Abstract
Aim: To systematically review the prophylactic and therapeutic interventions for reducing the incidence or severity of intestinal symptoms among cancer patients receiving radiotherapy. Materials & methods: A literature search was conducted in the PubMed database using various search terms, including ‘radiation enteritis’, ‘radiation enteropathy’, ‘radiation-induced intestinal disease’, ‘radiation-induced intestinal damage’ and ‘radiation mucositis’. The search was limited to in vivo studies, clinical trials and meta-analyses published in English with no limitation on publication date. Other relevant literature was identified based on the reference lists of selected studies. Results: The pathogenesis of acute and chronic radiation-induced intestinal damage as well as the prevention and treatment approaches were reviewed. Conclusion: There is inadequate evidence to strongly support the use of a particular strategy to reduce radiation-induced intestinal damage. More high-quality randomized controlled trials are required for interventions with limited evidence suggestive of potential benefits.
Papers of special note have been highlighted as: • of interest; •• of considerable interest
References
- 1. . The role of radiotherapy in cancer treatment: estimating optimal utilization from a review of evidence-based clinical guidelines. Cancer 104(6), 1129–1137 (2005).
- 2. Cancer treatment and survivorship statistics, 2019. CA Cancer J. Clin. 69(5), 363–385 (2019).
- 3. . Global surgical oncology: addressing the global surgical oncology disease burden. Ann. Surg. Oncol. 22(3), 708–709 (2015).
- 4. Protection of radiation-induced damage to the hematopoietic system, small intestine and salivary glands in rats by JNJ7777120 compound, a histamine H4 ligand. PLoS ONE 8(7), e69106 (2013).
- 5. . Trends in radiation therapy among cancer survivors in the United States, 2000-2030. Cancer Epidemiol. Biomarkers Prev. 26(6), 963–970 (2017).
- 6. Radiation injury to intestine following hysterectomy and adjuvant radiotherapy for cervical cancer. Gynecol. Oncol. 95(1), 208–214 (2004).
- 7. Protective effects of flagellin A N/C against radiation-induced NLR pyrin domain containing 3 inflammasome-dependent pyroptosis in intestinal cells. Int. J. Radiat. Oncol. Biol. Phys. 101(1), 107–117 (2018).
- 8. . Pirfenidone prevents radiation-induced intestinal fibrosis in rats by inhibiting fibroblast proliferation and differentiation and suppressing the TGF-beta1/Smad/CTGF signaling pathway. Eur. J. Pharmacol. 822, 199–206 (2018).
- 9. Lactobacillus rhamnosus GG protects the intestinal epithelium from radiation injury through release of lipoteichoic acid, macrophage activation and the migration of mesenchymal stem cells. Gut 68 (6), 1003–1013 (2018).
- 10. . [Treatment of 21 cases of chronic radiation intestinal injury by staging ileostomy and closure operation]. Zhonghua Wei Chang Wai Ke Za Zhi 21(7), 772–778 (2018).
- 11. . Synergistic actions of FGF2 and bone marrow transplantation mitigate radiation-induced intestinal injury. Cell Death Dis. 9(3), 383 (2018).
- 12. . Increased transgenerational intestinal tumorigenesis in offspring of ionizing radiation exposed parent APC(1638N/+) Mice. J. Cancer 8(10), 1769–1773 (2017).
- 13. . Synergistic effect of aluminum and ionizing radiation upon ultrastructure, oxidative stress and apoptotic alterations in Paneth cells of rat intestine. Environ. Sci. Pollut. Res. Int. 24(7), 6657–6666 (2017).
- 14. . Protracted upregulation of leptin and IGF1 is associated with activation of PI3K/Akt and JAK2 pathway in mouse intestine after ionizing radiation exposure. Int. J. Biol. Sci. 11(3), 274–283 (2015).
- 15. CpG-oligodeoxynucleotide treatment protects against ionizing radiation-induced intestine injury. PLoS ONE 8(6), e66586 (2013).
- 16. . Basic fibroblast growth factor suppresses radiation-induced apoptosis and TP53 pathway in rat small intestine. Radiat. Res. 174(1), 52–61 (2010).
- 17. Bone marrow derived macrophages fuse with intestine stromal cells and contribute to chronic fibrosis after radiation. Radiother. Oncol. 119(2), 250–258 (2016).
- 18. . Reduced mucosal perianastomotic capillary density in rat small intestine with chronic radiation damage. Radiat. Res. 150(5), 542–548 (1998).
- 19. Eosinophil depletion suppresses radiation-induced small intestinal fibrosis. Sci. Transl. Med. 10(429), 0333 (2018).
- 20. A modified inflammatory bowel disease questionnaire and the vaizey incontinence questionnaire are simple ways to identify patients with significant gastrointestinal symptoms after pelvic radiotherapy. Br. J. Cancer 92(9), 1663–1670 (2005).
- 21. . Combination treatment of podophyllotoxin and rutin promotes mouse Lgr5(+ve) intestinal stem cells survival against lethal radiation injury through Wnt signaling. Apoptosis
doi:10.1007/s10495-019-01519-x (2019). - 22. The LPA2 receptor agonist Radioprotectin-1 spares Lgr5-positive intestinal stem cells from radiation injury in murine enteroids. Cell. Signal. 51, 23–33 (2018).
- 23. . Physical activity, global DNA methylation, and breast cancer risk: a systematic literature review and meta-analysis. Cancer Epidemiol. Biomarkers Prev. 27(11), 1320–1331 (2018).
- 24. . Silibinin attenuates radiation-induced intestinal fibrosis and reverses epithelial-to-mesenchymal transition. Oncotarget 8(41), 69386–69397 (2017).
- 25. . The role of intestinal stem cells in epithelial regeneration following radiation-induced gut injury. Curr. Stem Cell Rep. 3(4), 320–332 (2017). •• Explores the regenerative capacity and mechanisms of various populations of intestinal stem cells in response to ionizing radiation.
- 26. Directional delivery of RSPO1 by mesenchymal stem cells ameliorates radiation-induced intestinal injury. Cytokine 95, 27–34 (2017).
- 27. . BCN057 induces intestinal stem cell repair and mitigates radiation-induced intestinal injury. Stem Cell Res. Ther. 9(1), 26 (2018).
- 28. 12-O-tetradecanoylphorbol-13-acetate (TPA) increases murine intestinal crypt stem cell survival following radiation injury. Oncotarget 8(28), 45566–45576 (2017).
- 29. Determination using synchrotron radiation-based Fourier transform infrared microspectroscopy of putative stem cells in human adenocarcinoma of the intestine: corresponding benign tissue as a template. Appl. Spectrosc. 68(8), 812–822 (2014).
- 30. Brief report: CD24 and CD44 mark human intestinal epithelial cell populations with characteristics of active and facultative stem cells. Stem Cells 31(9), 2024–2030 (2013).
- 31. . Intestinal stem cells. Curr. Gastroenterol. Rep. 12(5), 340–348 (2010).
- 32. . Intestinal stem cell niche: the extracellular matrix and cellular components. Stem Cells Int. 2017, 11 (2017).
- 33. . The gastrointestinal tract stem cell niche. Stem Cell Rev. 2(3), 203–212 (2006).
- 34. . Inflammation and immunity in radiation damage to the gut mucosa. Biomed. Res. Int. 2013, 123241–123241 (2013). • Focuses on what has been observed in the healthy gut and what needs to be done concerning the immunoinflammatory response after localized radiation exposure.
- 35. . Consequential late effects in normal tissues. Radiother. Oncol. 61(3), 223–231 (2001).
- 36. Rapid disruption of intestinal epithelial tight junction and barrier dysfunction by ionizing radiation in mouse colon in vivo: protection by N-acetyl-l-cysteine. Am. J. Physiol. Gastrointest. Liver Physiol. 310(9), G705–G715 (2016).
- 37. . The role of tissue resident cells in neutrophil recruitment. Trends Immunol. 36(9), 547–555 (2015).
- 38. . Subtle deregulation of the Wnt-signaling pathway through loss of Apc2 reduces the fitness of intestinal stem cells. Stem Cells 36(1), 114–122 (2018).
- 39. . WNT antagonist, DKK2, is a notch signaling target in intestinal stem cells: augmentation of a negative regulation system for canonical WNT signaling pathway by the Notch-DKK2 signaling loop in primates. Int. J. Mol. Med. 19(1), 197–201 (2007).
- 40. . Functional transcriptomics in diverse intestinal epithelial cell types reveals robust microRNA sensitivity in intestinal stem cells to microbial status. J. Biol. Chem. 292(7), 2586–2600 (2017).
- 41. . Coordination of insulin and Notch pathway activities by microRNA miR-305 mediates adaptive homeostasis in the intestinal stem cells of the Drosophila gut. Genes Dev. 28(21), 2421–2431 (2014).
- 42. . Geranylgeranylacetone ameliorates intestinal radiation toxicity by preventing endothelial cell dysfunction. Int. J. Mol. Sci. 18(10), 2103 (2017).
- 43. . 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(6), 2063–2072 (2002).
- 44. . Protective effects of 2-amino-5,6-dihydro-4h-1,3-thiazine and its derivative against radiation-induced hematopoietic and intestinal injury in mice. Int. J. Mol. Sci. 19(5), 1530 (2018).
- 45. Effect of different doses of radiation on intestinal injury in NOD/SCID Mice. Zhongguo Yi Xue Ke Xue Yuan Xue Bao 40(1), 7–12 (2018). • Studies the effect of different doses of radiation on intestinal injury, with an attempt to find the optimal radiation dose for establishing intestinal injury models in NOD/SCID mice.
- 46. . Low and high dose rate heavy ion radiation-induced intestinal and colonic tumorigenesis in APC(1638N/+) mice. Life Sci. Space Res. (Amst.) 13, 45–50 (2017).
- 47. Human umbilical cord blood-derived mesenchymal stromal cells and small intestinal submucosa hydrogel composite promotes combined radiation-wound healing of mice. Cytotherapy 19(9), 1048–1059 (2017).
- 48. . Regeneration potential of lymphoid tissue of small intestine in mice after exposure to low-intensity radiation. Bull. Exp. Biol. Med. 164(2), 214–217 (2017).
- 49. Effect of alpha-lipoic acid on radiation-induced small intestine injury in mice. Oncotarget 7(12), 15105–15117 (2016).
- 50. . [The effect of ionizing radiation with low dose rate on the state of electron transfer chain of enterocyte mitochondria of rat small intestine]. Ukr. Biokhim. Zh. (1999) 84(1), 45–52 (2012).
- 51. . Gastrointestinal symptoms after pelvic radiotherapy: a new understanding to improve management of symptomatic patients. Lancet Oncol. 8(11), 1007–1017 (2007).
- 52. . Space radiation triggers persistent stress response, increases senescent signaling, and decreases cell migration in mouse intestine. Proc. Natl Acad. Sci. USA 115(42), E9832–E9841 (2018).
- 53. . Proteomic identification of radiation response markers in mouse intestine and brain. Proteomics 11(7), 1254–1263 (2011).
- 54. . Regulation of early and delayed radiation responses in rat small intestine by capsaicin-sensitive nerves. Int. J. Radiat. Oncol. Biol. Phys. 64(5), 1528–1536 (2006).
- 55. . Prostaglandins and the epithelial response to radiation injury in the intestine. Curr. Opin. Gastroenterol. 20(2), 61–64 (2004).
- 56. Unique characteristics of radiation-induced apoptosis in the postnatally developing small intestine and colon of mice. Radiat. Res. 173(3), 310–318 (2010).
- 57. . Prosurvival and antiapoptotic effects of PGE2 in radiation injury are mediated by EP2 receptor in intestine. Am. J. Physiol. Gastrointest. Liver Physiol. 284(3), G490–G498 (2003).
- 58. Eutigoside C attenuates radiation-induced crypt injury in the mouse intestine. Phytother. Res. 24(6), 840–845 (2010).
- 59. . [Mitotic activity of epithelium in crypts of rats' empty intestine and tissue basophils in the event of intestinal syndrome of radiation disease treated with poly-radio-modification]. Aviakosm. Ekolog. Med. 35(4), 66–69 (2001).
- 60. . Randomized double-blind trial of amifostine versus placebo for radiation-induced xerostomia in patients with head and neck cancer. J. Med. Imaging Radiat. Oncol. 63(1), 142–150 (2019).
- 61. Amifostine suppresses the side effects of radiation on BMSCs by promoting cell proliferation and reducing ROS production. Stem Cells Int. 2019, 8749090 (2019).
- 62. Amifostine protects mouse liver against radiation-induced autophagy blockage. Anticancer Res. 38(1), 227–238 (2018).
- 63. Cancer incidence in C3H mice protected from lethal total-body radiation after amifostine. Radiat. Res. 189(5), 490–496 (2018).
- 64. . Examination of the effect of ovarian radiation injury induced by hysterosalpingography on ovarian proliferating cell nuclear antigen and the radioprotective effect of amifostine: an experimental study. Drug Des. Devel. Ther. 12, 1491–1500 (2018).
- 65. Effect of amifostine, a radiation-protecting drug, on oxygen concentration in tissue measured by EPR oximetry and imaging. J. Clin. Biochem. Nutr. 60(3), 151–155 (2017).
- 66. Histopathological and biochemical comparisons of the protective effects of amifostine and l-carnitine against radiation-induced acute testicular toxicity in rats. Andrologia 49(9), e12754 (2017).
- 67. . Structural and functional damages of whole body ionizing radiation on rat brain homogenate membranes and protective effect of amifostine. Int. J. Radiat. Biol. 92(12), 837–848 (2016).
- 68. Phase II multicenter randomized study of amifostine for prevention of acute radiation rectal toxicity: topical intrarectal versus subcutaneous application. Int. J. Radiat. Oncol. Biol. Phys. 62(2), 486–493 (2005).
- 69. Randomized phase II exploratory study of prophylactic amifostine in cancer patients who receive radical radiotherapy to the pelvis. J. Exp. Clin. Cancer Res. 29(1), 68 (2010).
- 70. Amifostine as radioprotective agent for the rectal mucosa during irradiation of pelvic tumors. A phase II randomized study using various toxicity scales and rectosigmoidoscopy. Strahlenther. Onkol. 179(3), 167–174 (2003).
- 71. . Intensity-modulated radiation therapy (IMRT) reduces small bowel, rectum, and bladder doses in patients with cervical cancer receiving pelvic and para-aortic irradiation. Int. J. Radiat. Oncol. Biol. Phys. 51(1), 261–266 (2001).
- 72. . Image-guided radiotherapy: a new dimension in radiation oncology. Dtsch. Arztebl. Int. 108(16), 274–280 (2011).
- 73. . Population and patient-specific target margins for 4D adaptive radiotherapy to account for intra-and inter-fraction variation in lung tumour position. Phys. Med. Biol. 52(1), 257 (2006).
- 74. . Radiation dose-volume effects in radiation-induced rectal injury. Int. J. Radiat. Oncol. Biol. Phys. 76(Suppl. 3), S123–S129 (2010).
- 75. . Systematic review of the role of a belly board device in radiotherapy delivery in patients with pelvic malignancies. Radiother. Oncol. 102(3), 325–334 (2012).
- 76. . Circadian rhythm of cellular proliferation in the human rectal mucosa. Gastroenterology 101(2), 410–415 (1991).
- 77. Hypofractionated versus conventionally fractionated radiotherapy for patients with prostate cancer (HYPRO): acute toxicity results from a randomised non-inferiority phase 3 trial. Lancet Oncol. 16(3), 274–283 (2015).
- 78. A prospective Phase III randomized trial of hypofractionation versus conventional fractionation in patients with high-risk prostate cancer. Int. J. Radiat. Oncol. Biol. Phys. 78(1), 11–18 (2010).
- 79. . A systematic review of hypofractionation for primary management of prostate cancer. Eur. Urol. 68(4), 683–691 (2015).
- 80. Beta-hydroxy-beta-methyl-butyrate, L-glutamine, and L-arginine supplementation improves radiation-induce acute intestinal toxicity. J. Diet. Suppl. 16 (5), 576–591 (2018).
- 81. . Efficacy of glutamine in the prevention of acute radiation enteritis: a randomized controlled trial. JPEN J. Parenter. Enteral Nutr. 38(2), 205–213 (2014).
- 82. Rebamipide ameliorates radiation-induced intestinal injury in a mouse model. Toxicol. Appl. Pharmacol. 329, 40–47 (2017).
- 83. . Cebpd is essential for gamma-tocotrienol mediated protection against radiation-induced hematopoietic and intestinal injury. Antioxidants (Basel) 7(4), 55 (2018).
- 84. Effect of pentoxifylline and tocopherol on radiation proctitis/enteritis. Strahlenther Onkol. 181(9), 606–614 (2005).
- 85. . Pyridoxamine protects intestinal epithelium from ionizing radiation-induced apoptosis. Free Radic. Biol. Med. 47(6), 779–785 (2009).
- 86. Radiation-induced reductions in transporter mRNA levels parallel reductions in intestinal sugar transport. Am. J. Physiol. Regul. Integr. Comp. Physiol. 298(1), R173–R182 (2010).
- 87. Marked changes in endogenous antioxidant expression precede vitamin A-, C-, and E-protectable, radiation-induced reductions in small intestinal nutrient transport. Free Radic. Biol. Med. 50(1), 55–65 (2011).
- 88. Treatment of irradiated mice with high-dose ascorbic acid reduced lethality. PloS ONE 10(2), e0117020 (2015).
- 89. . Successful and sustained treatment of chronic radiation proctitis with antioxidant vitamins E and C. Am. J. Gastroenterol. 96(4), 1080–1084 (2001).
- 90. . Effect of a chamomile extract in protecting against radiation-induced intestinal mucositis. Phytother. Res.
doi:10.1002/ptr.6263 (2019) (Epub ahead of print). - 91. A PPAR-gamma agonist protects from radiation-induced intestinal toxicity. United European Gastroenterol. J. 5(2), 218–226 (2017).
- 92. Non-surgical interventions for late rectal problems (proctopathy) of radiotherapy in people who have received radiotherapy to the pelvis. Cochrane Database Syst. Rev. 4, Cd003455 (2016).
- 93. . Simvastatin ameliorates radiation enteropathy development after localized, fractionated irradiation by a protein C-independent mechanism. Int. J. Radiat. Oncol. Biol. Phys. 68(5), 1483–1490 (2007).
- 94. Evaluating the efficacy of statins and ACE-inhibitors in reducing gastrointestinal toxicity in patients receiving radiotherapy for pelvic malignancies. Eur. J. Cancer 48(14), 2117–2124 (2012).
- 95. The protective effects of XH-105 against radiation-induced intestinal injury. J. Cell. Mol. Med. 23(3), 2238–2247 (2019).
- 96. . Prevention of acute radiation-induced proctosigmoiditis by balsalazide: a randomized, double-blind, placebo controlled trial in prostate cancer patients. Int. J. Radiat. Oncol. Biol. Phys. 63(5), 1483–1487 (2005).
- 97. . Modulatory effect of a new benzopyran derivative via COX-2 blocking and down regulation of NF-kappaB against gamma-radiation induced- intestinal inflammation. J. Photochem. Photobiol. B Biol. 192, 90–96 (2019).
- 98. A DPP-IV-resistant glucagon-like peptide-2 dimer with enhanced activity against radiation-induced intestinal injury. J. Control Release 260, 32–45 (2017).
- 99. . Probiotics. Am. Fam. Physician 78(9), 1073–1078 (2008).
- 100. . Radiation-induced small bowel disease: latest developments and clinical guidance. Ther. Adv. Chronic Dis. 5(1), 15–29 (2014).
- 101. . Systematic review: the efficacy of nutritional interventions to counteract acute gastrointestinal toxicity during therapeutic pelvic radiotherapy. Aliment. Pharmacol. Ther. 37(11), 1046–1056 (2013).
- 102. Lactobacillus probiotic protects intestinal epithelium from radiation injury in a TLR-2/cyclo-oxygenase-2-dependent manner. Gut 61(6), 829–838 (2012).
- 103. Administration of Lactobacillus plantarum 299v reduces side-effects of external radiation on colon anastomotic healing in an experimental model. Colorectal Dis. 3(4), 245–252 (2001).
- 104. Prophylaxis of diarrhoea in patients submitted to radiotherapeutic treatment on pelvic district: personal experience. Dig. Liver Dis. 34(Suppl. 2), S84–S86 (2002).
- 105. Use of probiotics for prevention of radiation-induced diarrhea. World J. Gastroenterol. 13(6), 912–915 (2007).
- 106. . Nutritional interventions for reducing gastrointestinal toxicity in adults undergoing radical pelvic radiotherapy. Cochrane Database Syst. Rev.
doi:10.1002/14651858.CD009896.pub2 (11), Cd009896 (2013). - 107. . Testing control of radiation-induced diarrhea with a psyllium bulking agent: a pilot study. Can. Oncol. Nurs. J. 10(3), 96–100 (2000).