Diseases of the Colon & Rectum

, Volume 38, Issue 2, pp 152–158 | Cite as

Adjuvant radiotherapy and anastomosis in rectal cancer—disturbing evidence from animal studies

  • J. L. McCue
  • J. P. Sheffield
  • R. K. S. Phillips
Original Contributions


PURPOSE: Adjuvant radiotherapy is used increasingly in the management of rectal cancer. However, ionizing radiation is mutagenic, and, superimposed on a background of increased cellular proliferation as seen around anastomoses and in colorectal cancer patients, there is the potential for enhanced metachronous cancer risk. METHOD: The influence of preoperative irradiation on both carcinogenesis and cellular proliferation at colonic anastomoses was explored in 180 adult male F344 rats. Orthovoltage x-rays were delivered to the distal descending colon by parallel opposed fields. Ninety rats received 16 Gy in one fraction; the remainder received 36 Gy in two fractions one week apart. In each irradiation group 18 rats either acted as controls or one week after radiotherapy underwent distal colotomy and repair. RESULTS: We found the descending colon susceptible to radiation carcinogenesis; 26 colorectal tumors developed in the low-dose irradiation group and 47 in the highdose group (P=0.0008; Mann-WhitneyUtest, 16vs.36 Gy). Preferential tumor development was seen in the anastomotic region. In those animals that underwent surgery and irradiation, among the low-dose irradiation group only 3 of 72 had tumors within the descending colon compared with 21 of 72 at the anastomotic site (McNemar's test chi-squared=40.9;P<0.001), and in the high-dose irradiation group 5 of 72 had tumors within the descending colon compared with 36 of 72 at the anastomotic site (McNemar's test chi-squared=22.0;P<0.001). Anastomotic crypt cell production rates were increased for at least three months following exposure to irradiation (16 Gy: f=15.1,P<0.005; 32 Gy: f=9.4,P<0.005). CONCLUSIONS: Radiation carcinogenesis is greatly enhanced at colonic anastomoses and may result from altered anastomotic proliferation. This has potentially disturbing implications in view of the increasing use of adjuvant radiotherapy for rectal carcinoma.

Key words

Colorectal carcinogenesis Radiation carcinogenesis Cellular proliferation 


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  1. 1.
    Gerard A, Buyse M, Nordlinger B,et al. Preoperative radiotherapy as adjuvant treatment in rectal cancer: final results of a randomized study of the European Organization for Research and Treatment of Cancer (EORTC). Ann Surg 1988;208:606–14.PubMedGoogle Scholar
  2. 2.
    Bruckner R, Kempf P, Kutzner J, Brunner H. Preliminary results of preoperative radiotherapy in carcinoma of the rectum. Dtsch Med Wochenschr 1977;102:195–8.PubMedGoogle Scholar
  3. 3.
    Stockholm Rectal Cancer Study Group. Pre-operative short-term radiation therapy in operable rectal carcinoma. Cancer 1990;66:49–55.Google Scholar
  4. 4.
    Kato H, Schull WJ. Studies of the mortality of A-bomb survivors, report 7. Mortality, 1950–1978: Part I. Cancer mortality. Radiat Res 1982;90:395–432.PubMedGoogle Scholar
  5. 5.
    Wakabayashi T, Kato H, Ikeda T, Schull WJ. Studies of the mortality of A-bomb survivors, report 7: Part III. Incidence of cancer in 1959–1978, based on the tumor registry, Nagasaki. Radiat Res 1983;93:112–46.PubMedGoogle Scholar
  6. 6.
    Polednak AP, Stehney AF, Rowland RE. Mortality among women first employed before 1930 in the U.S. radium dial-painting industry: a group ascertained from employment lists. Am J Epidemiol 1978;107:179–95.PubMedGoogle Scholar
  7. 7.
    Court Brown WM, Doll R. Mortality from cancer and other causes after radiotherapy for ankylosing spondylitis. BMJ 1965;2:1327–32.Google Scholar
  8. 8.
    Smith PG, Doll R. Mortality among patients with ankylosing spondylitis after a single treatment course with x rays. BMJ 1982;284:449–60.PubMedGoogle Scholar
  9. 9.
    Smith PG, Doll R, Radford EP. Cancer mortality among patients with ankylosing spondylitis not given x-ray therapy. Br J Radiol 1977;50:728–34.PubMedGoogle Scholar
  10. 10.
    Doll R, Smith PG. The long-term effects of x irradiation in patients treated for metropathia haemorrhagica. Br J Radiol 1968;41:362–8.PubMedGoogle Scholar
  11. 11.
    Brinkley D, Haybittle JL. The late effects of artificial menopause by x-radiation. Br J Radiol 1969;42:519–21.PubMedGoogle Scholar
  12. 12.
    Smith PG, Doll R. Late effects of x irradiation in patients treated for metropathia haemorrhagica. Br J Radiol 1976;49:224–32.PubMedGoogle Scholar
  13. 13.
    Dickson RJ. Late results of radium treatment of carcinoma of the cervix. Clin Radiol 1972;23:528–35.PubMedGoogle Scholar
  14. 14.
    Kleinerman RA, Curtis RE, Boice JD, FlanneryJT, Fraumeni JF. Second cancers following radiotherapy for cervical cancer. J Natl Cancer Inst 1982;69:1027–33.PubMedGoogle Scholar
  15. 15.
    Ingelman Sundeberg A. Rectal injuries following radiation treatment of carcinoma of the cervix uteri. Acta Radiol Diagn Stockh 1947;64(Suppl):3–79.Google Scholar
  16. 16.
    Kapp DS, Fischer D, Grady KJ, Schwartz PE. Subsequent malignancies associated with carcinoma of the uterine cervix: including an analysis of the effect of patient and treatment parameters on incidence and sites of metachronous malignancies. Int J Radiat Oncol Biol Phys 1982;8:197–205.PubMedGoogle Scholar
  17. 17.
    Lee JY, Perez CA, Ettinger N, Fineberg BB. The risk of second primaries subsequent to irradiation for cervix cancer. Int J Radiat Oncol Biol Phys 1982;8:207–11.PubMedGoogle Scholar
  18. 18.
    Sandler RS, Sandler DP. Radiation-induced cancers of the colon and rectum: assessing the risk. Gastroenterology 1983;84:51–7.PubMedGoogle Scholar
  19. 19.
    Ellis F. The relationship of biological effect to dosetime-fractionation factors in radiotherapy. Curr Top Rad Res 1968;4:357–97.Google Scholar
  20. 20.
    McCue JL, Phillips RK. Cellular proliferation at sutured and sutureless colonic anastomoses. Dis Colon Rectum 1993;36:468–74.PubMedGoogle Scholar
  21. 21.
    Blake JR, Reeve RS, Hardcastle JD, Dawson IM, Metcalf MJ, Thompson MJ. A study of the effect of colotomy and mucosal field changes in experimental colon cancer. Clin Oncol (R Coll Radiol) 1980;6:113–123.Google Scholar
  22. 22.
    Barkla DH, Tutton PM. The influence of surgical transection and anastomosis on the rate of cell proliferation in the colonic epithelium of normal and DMH-treated rats. Carcinogenesis 1983;4:1323–5.PubMedGoogle Scholar
  23. 23.
    Phillips RK, Cook HT. Effect of steel wire sutures on the incidence of chemically induced rodent colonic tumours. Br J Surg 1986;73:671–4.PubMedGoogle Scholar
  24. 24.
    Roe R, Fermor B, Williamson RC. Proliferative instability and experimental carcinogenesis at colonic anastomoses. Gut 1987;28:808–15.PubMedGoogle Scholar
  25. 25.
    Lisco H, Brues AM, Finkel MP, Grundhauser W. Carcinoma of the colon in rats following the feeding of radioactive yttrium. Cancer Res 1947;7:721.Google Scholar
  26. 26.
    Lebedeva GA. Data concerning the gastrointestinal tumours induced by radioactive cerium. Acta Unio Int Contra Cancrum 1964;20:1157–8.PubMedGoogle Scholar
  27. 27.
    Hirose F, Fukazawa K, Watanabe H, Terada Y, Fujii I, Otsuka S. Induction of rectal carcinoma in mice by local x-irradiation. Gann 1977;68:669–80.PubMedGoogle Scholar
  28. 28.
    Denman DL, Kirchner FR, Osborne JW. Induction of colonic adenocarcinoma in the rat by x-irradiation. Cancer Res 1978;38:1899–905.PubMedGoogle Scholar
  29. 29.
    Sharp JG, Crouse DA. Apparent synergism between radiation and the carcinogen 1,2-dimethylhydrazine in the induction of colonic tumors in rats. Radiat Res 1989;117:304–17.PubMedGoogle Scholar
  30. 30.
    Sindelar WF, Morrow BM, Travis EL,et al. Effects of intraoperative electron irradiation in the dog on cell turnover in intact and surgically-anastomosed aorta and intestine. Int J Radiat Oncol Biol Phys 1983;9:523–32.PubMedGoogle Scholar
  31. 31.
    Risio M, Lipkin M, Candelaresi G, Bertone A, Coverlizza S, Rossini FP. Correlations between rectal mucosa cell proliferation and the clinical and pathological features of nonfamilial neoplasia of the large intestine. Cancer Res 1991;51:1917–21.PubMedGoogle Scholar
  32. 32.
    Risio M, Coverlizza S, Candelaresi GL,et al. Late cytokinetic abnormalities in irradiated rectal mucosa. Int J Colorectal Dis 1990;5:98–102.PubMedGoogle Scholar
  33. 33.
    Bleiberg H, Mainguet P, Galand P, Chretien J, Dupont Mairesse N. Cell renewal in the human rectum: in vitro autoradiographic study on active ulcerative colitis. Gastroenterology 1970;58:851–5.PubMedGoogle Scholar
  34. 34.
    Lipkin M, Blattner WE, Fraumeni JF Jr, Lynch HT, Deschner E, Winawer S. Tritiated thymidine (phi p, phi h) labeling distribution as a marker for hereditary predisposition to colon cancer. Cancer Res 1983;43:1899–904.PubMedGoogle Scholar
  35. 35.
    Kanazawa K, Yamamoto T, Sato S. Experimental induction of colonic carcinomas in rats: analysis of factors influencing upon the incidence. Jpn J Exp Med 1975;45:439–56.PubMedGoogle Scholar
  36. 36.
    Matthews J, Carpenter R, Strachan P, Gregory P, Cooke T. Does cell proliferation play a part in anastomotic recurrence of colonic tumours. Eur J Surg Oncol 1987;13:273–4.Google Scholar
  37. 37.
    Jao SW, Beart RW, Reiman HM, Gunderson LL, Ilstrup DM. Colon and anorectal cancer after pelvic irradiation. Dis Colon Rectum 1987;30:953–8.PubMedGoogle Scholar
  38. 38.
    Castro EB, Rosen PP, Quan SH. Carcinoma of large intestine in patients irradiated for carcinoma of cervix and uterus. Cancer 1973;31:45–52.PubMedGoogle Scholar
  39. 39.
    Levitt MD, Millar DM, Stewart JO. Rectal cancer after pelvic irradiation. J R Soc Med 1990;83:152–4.PubMedGoogle Scholar
  40. 40.
    Shamsuddin AK, Trump BF. Colon epithelium. II. In vivo studies of colon carcinogenesis: light microscopic, histochemical, and ultrastructural studies of histogenesis of azoxymethane-induced colon carcinomas in Fischer 344 rats. J Natl Cancer Inst 1981;66:389–401.PubMedGoogle Scholar

Copyright information

© American Society of Colon and Rectal Surgeons 1995

Authors and Affiliations

  • J. L. McCue
    • 1
    • 2
  • J. P. Sheffield
    • 1
    • 2
  • R. K. S. Phillips
    • 1
    • 2
  1. 1.Professorial Surgical UnitSt. Bartholomew's HospitalUK
  2. 2.Department of Surgery and Imperial Cancer Research Fund Colorectal UnitSt. Mark's HospitalLondonUK

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