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

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Abstract
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. 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. We found the descending colon susceptible to radiation carcinogenesis; 26 colorectal tumors developed in the low-dose irradiation group and 47 in the high-dose group (P = 0.0008; Mann-Whitney U test, 16 vs. 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). 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.