The History and Radiobiology of Hypofractionation

  • Elaine M. Zeman


The use of hypofractionation in radiation therapy dates back to the first third of the twentieth century, but was largely abandoned thereafter due to unacceptable normal tissue complications. In recent years however, it has been “repurposed” thanks to more than a century of advances in physics and imaging that now allow most normal tissues to be excluded from the radiation field. Advances in clinical radiobiology—in particular an improved understanding of the differing fractionation sensitivities of normal tissues and tumors—have also contributed to hypofractionation’s return. The biology of hypofractionation is controversial however, not only in terms of hypofractionation’s mechanism(s) of action, but also the appropriateness of using isoeffect models that were developed with conventional and hyperfractionated radiotherapy in mind. The possible roles vascular injury, microimmune effects and volume effects play in hypofractionation’s efficacy remain unclear, so some have questioned the continued use of conventional isoeffect formulae, based largely on the 5Rs of radiotherapy.


Therapeutic ratio Dose response curves Isoeffect curves Linear-quadratic model α/β ratios BEDs 5Rs of radiotherapy Mechanisms of cell death Volume effects Radiation as an immunostimulant 


  1. 1.
    Roentgen WC. Uber eine neue Art von Strahlen. SitzungsberPhysik-Med Ges Wuerzburg. 1895;137:132–41.Google Scholar
  2. 2.
    Becquerel H. Emission of the new radiations by metallic uranium. C R Acad Sci. 1896;122:1086–8.Google Scholar
  3. 3.
    Curie P, Curie MS. Sur une substance nouvelle radioactive, contenue dans la pechblende. C R Acad Sci. 1898;127:175–8.Google Scholar
  4. 4.
    Stenbeck T. Ein Fall von Hautkrebs geheilt durch Rontgenbestrahlung. Mitteil Grenzgeb Med Chir. 1900;6:347–9.Google Scholar
  5. 5.
    Kogelnik HD. The history and evolution of radiotherapy and radiation oncology in Austria. Int J Radiat Oncol Biol Phys. 1996;35:219–26.PubMedCrossRefPubMedCentralGoogle Scholar
  6. 6.
    Leszczynski K, Boyko S. On the controversies surrounding the origins of radiation therapy. Radiother Oncol. 1997;42:213–7.PubMedCrossRefPubMedCentralGoogle Scholar
  7. 7.
    Bernier J, Hall EJ, Giaccia A. Radiation oncology: a century of achievements. Nat Rev Cancer. 2004;4:737–47.PubMedCrossRefPubMedCentralGoogle Scholar
  8. 8.
    Kaplan HS. Present status of radiation therapy of cancer: an overview. In: Becker FF, editor. Cancer 6: a comprehensive treatise. New York: Plenum Press; 1977. p. 1–34.Google Scholar
  9. 9.
    Thames HD, Hendry JH. Fractionation in radiotherapy. Philadelphia: Taylor and Francis; 1987.Google Scholar
  10. 10.
    Bergonié J, Tribondeau L. Interpretation de quelques resultats de la radiotherapie. C R Acad Sci. 1906;143:983–8.Google Scholar
  11. 11.
    Regaud C. The influence of the duration of irradiation on the changes produced in the testicle by radium (Translated). Int J Radiat Oncol Biol Phys. 1977;2:565–7.PubMedCrossRefPubMedCentralGoogle Scholar
  12. 12.
    Regaud C, Ferroux R. Discordance des effets de rayons X, d’une part dans le testicule, par le peau, d’autre part dans la fractionnement de la dose. C R Soc Biol. 1927;97:431–4.Google Scholar
  13. 13.
    Coutard H. Roentgen therapy of epitheliomas of the tonsillar region, hypopharynx and larynx from 1920 to 1926. Am J Roentgenol. 1932;28:313–31.Google Scholar
  14. 14.
    Coutard H. Present conception of treatment of cancer of the larynx. Radiology. 1940;34:136–45.CrossRefGoogle Scholar
  15. 15.
    Reisner A. Untersuchungen uber die veranderungen der Hauttoleranz bei verschiedener Unterterlung. Strahlentherapie. 1930;37:779–87.Google Scholar
  16. 16.
    Quimby E, MacComb WS. Further studies on the rate of recovery of human skin from the effects of roentgen or gamma rays. Radiology. 1937;29:305–12.CrossRefGoogle Scholar
  17. 17.
    Paterson R. The value of assessing and prescribing dosage in radiation therapy in simple terms. Radiology. 1939;32:221–7.CrossRefGoogle Scholar
  18. 18.
    Ellis F. Tolerance dose in radiotherapy with 200 keV X-rays. Br J Radiol. 1942;15:348–50.CrossRefGoogle Scholar
  19. 19.
    Strandqvist M. Studien uber die kumulative Wirkung der Roentgenstrahlen bei Fraktionierung. Acta Radiol Suppl. 1944;55:1–300.Google Scholar
  20. 20.
    Fletcher GH. Keynote address: the scientific basis of the present and future practice of clinical radiotherapy. Int J Radiat Oncol Biol Phys. 1983;9:1073–82.PubMedCrossRefPubMedCentralGoogle Scholar
  21. 21.
    Ellis F. Relationship of biological effect to dose-time-fractionation factors in radiotherapy. In: Ebert M, Howard M, editors. Current topics in radiation research. Amsterdam: North Holland Publishing; 1968. p. 357–97.Google Scholar
  22. 22.
    Ellis F. Dose, time and fractionation: a clinical hypothesis. Clin Radiol. 1969;20:1–8.PubMedCrossRefPubMedCentralGoogle Scholar
  23. 23.
    Fowler JF, Stern BE. Dose-time relationships in radiotherapy and the validity of cell survival curve models. Br J Radiol. 1963;36:163–73.PubMedCrossRefPubMedCentralGoogle Scholar
  24. 24.
    Fowler JF, Morgan RL, Silvester JA, et al. Experiments with fractionated X-ray treatment of the skin of pigs. I. Fractionation up to 28 days. Br J Radiol. 1963;36:188–96.PubMedCrossRefPubMedCentralGoogle Scholar
  25. 25.
    Orton CG, Ellis F. A simplification in the use of the NSD concept in practical radiotherapy. Br J Radiol. 1973;46:529–37.PubMedCrossRefPubMedCentralGoogle Scholar
  26. 26.
    Bentzen SM. Estimation of radiobiological parameters from clinical data. In: Hagen U, Jung H, Streffer C, editors. Radiation research 1895–1995: volume 2, congress lectures. Wurzburg: Universitatsdruckerei H. Sturtz AG; 1995. p. 833–8.Google Scholar
  27. 27.
    Thomlinson RH, Gray LH. The histological structure of some human lung cancers and the possible implications for radiotherapy. Br J Cancer. 1955;9:539–49.PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Palcic B, Skarsgard LD. Reduced oxygen enhancement ratio at low doses of ionizing radiation. Radiat Res. 1984;100:328–39.PubMedCrossRefPubMedCentralGoogle Scholar
  29. 29.
    Fowler JF, Morgan RL, Wood CAP. Pretherapeutic experiments with the fast neutron beam from the Medical Research Council cyclotron. I. The biological and physical advantages and problems of neutron therapy. Br J Radiol. 1963;36:163–73.PubMedCrossRefPubMedCentralGoogle Scholar
  30. 30.
    Withers HR. The four R’s of radiotherapy. In: Adler H, Lett JT, Zelle M, editors. Advances in radiation biology, vol. 5. New York: Academic Press; 1975. p. 241–71.Google Scholar
  31. 31.
    Steel GG, McMillan TJ, Peacock JH. The 5Rs of radiobiology. Int J Radiat Biol. 1989;56:1045–8.PubMedCrossRefGoogle Scholar
  32. 32.
    Elkind MM, Sutton H. X-ray damage and recovery in mammalian cells. Nature. 1959;184:1293–11295.PubMedCrossRefGoogle Scholar
  33. 33.
    Bedford JS, Mitchell JB, Fox MH. Variations in responses of several mammalian cell lines to low dose-rate irradiation. In: Meyn RE, Withers HR, editors. Radiation biology in cancer research. New York: Raven Press; 1980. p. 251–62.Google Scholar
  34. 34.
    Zeman EM, Bedford JS. Dose-rate effects in mammalian cells: V. Dose fractionation effects in noncycling C3H 10T1/2 cells. Int J Radiat Oncol Biol Phys. 1984;10:2089–98.PubMedCrossRefGoogle Scholar
  35. 35.
    Denekamp J. Changes in the rate of proliferation in normal tissues after irradiation. In: Nygaard O, Adler HI, Sinclair WK, editors. Radiation research: biomedical, chemical and physical perspectives. New York: Academic Press, Inc.; 1975. p. 810–25.CrossRefGoogle Scholar
  36. 36.
    Steel GG. The heyday of cell population kinetics: insights from the 1960’s and 1970’s. Semin Radiat Oncol. 1993;3:78–83.PubMedCrossRefGoogle Scholar
  37. 37.
    Alper T, Howard-Flanders P. The role of oxygen in modifying the radiosensitivity of E. coli B. Nature. 1956;178:978–9.PubMedCrossRefGoogle Scholar
  38. 38.
    Kallman RF. The phenomenon of reoxygenation and its implications for fractionated radiotherapy. Radiology. 1972;105:135–42.PubMedCrossRefGoogle Scholar
  39. 39.
    Brown JM. Evidence for acutely hypoxic cells in mouse tumours, and a possible mechnaism of reoxygenation. Br J Radiol. 1979;52:650–6.PubMedCrossRefGoogle Scholar
  40. 40.
    Chaplin DJ, Durand RE, Olive PL. Acute hypoxia in tumors: implication for modifiers of radiation effects. Int J Radiat Oncol Biol Phys. 1986;12:1279–82.PubMedCrossRefGoogle Scholar
  41. 41.
    Dewhirst MW. Relationships between cycling hypoxia, HIF-1, angiogenesis and oxidative stress. Radiat Res. 2009;172:653–65.PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Douglas BG, Fowler JF. The effect of multiple small doses of X-rays on skin reactions in the mouse and a basic interpretation. Radiat Res. 1976;66:401–26.PubMedCrossRefGoogle Scholar
  43. 43.
    Joiner M, Van Der Kogel A. Basic clinical radiobiology. 4th ed. London: Hodder Arnold; 2009.Google Scholar
  44. 44.
    Thames HD, Withers HR, Peters LJ, et al. Changes in early and late radiation responses with altered dose fractionation: implications for dose-survival relationships. Int J Radiat Oncol Biol Phys. 1982;8:219–26.PubMedCrossRefGoogle Scholar
  45. 45.
    Withers HR, Thames HD, Peters LJ. Differences in the fractionation response of acutely and late-responding tissues. In: Karcher KH, Kogelnik HD, Reinartz G, editors. Progress in radio oncology II. New York: Raven Press; 1982. p. 287–96.Google Scholar
  46. 46.
    Withers HR, Thames HD, Peters LJ. A new isoeffect curve for change in dose per fraction. Radiother Oncol. 1983;1:187–91.PubMedCrossRefGoogle Scholar
  47. 47.
    Zeman EM, Schreiber EC, Tepper JE. Basics of radiation therapy. In: Niederhuber JE, Armitage JO, Doroshow JH, Kastan MB, Tepper JE, editors. Abeloff's clinical oncology. 5th ed. Philadelphia: Churchill Livingstone; 2014. p. 393–422.Google Scholar
  48. 48.
    Fowler JF. Non-standard fractionation in radiotherapy. Int J Radiat Oncol Biol Phys. 1984;10:755–9.PubMedCrossRefGoogle Scholar
  49. 49.
    Fowler JF. The James Kirk memorial lecture. What next in fractionated radiotherapy? Br J Cancer Suppl. 1984;46:285–300.Google Scholar
  50. 50.
    Fowler JF. The linear-quadratic formula and progress in fractionated radiotherapy. Br J Radiol. 1989;62:679–94.PubMedCrossRefGoogle Scholar
  51. 51.
    Fowler JF. 21 years of biologically effective dose. Br J Radiol. 2010;83:554–68.PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Barendsen GW. Differences among tissues with respect to iso-effect relations for fractionated irradiation. Strahlentherapie. 1984;160:667–9.PubMedGoogle Scholar
  53. 53.
    Lee AW, Sze WM, Fowler JF, Chappell R, Leung SF, Teo P. Caution on the use of altered fractionation for nasopharyngeal carcinoma. Radiother Oncol. 1999;52:201–11.Google Scholar
  54. 54.
    Fowler JF, Harari PM, Leborgne F, Leborgne JH. Acute radiation reactions in oral and pharyngeal mucosa: tolerable levels in altered fractionation schedules. Radiother Oncol. 2003;69:161–8.PubMedCrossRefPubMedCentralGoogle Scholar
  55. 55.
    Leskel L. The stereotactic method and radiosurgery of the brain. Acta Chir Scand. 1951;102:316–9.Google Scholar
  56. 56.
    Martin A, Gaya A. Stereotactic body radiotherapy: a review. Clin Oncol (R Coll Radiol). 2010;22:157–72.CrossRefGoogle Scholar
  57. 57.
    Hickey BE, James ML, Lehman M, et al. Fraction size in radiation therapy for breast conservation in early breast cancer. Cochrane Database Syst Rev. 2016;7:CD003860.PubMedPubMedCentralGoogle Scholar
  58. 58.
    Chapman JD, Gillespie CJ. The power of radiation biophysics-let’s use it. Int J Radiat Oncol Biol Phys. 2012;84:309–11.PubMedCrossRefPubMedCentralGoogle Scholar
  59. 59.
    Brown JM, Brenner DJ, Carlson DJ. Dose escalation, not “new biology,” can account for the efficacy of stereotactic body radiation therapy with non-small cell lung cancer. Int J Radiat Oncol Biol Phys. 2013;85:1159–60.PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Brown JM, Carlson DJ, Brenner DJ. The tumor radiobiology of SRS and SBRT: are more than the 5 Rs involved? Int J Radiat Oncol Biol Phys. 2014;88:254–62.PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Nahum AE. The radiobiology of hypofractionation. Clin Oncol (R Coll Radiol). 2015;27:260–9.CrossRefGoogle Scholar
  62. 62.
    Astrahan M. Some implications of linear-quadratic-linear radiation dose-response with regard to hypofractionation. Med Phys. 2008;35:4161–72.PubMedCrossRefGoogle Scholar
  63. 63.
    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.PubMedCrossRefGoogle Scholar
  64. 64.
    Kirkpatrick JP, Brenner DJ, Orton CG. Point/counterpoint. The linear-quadratic model is inappropriate to model high dose per fraction effects in radiosurgery. Med Phys. 2009;36:3381–4.PubMedCrossRefGoogle Scholar
  65. 65.
    Wang JZ, Huang Z, Lo SS, et al. A generalized linear-quadratic model for radiosurgery, stereotactic body radiation therapy, and high-dose rate brachytherapy. Sci Transl Med. 2010;2:39ra48.PubMedCrossRefGoogle Scholar
  66. 66.
    Sheu T, Molkentine J, Transtrum MK, et al. Use of the LQ model with large fraction sizes results in underestimation of isoeffect doses. Radiother Oncol. 2013;109:21–5.PubMedCrossRefGoogle Scholar
  67. 67.
    Ritter M. Rationale, conduct, and outcome using hypofractionated radiotherapy in prostate cancer. Semin Radiat Oncol. 2008;18:249–56.PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Timmerman R, Paulus R, Galvin J, et al. Stereotactic body radiation therapy for inoperable early stage lung cancer. JAMA. 2010;303:1070–6.PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Mehta N, King CR, Agazaryan N, et al. Stereotactic body radiation therapy and 3-dimensional conformal radiotherapy for stage I non-small cell lung cancer: a pooled analysis of biological equivalent dose and local control. Pract Radiat Oncol. 2012;2:288–95.PubMedCrossRefGoogle Scholar
  70. 70.
    Shuryak I, Carlson DJ, Brown JM, et al. High-dose and fractionation effects in stereotactic radiation therapy: analysis of tumor control data from 2965 patients. Radiother Oncol. 2015;115:327–34.PubMedCrossRefPubMedCentralGoogle Scholar
  71. 71.
    Katsoulakis E, Laufer I, Bilsky M, et al. Pathological characteristics of spine metastases treated with high-dose single-fraction stereotactic radiosurgery. Neurosurg Focus. 2017;42:E7.PubMedPubMedCentralCrossRefGoogle Scholar
  72. 72.
    Park C, Papiez L, Zhang S, et al. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  73. 73.
    Fowler JF. Linear quadratics is alive and well: in regard to Park et al. (Int J Radiat Oncol Biol Phys 2008;70:847–852). Int J Radiat Oncol Biol Phys. 2008;72:957. author reply 958PubMedCrossRefPubMedCentralGoogle Scholar
  74. 74.
    Williams MV, Denekamp J, Fowler JF. A review of alpha/beta ratios for experimental tumors: implications for clinical studies of altered fractionation. Int J Radiat Oncol Biol Phys. 1985;11:87–96.PubMedCrossRefPubMedCentralGoogle Scholar
  75. 75.
    Vitale I, Galluzzi L, Castedo M, et al. Mitotic catastrophe: a mechanism for avoiding genomic instability. Nat Rev Mol Cell Biol. 2011;12:385–92.PubMedCrossRefPubMedCentralGoogle Scholar
  76. 76.
    Galluzzi L, Vitale I, Abrams JM, et al. Molecular definitions of cell death subroutines: recommendations of the nomenclature committee on cell death 2012. Cell Death Differ. 2012;19:107–20.PubMedCrossRefPubMedCentralGoogle Scholar
  77. 77.
    Kerr JFR, Wyllie AH, Currie AR. Apoptosis: a basic biological phenomenon with wide ranging implications in tissue kinetics. Br J Cancer. 1972;26:239–57.PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Meyn R. Apoptosis and response to radiation: implications for radiation therapy. Oncology. 1997;11:349–56.PubMedGoogle Scholar
  79. 79.
    Campisi J. Aging, cellular senescence, and cancer. Annu Rev Physiol. 2013;75:685–705.PubMedCrossRefGoogle Scholar
  80. 80.
    Gewirtz DA, Holt SE, Elmore LW. Accelerated senescence: an emerging role in tumor cell response to chemotherapy and radiation. Biochem Pharmacol. 2008;76:947–57.PubMedCrossRefPubMedCentralGoogle Scholar
  81. 81.
    Cho YS, Park SY, Shin HS, et al. Physiological consequences of programmed necrosis, an alternative form of cell demise. Mol Cells. 2010;29:327–32.PubMedCrossRefPubMedCentralGoogle Scholar
  82. 82.
    Golden EB, Pellicciotta I, Demaria S, et al. The convergence of radiation and immunogenic cell death signaling pathways. Front Oncol. 2012;2:88.PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Galluzzi L, Kepp O, Kroemer G. Immunogenic cell death in radiation therapy. Oncoimmunology. 2013;2:e26536.PubMedPubMedCentralCrossRefGoogle Scholar
  84. 84.
    D’Souza NM, Fang P, Logan J, et al. Combining radiation therapy with immune checkpoint blockade for central nervous system malignancies. Front Oncol. 2016;6:212.PubMedPubMedCentralCrossRefGoogle Scholar
  85. 85.
    Rubin P, Casarett GW. Clinical radiation pathology. Philadelphia: WB Saunders; 1968.Google Scholar
  86. 86.
    Denekamp J. Vascular endothelium as the vulnerable element in tumours. Acta Radiol Oncol. 1984;23:217–25.PubMedCrossRefPubMedCentralGoogle Scholar
  87. 87.
    Goel S, Duda DG, Xu L, et al. Normalization of the vasculature for treatment of cancer and other diseases. Physiol Rev. 2011;91:1071–121.PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Lan J, Wan XL, Deng L, et al. Ablative hypofractionated radiotherapy normalizes tumor vasculature in Lewis lung carcinoma mice model. Radiat Res. 2013;179:458–64.PubMedCrossRefPubMedCentralGoogle Scholar
  89. 89.
    Semenza GL. Hypoxia, clonal selection, and the role of HIF-1 in tumor progression. Crit Rev Biochem Mol Biol. 2000;35:71–103.PubMedCrossRefPubMedCentralGoogle Scholar
  90. 90.
    Semenza GL. Defining the role of hypoxia-inducible factor 1 in cancer biology and therapeutics. Oncogene. 2010;29:625–34.PubMedCrossRefPubMedCentralGoogle Scholar
  91. 91.
    Moeller BJ, Dreher MR, Rabbani ZN, et al. Pleiotropic effects of HIF-1 blockade on tumor radiosensitivity. Cancer Cell. 2005;8:99–110.PubMedCrossRefPubMedCentralGoogle Scholar
  92. 92.
    Garcia-Barros M, Paris F, Cordon-Cardo C, et al. Tumor response to radiotherapy regulated by endothelial cell apoptosis. Science. 2003;300:1155–9.PubMedCrossRefPubMedCentralGoogle Scholar
  93. 93.
    Fuks Z, Kolesnick R. Engaging the vascular component of the tumor response. Cancer Cell. 2005;8:89–91.PubMedCrossRefPubMedCentralGoogle Scholar
  94. 94.
    Moding EJ, Castle KD, Perez BA, et al. Tumor cells, but not endothelial cells, mediate eradication of primary sarcomas by stereotactic body radiation therapy. Sci Transl Med. 2015;7:278ra34.PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Song CW, Kim MS, Cho LC, et al. Radiobiological basis of SBRT and SRS. Int J Clin Oncol. 2014;19:570–8.PubMedCrossRefPubMedCentralGoogle Scholar
  96. 96.
    Kim MS, Kim W, Park IH, et al. Radiobiological mechanisms of stereotactic body radiation therapy and stereotactic radiation surgery. Radiat Oncol J. 2015;33:265–75.PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Song CW, Lee YJ, Griffin RJ, et al. Indirect tumor cell death after high-dose hypofractionated irradiation: implications for stereotactic body radiation therapy and stereotactic radiation surgery. Int J Radiat Oncol Biol Phys. 2015;93:166–72.PubMedPubMedCentralCrossRefGoogle Scholar
  98. 98.
    Hermens AF, Barendsen GW. Changes of cell proliferation characteristics in a rat rhabdomyosarcoma before and after X-irradiation. Eur J Cancer. 1969;5:173–89.PubMedCrossRefPubMedCentralGoogle Scholar
  99. 99.
    Formenti SC, Demaria S. Systemic effects of local radiotherapy. Lancet Oncol. 2009;10:718–26.PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Demaria S, Formenti SC. Radiation as an immunological adjuvant: current evidence on dose and fractionation. Front Oncol. 2012;2:153.PubMedPubMedCentralGoogle Scholar
  101. 101.
    Demaria S, Formenti SC. Radiotherapy effects on anti-tumor immunity: implications for cancer treatment. Front Oncol. 2013;3:128.PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    Burnette B, Weichselbaum RR. The immunology of ablative radiation. Semin Radiat Oncol. 2015;25:40–5.PubMedCrossRefPubMedCentralGoogle Scholar
  103. 103.
    Demaria S, Pilones KA, Vanpouille-Box C, et al. The optimal partnership of radiation and immunotherapy: from preclinical studies to clinical translation. Radiat Res. 2014;182:170–81.PubMedPubMedCentralCrossRefGoogle Scholar
  104. 104.
    Ishihara D, Pop L, Takeshima T, et al. Rationale and evidence to combine radiation therapy and immunotherapy for cancer treatment. Cancer Immunol Immunother. 2016;66:281–98.PubMedCrossRefPubMedCentralGoogle Scholar
  105. 105.
    Postow MA, Callahan MK, Barker CA, et al. Immunologic correlates of the abscopal effect in a patient with melanoma. N Engl J Med. 2012;366:925–31.PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Golden EB, Demaria S, Schiff PB, et al. An abscopal response to radiation and ipilimumab in a patient with metastatic non-small cell lung cancer. Immunol Res. 2013;1:365–72.Google Scholar
  107. 107.
    Vatner RE, Cooper BT, Vanpouille-Box C, et al. Combinations of immunotherapy and radiation in cancer therapy. Front Oncol. 2014;4:325.PubMedPubMedCentralCrossRefGoogle Scholar
  108. 108.
    Timmerman R, McGarry R, Yiannoutsos C, et al. Excessive toxicity when treating central tumors in a phase II study of stereotactic body radiation therapy for medically inoperable early-stage lung cancer. J Clin Oncol. 2006;24:4833–9.CrossRefPubMedGoogle Scholar
  109. 109.
    Lo SS, Sahgal A, Chang EL, et al. Serious complications associated with stereotactic ablative radiotherapy and strategies to mitigate the risk. Clin Oncol (R Coll Radiol). 2013;25:378–87.CrossRefGoogle Scholar
  110. 110.
    Cozzarini C, Fiorino C, Deantoni C, et al. Higher-than-expected severe (grade 3-4) late urinary toxicity after postprostatectomy hypofractionated radiotherapy: a single-institution analysis of 1176 patients. Eur Urol. 2014;66:1024–30.PubMedCrossRefPubMedCentralGoogle Scholar
  111. 111.
    Modh A, Rimner A, Williams E, et al. Local control and toxicity in a large cohort of central lung tumors treated with stereotactic body radiation therapy. Int J Radiat Oncol Biol Phys. 2014;90:1168–76.PubMedPubMedCentralCrossRefGoogle Scholar
  112. 112.
    Withers HR, Taylor JMG, Maciejewski B. Treatment volume and tissue tolerance. Int J Radiat Oncol Biol Phys. 1988;14:751.PubMedCrossRefPubMedCentralGoogle Scholar
  113. 113.
    Brown JM, Diehn M, Loo BWJ. Stereotactic ablative radiotherapy should be combined with a hypoxic cell radiosensitizer. Int J Radiat Oncol Biol Phys. 2010;78:323–7.PubMedPubMedCentralCrossRefGoogle Scholar
  114. 114.
    Brenner DJ, Hlatky LR, Hahnfeldt PJ, et al. The linear-quadratic model and most other common radiobiological models result in similar predictions of time-dose relationships. Radiat Res. 1998;150:83–91.PubMedCrossRefPubMedCentralGoogle Scholar
  115. 115.
    Brenner DJ. The linear-quadratic model is an appropriate methodology for determining isoeffective doses at large doses per fraction. Semin Radiat Oncol. 2008;18:234–9.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Radiation OncologyUNC School of MedicineChapel HillUSA

Personalised recommendations