Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Radiation enteropathy—pathogenesis, treatment and prevention

Nature Reviews Gastroenterology & Hepatology volume 11, pages 470–479 (2014)Cite this article

Subjects

A Correction to this article was published on 26 August 2014

This article has been updated

Key Points

  • Radiation therapy planning and delivery methods have improved substantially, but the risk of intestinal radiation injury remains the single most important dose-limiting factor in radiation therapy for abdominal and pelvic tumours

  • Early (acute) radiation enteropathy generally occurs during the course of radiation therapy, whereas delayed (chronic) radiation enteropathy develops after a latency period of variable length

  • Delayed radiation enteropathy is among the most common radiation-therapy-related adverse effects; the prevalence of radiation enteropathy exceeds that of IBD

  • The risk of radiation enteropathy limits the uncomplicated cancer cure rate and adversely affects the quality of life of cancer survivors

  • As the number of cancer survivors steadily increases, radiation enteropathy represents a significant challenge for future research

  • Finding safe and effective pharmacological methods to reduce the incidence and severity of radiation enteropathy is an unmet need

Abstract

Changes in cancer incidence and mortality have been modest during the past several decades, but the number of cancer survivors has almost tripled during the same period. With an increasing cohort of cancer survivors, efforts to prevent, diagnose and manage adverse effects of cancer therapy, in general, and those of radiation therapy specifically, have intensified. Many cancer survivors have undergone radiation therapy of tumours in the pelvis or abdomen, thus rendering the bowel at risk of injury. In fact, the current prevalence of patients who have long-term radiation-induced intestinal adverse effects exceeds that of IBD. Considerable progress towards reducing toxicity of radiation therapy has been made by the introduction of so-called dose-sculpting treatment techniques, which enable precise delivery of the radiation beam. Moreover, new insights into the underlying pathophysiology have resulted in an improved understanding of mechanisms of radiation-induced bowel toxicity and in development of new diagnostic strategies and management opportunities. This Review discusses the pathogenesis of early and delayed radiation-induced bowel toxicity, presents current management options and outlines priorities for future research. By adding insight into molecular and cellular mechanisms of related bowel disorders, gastroenterologists can substantially strengthen these efforts.

Access through your institution
Buy or subscribe

This is a preview of subscription content, access via your institution

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Cancer survivors and cancer prevalence rates in the USA.
Figure 2: Radiation mucositis in the rat intestine.
Figure 3: Human endoscopic biopsy samples of rectal mucosa obtained from a patient before and during ongoing radiation therapy of prostate cancer.
Figure 4: Resection specimens of small intestine.
Figure 5: Involvement of the intestinal immune system and microvascular endothelium in the regulation of acute radiation mucositis and subsequent adverse tissue remodelling (intestinal fibrosis).
Figure 6: Radiation-induced changes in the proximal jejunum from non-human primates.
Figure 7: Algorithm depicting simplified principles of work-up and common approaches for managing patients with delayed gastrointestinal symptoms after radiation therapy used at the Royal Marsden Hospital, London, UK.

Similar content being viewed by others

Change history

  • 26 August 2013

    In the version of this article originally published online and in print, the definition for PAS was listed incorrectly as para-aminosalicylic acid instead of periodic acid–Schiff in the legend for Figure 3. The error has been corrected for the HTML and PDF versions of the article.

References

  1. DeVita, V. T., Lawrence, T. S. & Rosenberg, S. A. DeVita, Hellman, and Rosenberg's Cancer. Principles & Practice of Oncology (Wolters Kluwer Health/Lippincott Williams & Wilkins, 2011).

    Google Scholar 

  2. Goitein, M. How best to dispose of extra-tumoral dose: a cautionary note for intensity-modulated radiation therapy. Int. J. Radiat. Oncol. Biol. Phys. 75, 1–3 (2009).

    Article  PubMed  Google Scholar 

  3. Eifel, P. J., Jhingran, A., Bodurka, D. C., Levenback, C. & Thames, H. Correlation of smoking history and other patient characteristics with major complications of pelvic radiation therapy for cervical cancer. J. Clin. Oncol. 20, 3651–3657 (2002).

    Article  PubMed  Google Scholar 

  4. Wedlake, L. J. et al. Predicting late effects of pelvic radiotherapy: is there a better approach? Int. J. Radiat. Oncol. Biol. Phys. 78, 1163–1170 (2010).

    Article  PubMed  Google Scholar 

  5. Willett, C. G. et al. Acute and late toxicity of patients with inflammatory bowel disease undergoing irradiation for abdominal and pelvic neoplasms. Int. J. Radiat. Oncol. Biol. Phys. 46, 995–998 (2000).

    Article  CAS  PubMed  Google Scholar 

  6. Herold, D. M., Hanlon, A. L. & Hanks, G. E. Diabetes mellitus: a predictor for late radiation morbidity. Int. J. Radiat. Oncol. Biol. Phys. 43, 475–479 (1999).

    Article  CAS  PubMed  Google Scholar 

  7. Potish, R. A., Twiggs, L. B., Adcock, L. L. & Prem, K. A. Logistic models for prediction of enteric morbidity in the treatment of ovarian and cervical cancers. Am. J. Obstet. Gynecol. 147, 65–72 (1983).

    Article  CAS  PubMed  Google Scholar 

  8. Ross, J. G., Hussey, D. H., Mayr, N. A. & Davis, C. S. Acute and late reactions to radiation therapy in patients with collagen vascular diseases. Cancer 71, 3744–3752 (1993).

    Article  CAS  PubMed  Google Scholar 

  9. Lin, A., Abu-Isa, E., Griffith, K. A. & Ben-Josef, E. Toxicity of radiotherapy in patients with collagen vascular disease. Cancer 113, 648–653 (2008).

    Article  PubMed  Google Scholar 

  10. West, C. M. & Barnett, G. C. Genetics and genomics of radiotherapy toxicity: towards prediction. Genome Med. 3, 52 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Siegel, R. et al. Cancer treatment and survivorship statistics, 2012. CA Cancer J. Clin. 62, 220–241 (2012).

    Article  PubMed  Google Scholar 

  12. Hewitt, M. E., Greenfield, S. & Stovall, E. From Cancer Patient to Cancer Survivor. Lost in Transition (National Academies Press, 2006).

    Google Scholar 

  13. Bentzen, S. M. et al. Normal tissue effects: reporting and analysis. Semin. Radiat. Oncol. 13, 189–202 (2003).

    Article  PubMed  Google Scholar 

  14. Fransson, P. & Widmark, A. 15-year prospective follow-up of patient-reported outcomes of late bowel toxicity after external beam radiotherapy for localized prostate cancer. A comparison with age-matched controls. Acta Oncol. 46, 517–524 (2007).

    Article  PubMed  Google Scholar 

  15. Yeoh, E. et al. Effect of pelvic irradiation on gastrointestinal function: a prospective longitudinal study. Am. J. Med. 95, 397–406 (1993).

    Article  CAS  PubMed  Google Scholar 

  16. Lakatos, P.-L. Recent trends in the epidemiology of inflammatory bowel diseases: up or down? World J. Gastroenterol. 12, 6102–6108 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  17. Centers for Disease Control and Prevention Inflammatory Bowel Disease (IBD) [online], (2014).

  18. Hauer-Jensen, M., Poulakos, L. & Osborne, J. W. Effects of accelerated fractionation on radiation injury of the small intestine: a new rat model. Int. J. Radiat. Oncol. Biol. Phys. 14, 1205–1212 (1988).

    Article  CAS  PubMed  Google Scholar 

  19. Husebye, E., Hauer-Jensen, M., Kjorstad, K. & Skar, V. Severe late radiation enteropathy is characterized by impaired motility of proximal small intestine. Dig. Dis. Sci. 39, 2341–2349 (1994).

    Article  CAS  PubMed  Google Scholar 

  20. Vale, C. L., Tierney, J. F., Davidson, S. E., Drinkwater, K. J. & Symonds, P. Substantial improvement in UK cervical cancer survival with chemoradiotherapy: results of a Royal College of Radiologists' audit. Clin. Oncol. (R. Coll. Radiol.) 22, 590–601 (2010).

    Article  CAS  Google Scholar 

  21. Regimbeau, J. M., Panis, Y., Gouzi, J. L. & Fagniez, P. L. Operative and long term results after surgery for chronic radiation enteritis. Am. J. Surg. 182, 237–242 (2001).

    Article  CAS  PubMed  Google Scholar 

  22. Larsen, A., Reitan, J. B., Aase, S. T. & Hauer-Jensen, M. Long-term prognosis in patients with severe late radiation enteropathy: a prospective cohort study. World J. Gastroenterol. 13, 3610–3613 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  23. Fajardo, L. F., Berthrong, M. & Anderson, R. E. Radiation Pathology 209–248 (Oxford University Press, 2001).

    Google Scholar 

  24. Carr, K. E. Effects of radiation damage on intestinal morphology. Int. Rev. Cytol. 208, 1–119 (2001).

    Article  CAS  PubMed  Google Scholar 

  25. Hauer-Jensen, M. et al. in Human Radiation Injury Ch. 38 (eds Shrieve, D. C. & Loeffler, J. S.) 421–440 (Wolters Kluwer Health/Lippincott Williams & Wilkins, 2011).

    Google Scholar 

  26. Atwood, K. C. & Norman, A. On the interpretation of multi-hit survival curves. Proc. Natl Acad. Sci. USA 35, 696–709 (1949).

    Article  CAS  PubMed  Google Scholar 

  27. Wang, J. & Hauer-Jensen, M. Neuroimmune interactions: potential target for mitigating or treating intestinal radiation injury. Br. J. Radiol. 80 (Spec. 1), S41–S48 (2007).

    Article  CAS  PubMed  Google Scholar 

  28. Packey, C. D. & Ciorba, M. A. Microbial influences on the small intestinal response to radiation injury. Curr. Opin. Gastroenterol. 26, 88–94 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  29. Bourne, R. G., Kearsley, J. H., Grove, W. D. & Roberts, S. J. The relationship between early and late gastrointestinal complications of radiation therapy for carcinoma of the cervix. Int. J. Radiat. Oncol. Biol. Phys. 9, 1445–1450 (1983).

    Article  CAS  PubMed  Google Scholar 

  30. Peters, L. J., Ang, K. K. & Thames, H. D. Jr. Accelerated fractionation in the radiation treatment of head and neck cancer. A critical comparison of different strategies. Acta Oncol. 27, 185–194 (1988).

    Article  CAS  PubMed  Google Scholar 

  31. Wang, J., Qiu, X., Kulkarni, A. & Hauer-Jensen, M. Calcitonin gene-related peptide and substance P regulate the intestinal radiation response. Clin. Cancer Res. 12, 4112–4118 (2006).

    Article  CAS  PubMed  Google Scholar 

  32. Wang, J., Zheng, H. & Hauer-Jensen, M. Influence of short-term octreotide administration on chronic tissue injury, transforming growth factor β (TGF-β) overexpression, and collagen accumulation in irradiated rat intestine. J. Pharmacol. Exp. Ther. 297, 35–42 (2001).

    CAS  PubMed  Google Scholar 

  33. Wang, J., Zheng, H., Kulkarni, A., Ou, X. & Hauer-Jensen, M. Regulation of early and delayed radiation responses in rat small intestine by capsaicin-sensitive nerves. Int. J. Radiat. Oncol. Biol. Phys. 64, 1528–1536 (2006).

    Article  CAS  PubMed  Google Scholar 

  34. Zheng, H., Wang, J. & Hauer-Jensen, M. Role of mast cells in early and delayed radiation injury in rat intestine. Radiat. Res. 153, 533–539 (2000).

    Article  CAS  PubMed  Google Scholar 

  35. Denham, J. W., Hauer-Jensen, M. & Peters, L. J. Is it time for a new formalism to categorize normal tissue radiation injury? Int. J. Radiat. Oncol. Biol. Phys. 50, 1105–1106 (2001).

    Article  CAS  PubMed  Google Scholar 

  36. Denham, J. W. & Hauer-Jensen, M. The radiotherapeutic injury--a complex 'wound'. Radiother. Oncol. 63, 129–145 (2002).

    Article  PubMed  Google Scholar 

  37. Hovdenak, N., Fajardo, L. F. & Hauer-Jensen, M. Acute radiation proctitis: a sequential clinicopathologic study during pelvic radiotherapy. Int. J. Radiat. Oncol. Biol. Phys. 48, 1111–1117 (2000).

    Article  CAS  PubMed  Google Scholar 

  38. Carratu, R. et al. Assessment of small intestinal damage in patients treated with pelvic radiotherapy. Oncol. Rep. 5, 635–639 (1998).

    CAS  PubMed  Google Scholar 

  39. Hauer-Jensen, M., Poulakos, L. & Osborne, J. W. Effects of accelerated fractionation on radiation injury of the small intestine: a new rat model. Int. J. Radiat. Oncol. Biol. Phys. 14, 1205–1212 (1988).

    Article  CAS  PubMed  Google Scholar 

  40. Boerma, M., Wang, J., Richter, K. K. & Hauer-Jensen, M. Orazipone, a locally acting immunomodulator, ameliorates intestinal radiation injury: a preclinical study in a novel rat model. Int. J. Radiat. Oncol. Biol. Phys. 66, 552–559 (2006).

    Article  CAS  PubMed  Google Scholar 

  41. Potten, C. S., Merritt, A., Hickman, J., Hall, P. & Faranda, A. Characterization of radiation-induced apoptosis in the small intestine and its biological implications. Int. J. Radiat. Biol. 65, 71–78 (1994).

    Article  CAS  PubMed  Google Scholar 

  42. Komarova, E. A. et al. Dual effect of p53 on radiation sensitivity in vivo: p53 promotes hematopoietic injury, but protects from gastro-intestinal syndrome in mice. Oncogene 23, 3265–3271 (2004).

    Article  CAS  PubMed  Google Scholar 

  43. Kirsch, D. G. et al. p53 controls radiation-induced gastrointestinal syndrome in mice independent of apoptosis. Science 327, 593–596 (2010).

    Article  CAS  PubMed  Google Scholar 

  44. Leibowitz, B. J. et al. Uncoupling p53 functions in radiation-induced intestinal damage via PUMA and p21. Mol. Cancer Res. 9, 616–625 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Cheng, H. & Leblond, C. P. Origin, differentiation and renewal of the four main epithelial cell types in the mouse small intestine. V. Unitarian theory of the origin of the four epithelial cell types. Am. J. Anat. 141, 537–561 (1974).

    Article  CAS  PubMed  Google Scholar 

  46. Potten, C. S. Extreme sensitivity of some intestinal crypt cells to X and gamma irradiation. Nature 269, 518–521 (1977).

    Article  CAS  PubMed  Google Scholar 

  47. Yan, K. S. et al. The intestinal stem cell markers Bmi1 and Lgr5 identify two functionally distinct populations. Proc. Natl Acad. Sci. USA 109, 466–471 (2012).

    Article  CAS  PubMed  Google Scholar 

  48. Hua, G. et al. Crypt base columnar stem cells in small intestines of mice are radioresistant. Gastroenterology 143, 1266–1276 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. van Landeghem, L. et al. Activation of two distinct Sox9-EGFP-expressing intestinal stem cell populations during crypt regeneration after irradiation. Am. J. Physiol. Gastrointest. Liver Physiol. 302, G1111–G1132 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Metcalfe, C., Kljavin, N. M., Ybarra, R. & de Sauvage, F. J. Lgr5+ stem cells are indispensable for radiation-induced intestinal regeneration. Cell Stem Cell 14, 149–159 (2014).

    Article  CAS  PubMed  Google Scholar 

  51. Hopewell, J. W. et al. Microvasculature and radiation damage. Recent Results. Cancer Res. 130, 1–16 (1993).

    CAS  Google Scholar 

  52. Baker, D. G. & Krochak, R. J. The response of the microvascular system to radiation: a review. Cancer Invest. 7, 287–294 (1989).

    Article  CAS  PubMed  Google Scholar 

  53. Rezvani, M., Hopewell, J. W. & Robbins, M. E. Initiation of non-neoplastic late effects: the role of endothelium and connective tissue. Stem Cells 13 (Suppl. 1), 248–256 (1995).

    Article  PubMed  Google Scholar 

  54. Wang, J., Zheng, H., Ou, X., Fink, L. M. & Hauer-Jensen, M. Deficiency of microvascular thrombomodulin and up-regulation of protease-activated receptor-1 in irradiated rat intestine: possible link between endothelial dysfunction and chronic radiation fibrosis. Am. J. Pathol. 160, 2063–2072 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Richter, K. K., Fink, L. M., Hughes, B. M., Sung, C. C. & Hauer-Jensen, M. Is the loss of endothelial thrombomodulin involved in the mechanism of chronicity in late radiation enteropathy? Radiother. Oncol. 44, 65–71 (1997).

    Article  CAS  PubMed  Google Scholar 

  56. Paris, F. et al. Endothelial apoptosis as the primary lesion initiating intestinal radiation damage in mice. Science 293, 293–297 (2001).

    Article  CAS  PubMed  Google Scholar 

  57. Rotolo, J. et al. Anti-ceramide antibody prevents the radiation gastrointestinal syndrome in mice. J. Clin. Invest. 122, 1786–1790 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Schuller, B. W. et al. Selective irradiation of the vascular endothelium has no effect on the survival of murine intestinal crypt stem cells. Proc. Natl Acad. Sci. USA 103, 3787–3792 (2006).

    Article  CAS  PubMed  Google Scholar 

  59. Schuller, B. W. et al. No significant endothelial apoptosis in the radiation-induced gastrointestinal syndrome. Int. J. Radiat. Oncol. Biol. Phys. 68, 205–210 (2007).

    Article  CAS  PubMed  Google Scholar 

  60. Laroux, F. S. & Grisham, M. B. Immunological basis of inflammatory bowel disease: role of the microcirculation. Microcirculation 8, 283–301 (2001).

    Article  CAS  PubMed  Google Scholar 

  61. Wang, J., Boerma, M., Fu, Q. & Hauer-Jensen, M. Significance of endothelial dysfunction in the pathogenesis of early and delayed radiation enteropathy. World J. Gastroenterol. 13, 3047–3055 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Geiger, H. et al. Pharmacological targeting of the thrombomodulin-activated protein C pathway mitigates radiation toxicity. Nat. Med. 18, 1123–1129 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Shanahan, F. The host–microbe interface within the gut. Best Pract. Res. Clin. Gastroenterol. 16, 915–931 (2002).

    Article  PubMed  Google Scholar 

  64. Robert, A. & Asano, T. Resistance of germfree rats to indomethacin-induced intestinal lesions. Prostaglandins 14, 333–341 (1977).

    Article  CAS  PubMed  Google Scholar 

  65. Osborne, J. W., Bryan, H. S., Quastler, H. & Rhoades, H. E. X-irradiation and bacteremia; studies on roentgen death in mice. IV. Am. J. Physiol. 170, 414–417 (1952).

    Article  CAS  PubMed  Google Scholar 

  66. Wilson, B. R. Survival studies of whole body X-irradiated germfree (axenic) mice. Radiat. Res. 20, 477–483 (1963).

    Article  CAS  PubMed  Google Scholar 

  67. Crawford, P. A. & Gordon, J. I. Microbial regulation of intestinal radiosensitivity. Proc. Natl Acad. Sci. USA 102, 13254–13259 (2005).

    Article  CAS  PubMed  Google Scholar 

  68. Delia, P. et al. Prevention of radiation-induced diarrhea with the use of VSL#3, a new high-potency probiotic preparation. Am. J. Gastroenterol. 97, 2150–2152 (2002).

    Article  PubMed  Google Scholar 

  69. Ciorba, M. A. et al. Lactobacillus probiotic protects intestinal epithelium from radiation injury in a TLR-2/cyclo-oxygenase-2-dependent manner. Gut 61, 829–838 (2012).

    Article  CAS  PubMed  Google Scholar 

  70. Urbancsek, H., Kazar, T., Mezes, I. & Neumann, K. Results of a double-blind, randomized study to evaluate the efficacy and safety of Antibiophilus in patients with radiation-induced diarrhoea. Eur. J. Gastroenterol. Hepatol. 13, 391–396 (2001).

    Article  CAS  PubMed  Google Scholar 

  71. Osterlund, P. et al. Lactobacillus supplementation for diarrhoea related to chemotherapy of colorectal cancer: a randomised study. Br. J. Cancer 97, 1028–1034 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Gibson, R. J. et al. Systematic review of agents for the management of gastrointestinal mucositis in cancer patients. Support Care Cancer 21, 313–326 (2013).

    Article  PubMed  Google Scholar 

  73. Dave, M., Higgins, P. D., Middha, S. & Rioux, K. P. The human gut microbiome: current knowledge, challenges, and future directions. Transl. Res. 160, 246–257 (2012).

    Article  CAS  PubMed  Google Scholar 

  74. Lamendella, R., VerBerkmoes, N. & Jansson, J. K. 'Omics' of the mammalian gut—new insights into function. Curr. Opin. Biotechnol. 23, 491–500 (2012).

    Article  CAS  PubMed  Google Scholar 

  75. Damman, C. J. & Surawicz, C. M. The gut microbiota: a microbial arsenal protecting us from infectious and radiation-induced diarrhea. Gastroenterology 136, 722–724 (2009).

    Article  PubMed  Google Scholar 

  76. Nam, Y.-D., Kim, H. J., Seo, J.-G., Kang, S. W. & Bae, J.-W. Impact of pelvic radiotherapy on gut microbiota of gynecological cancer patients revealed by massive pyrosequencing. PLoS ONE 8, e82659 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Tlaskalova-Hogenova, H. et al. The role of gut microbiota (commensal bacteria) and the mucosal barrier in the pathogenesis of inflammatory and autoimmune diseases and cancer: contribution of germ-free and gnotobiotic animal models of human diseases. Cell. Mol. Immunol. 8, 110–120 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Yi, P. & Li, L. The germfree murine animal: an important animal model for research on the relationship between gut microbiota and the host. Vet. Microbiol. 157, 1–7 (2012).

    Article  PubMed  Google Scholar 

  79. Lalla, R. V. et al. MASCC/ISOO clinical practice guidelines for the management of mucositis secondary to cancer therapy. Cancer http://dx.doi.org/10.1002/cncr.28592.

  80. Nicolatou-Galitis, O. et al. Systematic review of amifostine for the management of oral mucositis in cancer patients. Support Care Cancer 21, 357–364 (2013).

    Article  PubMed  Google Scholar 

  81. Andreyev, H. J. N., Davidson, S. E., Gillespie, C., Allum, W. H. & Swarbrick, E. Practice guidance on the management of acute and chronic gastrointestinal problems arising as a result of treatment for cancer. Gut 61, 179–192 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Kochhar, R. et al. Radiation-induced proctosigmoiditis. Prospective, randomized, double-blind controlled trial of oral sulfasalazine plus rectal steroids versus rectal sucralfate. Dig. Dis. Sci. 36, 103–107 (1991).

    Article  CAS  PubMed  Google Scholar 

  83. Sanguineti, G., Franzone, P., Marcenaro, M., Foppiano, F. & Vitale, V. Sucralfate versus mesalazine versus hydrocortisone in the prevention of acute radiation proctitis during conformal radiotherapy for prostate carcinoma. A randomized study. Strahlenther Onkol. 179, 464–470 (2003).

    Article  PubMed  Google Scholar 

  84. Clarke, R. E. et al. Hyperbaric oxygen treatment of chronic refractory radiation proctitis: a randomized and controlled double-blind crossover trial with long-term follow-up. Int. J. Radiat. Oncol. Biol. Phys. 72, 134–143 (2008).

    Article  CAS  PubMed  Google Scholar 

  85. Ben-Josef, E. et al. Intrarectal application of amifostine for the prevention of radiation-induced rectal injury. Semin. Radiat. Oncol. 12, 81–85 (2002).

    Article  PubMed  Google Scholar 

  86. Salvemini, D., Riley, D. P. & Cuzzocrea, S. SOD mimetics are coming of age. Nat. Rev. Drug Discov. 1, 367–374 (2002).

    Article  CAS  PubMed  Google Scholar 

  87. Berbee, M. et al. γ-Tocotrienol ameliorates intestinal radiation injury and reduces vascular oxidative stress after total-body irradiation by an HMG-CoA reductase-dependent mechanism. Radiat. Res. 171, 596–605 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Boerma, M. et al. Local administration of interleukin-11 ameliorates intestinal radiation injury in rats. Cancer Res. 67, 9501–9506 (2007).

    Article  CAS  PubMed  Google Scholar 

  89. Booth, C., Booth, D., Williamson, S., Demchyshyn, L. L. & Potten, C. S. Teduglutide (Gly2GLP-2) protects small intestinal stem cells from radiation damage. Cell. Prolif. 37, 385–400 (2004).

    Article  CAS  PubMed  Google Scholar 

  90. Cai, Y. et al. Keratinocyte growth factor pretreatment prevents radiation-induced intestinal damage in a mouse model. Scand. J. Gastroenterol. 48, 419–426 (2013).

    Article  CAS  PubMed  Google Scholar 

  91. Bhanja, P. et al. Protective role of R.-spondin1, an intestinal stem cell growth factor, against radiation-induced gastrointestinal syndrome in mice. PLoS ONE 4, e8014 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. de Lau, Wim B M, Snel, B. & Clevers, H. C. The R.-spondin protein family. Genome Biol. 13, 242 (2012).

    Article  CAS  Google Scholar 

  93. Khan, W. B., Shui, C., Ning, S. & Knox, S. J. Enhancement of murine intestinal stem cell survival after irradiation by keratinocyte growth factor. Radiat. Res. 148, 248–253 (1997).

    Article  CAS  PubMed  Google Scholar 

  94. Matthews, M. A., Watkins, D., Darbyshire, A., Carson, W. E. & Besner, G. E. Heparin-binding EGF-like growth factor (HB-EGF) protects the intestines from radiation therapy-induced intestinal injury. J. Pediatr. Surg. 48, 1316–1322 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  95. Torres, S. et al. Glucagon-like peptide-2 improves both acute and late experimental radiation enteritis in the rat. Int. J. Radiat. Oncol. Biol. Phys. 69, 1563–1571 (2007).

    Article  CAS  PubMed  Google Scholar 

  96. Zhou, W.-J., Geng, Z. H., Spence, J. R. & Geng, J.-G. Induction of intestinal stem cells by R.-spondin 1 and Slit2 augments chemoradioprotection. Nature 501, 107–111 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Fu, Q. et al. The somatostatin analog SOM230 (pasireotide) ameliorates injury of the intestinal mucosa and increases survival after total-body irradiation by inhibiting exocrine pancreatic secretion. Radiat. Res. 171, 698–707 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Fu, Q. et al. Preclinical evaluation of Som230 as a radiation mitigator in a mouse model: postexposure time window and mechanisms of action. Radiat. Res. 175, 728–735 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Burdelya, L. G. et al. An agonist of Toll-like receptor 5 has radioprotective activity in mouse and primate models. Science 320, 226–230 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Deng, W. et al. Lysophosphatidic acid protects and rescues intestinal epithelial cells from radiation- and chemotherapy-induced apoptosis. Gastroenterology 123, 206–216 (2002).

    Article  CAS  PubMed  Google Scholar 

  101. Deng, W. et al. The lysophosphatidic acid type 2 receptor is required for protection against radiation-induced intestinal injury. Gastroenterology 132, 1834–1851 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Saha, S. et al. TLR9 agonist protects mice from radiation-induced gastrointestinal syndrome. PLoS ONE 7, e29357 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Shakhov, A. N. et al. Prevention and mitigation of acute radiation syndrome in mice by synthetic lipopeptide agonists of Toll-like receptor 2 (TLR2). PLoS ONE 7, e33044 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Singh, V. K. et al. CBLB613: a TLR 2/6 agonist, natural lipopeptide of Mycoplasma arginini, as a novel radiation countermeasure. Radiat. Res. 177, 628–642 (2012).

    Article  CAS  PubMed  Google Scholar 

  105. Movsas, B. et al. Decreasing the adverse effects of cancer therapy: National Cancer Institute guidance for the clinical development of radiation injury mitigators. Clin. Cancer Res. 17, 222–228 (2011).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

M.H.-J. has received support related to the submitted work from the US NIH (grants R37 CA71382 and U19 AI67798), the US Biomedical Advanced Research and Development Authority (BARDA, contract HHSO100201100045C) and from the US Veterans Administration. All authors declare that there is no support from any other organization.

Author information

Authors and Affiliations

  1. Central Arkansas Veterans Healthcare System and Division of Radiation Health, Surgical Service, University of Arkansas for Medical Sciences, 4301 West Markham, Little Rock, 72205, AR, USA

    Martin Hauer-Jensen

  2. Department of Radiation Oncology, University of Newcastle, Newcastle, 2308, NSW, Australia

    James W. Denham

  3. Department of Medicine, Royal Marsden Hospital, Fulham Road, London, SW3 6JJ, UK

    H. Jervoise N. Andreyev

Authors
  1. Martin Hauer-Jensen
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. James W. Denham
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. H. Jervoise N. Andreyev
    View author publications

    You can also search for this author inPubMed Google Scholar

Contributions

M.H.-J. contributed to all aspects in the preparation of this article. J.W.D. substantially contributed to the discussion of content and reviewed/edited the manuscript before submission. H.J.N.A. researched data for the article, substantially contributed to the discussion of content and reviewed/edited the manuscript before submission.

Corresponding author

Correspondence to Martin Hauer-Jensen.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hauer-Jensen, M., Denham, J. & Andreyev, H. Radiation enteropathy—pathogenesis, treatment and prevention. Nat Rev Gastroenterol Hepatol 11, 470–479 (2014). https://doi.org/10.1038/nrgastro.2014.46

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrgastro.2014.46

Search

Advanced search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer