Skip to main content
SpringerLink
Log in

Radiobiological basis of SBRT and SRS

  • Review Article
  • Published:
International Journal of Clinical Oncology Aims and scope Submit manuscript

Abstract

Stereotactic body radiation therapy (SBRT) and stereotactic radiosurgery (SRS) have been demonstrated to be highly effective for a variety of tumors. However, the radiobiological principles of SBRT and SRS have not yet been clearly defined. It is well known that newly formed tumor blood vessels are fragile and extremely sensitive to ionizing radiation. Various lines of evidence indicate that irradiation of tumors with high dose per fraction, i.e. >10 Gy per fraction, not only kills tumor cells but also causes significant damage in tumor vasculatures. Such vascular damage and ensuing deterioration of the intratumor environment then cause ischemic or indirect/secondary tumor cell death within a few days after radiation exposure, indicating that vascular damage plays an important role in the response of tumors to SBRT and SRS. Indications are that the extensive tumor cell death due to the direct effect of radiation on tumor cells and the secondary effect through vascular damage may lead to massive release of tumor-associated antigens and various pro-inflammatory cytokines, thereby triggering an anti-tumor immune response. However, the precise role of immune assault on tumor cells in SBRT and SRS has not yet been clearly defined. The “4 Rs” for conventional fractionated radiotherapy do not include indirect cell death and thus 4 Rs cannot account for the effective tumor control by SBRT and SRS. The linear-quadratic model is for cell death caused by DNA breaks and thus the usefulness of this model for ablative high-dose SBRT and SRS is limited.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Nagata Y (2013) Stereotactic body radiotherapy for early stage lung cancer. Cancer Res Treat 45:155–161

    Article  PubMed Central  PubMed  Google Scholar 

  2. Timmerman R, Paulus R, Galvin J et al (2010) Stereo-tactic body radiotherapy to treat medically inoperable early stage lung cancer patients. J Am Med Assoc 303(11):1070–1076

    Article  CAS  Google Scholar 

  3. Folkert MR, Bilsky MH, Tom AK, et al. (2014) Outcome and toxicity for hypofractionated and single-fraction image-guided stereotactic radiosurgery for sarcomas metastasizing to the spine. Int J Radiat Oncol Biol Phys 88:1085–1091

  4. Kim YJ, Cho KH, Kim JY et al (2010) Single-dose versus fractionated stereotactic radiotherapy for brain metastases. Int J Radiat Oncol Biol Phys 81:483–489

    Article  PubMed  Google Scholar 

  5. Jang WI, Kim MS, Bae SH et al (2013) High-dose stereotactic body radiotherapy correlates increased local control and overall survival in patients with inoperable hepatocellular carcinoma. Radiat Oncol 8:250–262

    Article  PubMed  Google Scholar 

  6. Cho LC, Fonteyne V, DeNeve W, et al (2012) Stereotactic body radiotherapy. In: Levitt et al SH (eds) Technical basis of radiation therapy, medical radiology. Radiation oncology. Springer, Berlin, pp 363–400

  7. Sperduto PW (2003) A review of stereotactic radiosurgery in the management of brain metastases. Technol Cancer Res Treat 2:105–110

    PubMed  Google Scholar 

  8. Fowler JF, Wolfgan AT, Fenwik JD et al (2004) A challenge to traditional radiation oncology. Int J Radiat Oncol Biol Phys 60:1241–1256

    Article  PubMed  Google Scholar 

  9. Brown JM, Koong AC (2008) High-dose single-fraction radiotherapy: exploiting a new biology? Int J Radiat Oncol Biol Phys 71:324–325

    Article  PubMed  Google Scholar 

  10. Brown JM, Diehn M, Loo BW (2010) Stereotactic ablative radiotherapy should be combined with a hypoxic cell radiosensitizer. Int J Radiat Oncol Biol Phys 78:323–327

    Article  PubMed Central  PubMed  Google Scholar 

  11. Brown JM, Brenner DJ, Carlson DJ (2013) Does 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 85:1159–1160

    Article  PubMed Central  PubMed  Google Scholar 

  12. Song CW, Park HJ, Griffin RJ, et al (2012) Radiobiology of stereotactic radiosurgery and stereotactic body radiation therapy. In: Levitt et al SH (eds) Technical basis of radiation therapy, medical radiology. Radiation oncology. Springer, Berlin, pp 51–61

  13. Park HJ, Griffin RJ, Hui S et al (2012) Radiation-induced vascular damage in tumors: implications of vascular damage in ablative hypofractionated radiotherapy (SBRT and SRS). Radiat Res 177:311–327

    Article  CAS  PubMed  Google Scholar 

  14. Song CW, Cho LC, Yuan J et al (2013) Radiobiology of stereotactic body radiation therapy/stereotactic radiosurgery and the linear-quadratic mode. Int J Radiat Oncol Biol Phys 87:18–19

    Article  PubMed  Google Scholar 

  15. Song CW, Park I, Cho LC et al (2014) Is there indirect cell death involved in response of tumor to SRS and SBRT? Int J Radiat Oncol Biol Phys 89:924–925

    Article  PubMed  Google Scholar 

  16. Kirkpatrick JP, Meyer JJ, Marks LB (2008) The linear-quadratic model is appropriate to model high dose per fraction effects in radiosurgery. Semin Radiat Oncol 18:240–243

    Article  PubMed  Google Scholar 

  17. Kocher M, Treuer H, Voges J et al (2000) Computer simulation of cytotoxic and vascular effects of radiosurgery in solid and necrotic brain metastases. Radiother Oncol 54:149–156

    Article  CAS  PubMed  Google Scholar 

  18. Brown JM, Carlson DJ, Brenner DJ (2014) The tumor radiobiology of SRS and SBRT: are more than the 5 Rs involved? Int J Radiat Oncol Bio Phys 88:254–262

    Article  Google Scholar 

  19. McBride WH, Schaue D (2013) In situ tumor ablation with radiation therapy: Its effect on the tumor microenvironment and anti-tumor immunity. In: Keisari Y (eds) Tumor ablation. Springer Science + Business Media, Dordrecht

  20. Finkelstein SE, Timmerman R, McBride WH et al (2011) The confluence of stereotactic ablative radiotherapy and tumor immunology. Clin Dev Immunol 2011:7–13 Article ID 439752

    Article  Google Scholar 

  21. Monte UD (2009) Does the cell number 109 still really fit one gram of tumor tissue? Cell Cycle 8(3):505–506

    Article  PubMed  Google Scholar 

  22. Leith JT, Cook S, Choughle P et al (1994) Intrinsic and extrinsic characteristics of human tumors relevant to radiosurgery: comparative cellular radiosensivity and hypoxic percentages. Acta Neurochir Supp 62:18–27

    Article  CAS  Google Scholar 

  23. Cramer W (1932) Experimental observations on the therapeutic action of radium. Tenth Sci Rep Invest Imp Cancer Research Fund, pp 95–122

  24. Lasnitzki I (1947) Quantitative analysis of the direct and indirect action of X radiation on malignant cells. Br J Radiol 20:240–247

    Article  CAS  PubMed  Google Scholar 

  25. Merwin R, Algire GH (1950) Transparent-chamber observations of the response of transplantable mouse mammary tumor to local roentgen irradiation. J Natl Cancer Inst 2:593–623

    Google Scholar 

  26. Clement JJ, Tanaka N, Song CW (1978) Tumor reoxygenation and postirradiation vascular changes. Radiology 127:799–803

    Article  CAS  PubMed  Google Scholar 

  27. Clement JJ, Song CW, Levitt SH (1976) Changes in functional vascularity and cell number following X-irradiation of a murine carcinoma. Int J Radiat Oncol Biol Phys 1:671–678

    Article  CAS  PubMed  Google Scholar 

  28. Folkman J (1985) Tumor angiogenesis. Adv Cancer Res 43:175–203

    Article  CAS  PubMed  Google Scholar 

  29. Hammersen F, Endrich B, Messmer K (1985) The fine structure of tumor blood vessels. I. Participation of non-endothelial cells in tumor angiogenesis. Int J Microcirc Clin Exp 4:31–43

    CAS  PubMed  Google Scholar 

  30. Carmeliet P, Jain RK (2011) Principles and mechanisms of vessel normalization for cancer and other angiogenic diseases. Nature Rev 10:417–425

    CAS  Google Scholar 

  31. Song CW (1998) Modification of blood flow. In: Mools M, Vaupel P (eds) Blood perfusion and microenvironment of human tumors, implications for clinical radio oncology. Springer, Berlin, pp 194–207

    Google Scholar 

  32. Reyes M, Dudek A, Jahagirdar B et al (2002) Origin of endothelial progenitors in human postnatal bone marrow. J Clin Invest 109:337–346

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  33. Dewhirst MW, Cao Y, Moeller B et al (1996) The cycle between angiogenesis, perfusion, and hypoxia in tumors. In: Teicher BA (ed) Cancer drug resistance. Humana Press, Totowa, pp 3–24

    Google Scholar 

  34. Vaupel P, Kallinowski F, Okunieff P (1989) Blood flow, oxygenation and nutrient supply, and metabolic microenvironment of human tumors. Cancer Res 49:6449–6465

    CAS  PubMed  Google Scholar 

  35. Ahn JB, Rha SY, Shin SJ et al (2010) Circulating endothelial progenitor cells (EPC) for tumor vasculogenesis in gastric cancer patients. Cancer Lett 288:124–132

    Article  CAS  PubMed  Google Scholar 

  36. Mäntylä MJ, Toivanen JT, Pitkänen MA et al (1982) Radiation-induced changes in regional blood flow in human tumors. Int J Radiat Oncol Biol Phys 8:1711–1717

    Article  PubMed  Google Scholar 

  37. Pirhonen JP, Grenman SA, Breadbacka AB et al (1995) Effects of external radiotherapy on uterine blood flow in patients with advanced cervical carcinoma assessed by color Doppler ultrasonography. Cancer 76:67–71

    Article  CAS  PubMed  Google Scholar 

  38. Mayr NA, Yuh WT, Magnotta VA et al (1996) Tumor perfusion studies using fast magnetic resonance imaging technique in advanced cervical cancer: a new noninvasive predictive assay. Int J Radiat Oncol Biol Phys 36:623–633

    Article  CAS  PubMed  Google Scholar 

  39. Ng QS, Goh V, Milner J et al (2007) Acute tumor vascular effects following fractionated radiotherapy in human lung cancer: in vivo whole tumor assessment using volumetric perfusion computed tomography. Int J Radiat Oncol Biol Phys 67:417–424

    Article  PubMed  Google Scholar 

  40. Solesvik OV, Rofstad EK, Brustad T (1984) Vascular changes in a human malignant melanoma xenograft following single-dose irradiation. Radiat Res 98:115–128

    Article  CAS  PubMed  Google Scholar 

  41. Kioi M, Vogel H, Schultz G et al (2010) Inhibition of vasculogenesis, but not angiogenesis, prevents the recurrence of glioblastoma after irradiation in mice. J Clin Invest 120:694–705

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  42. Rubin P, Casarett G (1966) Microcirculation of tumors Part II: the supervascularized state of irradiated regressing tumors. Clin Radiol 17:346–355

    Article  CAS  PubMed  Google Scholar 

  43. Song CW, Levitt SH (1970) Effect of X irradiation on vascularity of normal tissues and experimental tumor. Radiology 94:445–447

    Article  CAS  PubMed  Google Scholar 

  44. Song CW, Levitt SH (1971) Vascular changes in Walker 256 carcinoma of rats following x irradiation. Radiology 100:397–407

    Article  CAS  PubMed  Google Scholar 

  45. Song CW, Payne T, Levitt SH (1972) Vascularity and blood flow in X-irradiated Walker carcinoma 256 of rats. Radiology 104:693–697

    Article  CAS  PubMed  Google Scholar 

  46. Wong HH, Song CW, Levitt SH (1973) Early changes in the functional vasculature of Walker carcinoma 256 following irradiation. Radiology 108:429–434

    Article  CAS  PubMed  Google Scholar 

  47. Song CW, Sung JH, Clement JJ et al (1974) Vascular changes in neuroblastoma of mice following X-irradiation. Cancer Res 34:2344–2350

    CAS  PubMed  Google Scholar 

  48. Kim DWN, Huamani J, Niemann KJ et al (2006) Noninvasive assessment of tumor vasculature response to radiation-mediated, vasculature-targeted therapy using quantified power Doppler sonography. J Ultrasound Med 25:1507–1517

    PubMed  Google Scholar 

  49. Kaffas AE, Gilles A, Czarnota GJ (2013) Dose-dependent response of tumor vasculature to radiation therapy in combination with Sunitinib by three-dimensional high-frequency power Doppler ultrasound. Angiogenesis 16:443–454

    Article  PubMed  Google Scholar 

  50. Denis F, Bougnoux P, Paon L et al (2003) Radiosensitivity of rat mammary tumors correlates with early vessel changes assessed by power Doppler sonography. J Ultrasound Med 22:921–929

    PubMed  Google Scholar 

  51. Tsai JH, Makonnen S, Hyman T, et al. (2005) Ionizing radiation inhibits tumor neovascularization by inducing ineffective angiogenesis. Proc Am Assoc Cancer Res 46: Abstract #3032

  52. Ogawa K, Boucher Y, Kashiwagi S et al (2007) Influence of tumor cell and stroma sensitivity of tumor response to radiation. Cancer Res 67:4016–4021

    Article  CAS  PubMed  Google Scholar 

  53. Chen FH, Chiang CS, Wang CC et al (2009) Radiotherapy decreases vascular density and causes hypoxia with macrophage aggregation in TRAMP-C1 prostate tumors. Clin Cancer Res 15:1721–1729

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  54. Oh ET, Park MT, Song MJ et al (2014) Radiation-induced angiogenic signaling pathway in endothelial cells obtained from normal and cancer tissue of human breast. Oncogene 33:1229–1238

    Article  CAS  PubMed  Google Scholar 

  55. Garcia-Barros M, Paris F, Cordon-Cardo C et al (2003) Tumor response to radiotherapy regulated by endothelial cell apoptosis. Science 300:1155–1159

    Article  CAS  PubMed  Google Scholar 

  56. Denekamp J (1984) Vascular endothelium as the vulnerable element in tumours. Acta Radiol Oncol 23:217–225

    Article  CAS  PubMed  Google Scholar 

  57. Lugada AA, Moran JP, Gerbe SA et al (2005) Local radiation therapy of B16 Melanoma tumors increases the generation of tumor antigen-specific effector cells that traffic to the tumor. J Immunol 174:7516–7523

    Article  Google Scholar 

  58. Lee Y, Auh SL, Wang Y et al (2009) Therapeutic effects of ablative radiation on local tumor require CD8+ T cells: changing strategies for cancer treatment. Blood 114:589–595

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  59. Matsumura S, Wang B, Kawashima N et al (2008) Radiation-induced CXCL16 release by breast cancer cells attracts effector T cells. J Immunol 181:3009–3107

    Article  Google Scholar 

  60. Chiang CS, Hong JH, Stalder A et al (1997) Delayed molecular response to brain irradiation. Int J Radiat Biol 72:45–53

    Article  CAS  PubMed  Google Scholar 

  61. Kaur P, Asea A (2012) Radiation-induced effects and the immune system in cancer. Front Oncol 2:10–11

    Article  Google Scholar 

  62. Seung SK, Curti BD, Drittenden M et al (2012) Phase I study of stereotactic body radiotherapy and interleukin-2: tumor and immunological responses. Sci Transl Med 4:137–174

    Article  Google Scholar 

  63. Shibamoto Y, Hashizume C, Baba F et al (2011) Stereotactic body radiotherapy using a radiobiology-based regimen for stage I nonsmall cell lung cancer. Cancer 118:2078–2084

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by research funds from Elekta and Minnesota Medical Foundation.

Conflict of interest

I, Chang Won Song, declare that the authors have no conflict of interest.

Author information

Authors and Affiliations

  1. Department of Therapeutic Radiology-Radiation Oncology, University of Minnesota Medical School, K119 Diehl Hall, 424 Harvard Street S.E., MMC 494, Minneapolis, MN, 55455, USA

    Chang W. Song, L. Chinsoo Cho, Kathryn Dusenbery & Paul W. Sperduto

  2. Department of Radiation Oncology, Korea Institute of Radiological and Medical Science, Seoul, Korea

    Mi-Sook Kim

Authors
  1. Chang W. Song
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mi-Sook Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. L. Chinsoo Cho
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kathryn Dusenbery
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Paul W. Sperduto
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Chang W. Song.

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Song, C.W., Kim, MS., Cho, L.C. et al. Radiobiological basis of SBRT and SRS. Int J Clin Oncol 19, 570–578 (2014). https://doi.org/10.1007/s10147-014-0717-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10147-014-0717-z

Keywords

Search

Navigation