tissues which have low α/β ratios. For normal tissues, this is probably advantageous since the model provides a ‘worst case scenario’, and protects against overdosage. Substantial benefits in the therapeutic ratio with increasing fractionation only apply where there is a marked difference between the α/β ratios of the tumour and relevant normal tissues. Thus slow growing tumours with low α/β ratios are preferred candidates for hypofractionation. Where high dose fractions are employed it is vital to ensure that the prescribed dose is not exceeded in relevant normal tissue where overdosage can be harmful.

Some worked examples are given to illustrate these principles, using BED calculations, with examples of how to include straightening out of the dose response curve.

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References

  1. Barendsen GW. Dose fractionation, dose-rate and iso-effect relationships for normal tissue responses. Int J Radiat Oncol Biol Phys. 1982;8:1981–97.

    Article  CAS  PubMed  Google Scholar 

  2. Fowler JF. The linear-quadratic formula and progress in fractionated radiotherapy. Br J Radiol. 1989;62:679–94.

    Article  CAS  PubMed  Google Scholar 

  3. Fowler JF. 21 years of biologically effective dose. Br J Radiol. 2010;83:554–68.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  4. Dale RG, Jones B. The clinical radiobiology of brachytherapy. Br J Radiol. 1998;71:465–83.

    Article  CAS  PubMed  Google Scholar 

  5. Dale RG, Jones B. The assessment of RBE effects using the concept of biologically effective dose. Int J Radiat Oncol Biol Phys. 1999;43:639–45.

    Article  CAS  PubMed  Google Scholar 

  6. Jones B, Dale RG. The clinical radiobiology of high-LET radiotherapy with particular reference to proton radiotherapy. Clin Oncol. 2003;15:S16–22.

    Article  CAS  Google Scholar 

  7. Armpilia CI, Dale RG, Coles IP, Jones B, Antipas V. The determination of radiobiologically optimized half-lives for radionuclides used in permanent brachytherapy implants. Int J Radiat Oncol Biol Phys. 2003;55:378–85.

    Article  CAS  PubMed  Google Scholar 

  8. Carabe-Fernandez A, Dale RG, Jones B. The incorporation of the concept of minimum RBE (RBEmin) into the linear-quadratic model and the potential for improved radiobiological analysis of high-LET treatments. Int J Radiat Biol. 2007;83:27–39.

    Article  CAS  PubMed  Google Scholar 

  9. Lea DE, Catcheside DG. The mechanism of the induction by radiation of chromosome aberrations in Tradescantia. J Genet. 1942;44:216–45.

    Article  Google Scholar 

  10. Gray LH, Scholes MF. The effect of ionising radiation on the broad bean root. Br J Radiol. 1951;24:285–91.

    Article  CAS  PubMed  Google Scholar 

  11. Kellerer AM, Rossi HH. The theory of dual radiation action. Curr Top Radiat Res Q. 1972;8:85–158.

    CAS  Google Scholar 

  12. Chadwick KH, Leenhouts HP. A molecular theory of cell survival. Phys Med Biol. 1973;18:78–87.

    Article  CAS  PubMed  Google Scholar 

  13. Park C, Papiez L, Zhang S, Story M, Timmerman RD. Universal survival curve and single fraction equivalent dose: useful tools in understanding potency of ablative radiotherapy. Int J Radiat Oncol Biol Phys. 2008;70:847–52.

    Article  PubMed  Google Scholar 

  14. Fowler JF. Linear quadratics is alive and well: in response to Park et al. (IJROBP 2008: 70: 847–852). Int J Radiat Oncol Biol Phys. 2008;72:957.

    Article  PubMed  Google Scholar 

  15. Jones B, Dale RG, Khaksar SJ. Biological equivalent dose assessment of the consequences of hypofractionated radiotherapy. Int J Radiat Oncol Biol Phys. 2000;47:1379–84.

    Article  CAS  PubMed  Google Scholar 

  16. Niemierko A. Reporting and analyzing dose distributions: a concept of equivalent uniform dose. Med Phys. 1997;24:103–10.

    Article  CAS  PubMed  Google Scholar 

  17. Fuks Z, Kolesnick R. Engaging the vascular component of the tumor response. Cancer Cell. 2005;8(2):89–91.

    Article  CAS  PubMed  Google Scholar 

  18. Park HJ, Griffin RJ, Hui S, Levitt SH, Song CW. Radiation-induced vascular damage in tumors: implications of vascular damage in ablative hypofractionated radiotherapy (SBRT and SRS). Radiat Res. 2012;177(3):311–27.

    Article  CAS  PubMed  Google Scholar 

  19. Kirkpatrick JP, Meyer JJ, Marks LB. The linear-quadratic model is inappropriate to model high dose per fraction effects in radiosurgery. Semin Radiat Oncol. 2008;18:240–3.

    Article  PubMed  Google Scholar 

  20. Hendry JH, Roberts SA, Slevin NJ, Keane TJ, Barton MB, Agren-Conqvst A. Influence of radiotherapy treatment time on control of laryngeal cancer: comparisons between centres in Manchester, UK and Toronto, Canada. Radiother Oncol. 1994;31:14–22.

    Article  CAS  PubMed  Google Scholar 

  21. Roberts SA, Hendry JH, Brewster AE, Slevin NJ. The influence of radiotherapy treatment time on the control of laryngeal cancer: a direct analysis of data from two British Institute of Radiology trials to calculate the lag period and the time factor. Br J Radiol. 1994;67:790–4.

    Article  CAS  PubMed  Google Scholar 

  22. Dale RG. Time-dependent tumour repopulation factors in linear-quadratic equations—implications for treatment strategies. Radiother Oncol. 1989;15:371–82.

    Article  CAS  PubMed  Google Scholar 

  23. Dale RG, Hendry JH, Jones B, Robertson G, Deehan C, Sinclair JA. Practical methods for compensating for missed treatment days in radiotherapy, with particular reference to head and neck schedules. Clin Oncol. 2002;14:382–93.

    Article  CAS  Google Scholar 

  24. Thames HD, Hendry JH, editors. Fractionation in radiotherapy. London/Philadelphia: Taylor and Francis; 1987. ISBN 0–85066–374–1.

    Google Scholar 

  25. Jones B, Dale RG, Deehan C, Hopkins KI, Morgan DA. The role of biologically effective dose (BED) in clinical oncology. Clin Oncol. 2001;13:71–81.

    CAS  Google Scholar 

  26. Pop LA, van der Plas M, Ruifrok AC, Schalkwijk LJ, Hanssen AE, van der Kogel AJ. Tolerance of rat spinal cord to continuous interstitial irradiation. Int J Radiat Oncol Biol Phys. 1998;40(3):681–9.

    Article  CAS  PubMed  Google Scholar 

  27. Van den Aardweg GJMJ, Hopewell JW. The kinetics of repair of sublethal radiation—induced damage in the pig epidermis: an interpretation based on a fast and a slow component of repair. Radiother Oncol. 1992;23:94–104.

    Article  PubMed  Google Scholar 

  28. Ruifrok ACC, Kleiber BJ, van der Kogel AJ. Repair kinetics of radiation damage in the developing rat cervical spinal cord. Int J Radiat Biol. 1993;63:501–8.

    Article  CAS  PubMed  Google Scholar 

  29. Dale RG. The application of the linear-quadratic dose-effect equation to fractionated and protracted radiotherapy. Br J Radiol. 1985;55:515–28.

    Article  Google Scholar 

  30. Hopewell JW, Millar WT, Lindquist C, Nordström H, Lidberg P, Gårding J. Application of the concept of biologically effective dose (BED) to patients with Vestibular Schwannomas treated by radiosurgery. J Radiosurg SBRT. 2013;2:259–71.

    Google Scholar 

  31. Fowler JF, Sheldon PW, Denekamp J, Field SB. Optimum fractionation of the C3H mouse mammary carcinoma using x-rays, the hypoxic-cell radiosensitizer Ro-07–0582, or fast neutrons. Int J Radiat Oncol Biol Phys. 1976;1(7–8):579–92.

    Article  CAS  PubMed  Google Scholar 

  32. Fowler JF, Denekamp J. A review of cell radiosensitisation in experimental tumours. Pharmacol Ther. 1979;7:413–44.

    Article  CAS  PubMed  Google Scholar 

  33. Niemierko A, Goitein M. Dose-volume effects in the spinal cord. Radiother Oncol. 1994;31:265–7.

    Article  CAS  PubMed  Google Scholar 

  34. Sanchez-Nieto B, Nahum AE, Dearnaley DP. Individualisation of dose prescription based on normal-tissue-dose-volume and radiosensitivity data. Int J Radiat Oncol Biol Phys. 2001;49:487–99.

    Article  CAS  PubMed  Google Scholar 

  35. Seppenwoolde Y, Lebesque JV, de Jaeger K, Belderbos JS, Boersma LJ, Schilstra C, Henning GT, Hayman JA, Martel MK, Ten Haken RK. Comparing different NTCP models that predict the incidence of radiation pneumonitis. Normal tissue complication probability. Int J Radiat Oncol Biol Phys. 2003;55:724–35.

    Article  PubMed  Google Scholar 

  36. Werner-Wasik M, Yorke E, Deasy J, Nam J, Marks LB. Radiation dose-volume effects in the esophagus. Int J Radiat Oncol Biol Phys. 2010;76:S86–93.

    Article  PubMed Central  PubMed  Google Scholar 

  37. Marks LB, Bentzen SM, Deasy JO, Kong FM, Bradley JD, Vogelius IS, El Naga I, Hubbs JL, Lebesque JV, Timmerman RD, Martel MK, Jackson A. Int J Radiat Oncol Biol Phys. 2010;76:S70–6.

    Article  PubMed Central  PubMed  Google Scholar 

  38. Rutkowska ES, Syndikus I, Baker CR, Nahum AE. Mechanistic modelling of radiotherapy-induced lung toxicity. Br J Radiol. 2012;85:1242–8.

    Article  Google Scholar 

  39. Schultheiss TE. The controversies and pitfalls in modelling normal tissue radiation injury/damage. Semin Radiat Oncol. 2001;11:210–4.

    Article  CAS  PubMed  Google Scholar 

  40. Jones B, Dale RG, Gaya A. Linear quadratic modelling of increased late normal tissue effects in special clinical situations. Int J Radiat Oncol Biol Phys. 2006;64:948–53.

    Article  PubMed  Google Scholar 

  41. Jones B, Dale RG. The potential for mathematical modelling in the assessment of the radiation dose equivalent of cytotoxic chemotherapy given concomitantly with radiotherapy. Br J Radiol. 2005;78:939–44.

    Article  CAS  PubMed  Google Scholar 

  42. Plataniotis GA, Dale RG. Biologically effective dose-response relationships for breast cancer treated by conservative surgery and postoperative radiotherapy. Int J Radiat Oncol Biol Phys. 2009;75:512–7.

    Article  PubMed  Google Scholar 

  43. Cattaneo GM, Passoni P, Longobardi B, Slim N, Reni M, Cereda S, di Muzio N, Calandrino R. Dosimetric and clinical predictors of toxicity following combined chemotherapy and moderately hypofractionated rotational radiotherapy of locally advanced pancreatic adenocarcinoma. Radiother Oncol. 2013. doi:10.1016/j.radonc.2013.05.011. pii S0167–8140(13)00224–7.

    Google Scholar 

  44. Meade S, Sanghera P, McConkey C, Fowler J, Fountzilas G, Glaholm J, Hartley A. Revising the radiobiological model of synchronous chemotherapy in head-and—neck cancer: a new analysis examining reduced weighting of accelerated repopulation. Int J Radiat Oncol Biol Phys. 2013;86:157–63.

    Article  PubMed  Google Scholar 

  45. Schultz-Ertner D, Tsujii H. Particle radiation therapy using proton and heavier ion beams. J Clin Oncol. 2007;25:953–64.

    Article  Google Scholar 

  46. Jones B. The case for particle therapy. Br J Radiol. 2006;79:24–31.

    Article  CAS  PubMed  Google Scholar 

  47. Jones B. Modelling carcinogenesis after radiotherapy using Poisson statistics: implications for IMRT, protons and ions. J Radiol Prot. 2009;29:A143–57.

    Article  CAS  PubMed  Google Scholar 

  48. Weber U, Kraft G. Comparison of carbon ions versus protons. Cancer J. 2009;15:325–32.

    Article  CAS  PubMed  Google Scholar 

  49. Jiang GL. Particle therapy for cancers: a new weapon in radiation therapy. Front Med. 2012;6:165–72.

    Article  PubMed  Google Scholar 

  50. Loeffler JS, Durante M. Charged particle therapy—optimisation, challenges and future directions. Nat Rev Clin Oncol. 2013;10:411–24.

    Article  PubMed  Google Scholar 

  51. Jones B, Dale RG, Carabe-Fernandez A. High LET radiotherapy: chapter 15. In: Dale RG, Jones B, editors. Radiobiological modelling in radiation oncology. London: Brit Inst Radiol; 2007. p. 265–75.

    Google Scholar 

  52. Jones B, Underwood TC, Carabe-Fernandez A, Dale RG. Further analysis of fast neutron relative biological effects and implications for charged particle therapy. Br J Radiol. 2011;84:S11–8.

    Article  PubMed  Google Scholar 

  53. Zhang B, Davidson MM, Zhou H, Wang C, Walker WF, Hei TK. Cytoplasmic irradiation results in mitochondrial dysfunction and DRP1-dependent mitochondrial fission. Cancer Res. 2013;73(22):6700–10. doi:10.1158/0008–5472.CAN-13–1411. Epub 2013 Sep 30.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  54. Jones B, Tan LT, Dale RG. Derivation of the optimum dose per fraction from the linear quadratic model. Br J Radiol. 1995;68:894–902.

    Article  CAS  PubMed  Google Scholar 

  55. Armpilia CI, Dale RG, Jones B. Determination of the optimum doe per fraction in fractionated radiotherapy when there is delayed onset of tumour repopulation during treatment. Br J Radiol. 2004;77:765–7.

    Article  CAS  PubMed  Google Scholar 

  56. Jackson A, Yorke ED, Rosenzweig KE. The atlas of complication incidence: a proposal for a new standard for reporting the results of radiotherapy protocols. Semin Radiat Oncol. 2006;16:260–8.

    Article  PubMed  Google Scholar 

  57. Bentzen SM, Constine LS, Deasy JO, Fisbruch A, Jackson A, Marks LB, Ten Haken RK, Yorke ED. Quantitative analysis of normal tissue effects in the clinic (QUANTEC): an introduction to the scientific issues. Int J Radiat Oncol Biol Phys. 2010;76(3 Supp):S3–9.

    Article  PubMed Central  PubMed  Google Scholar 

  58. Deasy JO, Bentzen SM, Jackson A, Ten Haken RK, Yorke ED, Constine LS, et al. Improving normal tissues complications probability models: the need to adopt a “data pooling” culture. Int J Radiat Oncol Biol Phys. 2010;73(3 Supp):S151–4.

    Article  Google Scholar 

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Authors and Affiliations

  1. CRUK-MRC Oxford Institute, ORCRB Building, University of Oxford, OX37DQ, Oxford, Oxfordshire, UK

    Bleddyn Jones MA, MSc, MB, BChir, MD, FRCP

  2. Department of Surgery and Cancer, Faculty of Medicine, Imperial College, London, UK

    Roger G. Dale PhD

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  1. Bleddyn Jones MA, MSc, MB, BChir, MD, FRCP
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  2. Roger G. Dale PhD
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Correspondence to Bleddyn Jones MA, MSc, MB, BChir, MD, FRCP .

Editor information

Editors and Affiliations

  1. Guy's Hospital, London, United Kingdom

    Andrew Gaya

  2. Dept. Radiation Oncology, Harvard Medical School Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA

    Anand Mahadevan

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Jones, B., Dale, R.G. (2015). Radiobiology of High Dose Fractions. In: Gaya, A., Mahadevan, A. (eds) Stereotactic Body Radiotherapy. Springer, London. https://doi.org/10.1007/978-0-85729-597-2_5

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  • DOI: https://doi.org/10.1007/978-0-85729-597-2_5

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