Influence of fraction size on the development of late radiation enteropathy - An experimental study in the rat

The use of large fraction sizes in radiotherapy may be associated with an increased risk of complications from late responding normal tissues. However, in the intestine, chronic injury may develop either as primary late effect or secondary to disruption of mucosal integrity as so-called consequential injury. Mucosal damage is relatively less sensitive to changes in fraction size than late reacting, slowly proliferating cells. The relationship between fraction size and chronic radiation enteropathy in a given situation may thus depend on which of the two mechanisms that predominates. Most previous studies of the influence of fraction size on radiation injury are confounded by differences in treatment time. The present study was therefore designed to assess subacute and chronic radiation enteropathy after three different fractionation regimens where fraction size was the only experimental variable. A total of 96 male Sprague-Dawley rats were orchiectomized and a functionally intact loop of small intestine was transposed into the left scrotum. These 'scrotal hernias' containing intestine were subsequently exposed to 50.4 Gy localized fractionated irradiation over 18 days with either 2.8 Gy every 24 h, 4.2 Gy every 36 h, or 5.6 Gy every 48 h. Control animals were sham irradiated. The animals were observed for development of intestinal complications (intestinal obstruction or enterocutaneous fistula formation) up to 6 months after irradiation. Histologic damage was assessed in groups of animals at 2 weeks (subacute injury) and 26 weeks (chronic injury), using a previously validated radiation injury score (RIS). RIS increased significantly with increasing fraction size at both observation times. However, the increase was more pronounced at 26 weeks than at 2 weeks. Increased chronic injury was characterized by increased incidence and severity of mucosal ulceration, serosal thickening, vascular sclerosis and intestinal wall fibrosis. We conclude that increasing fraction size increases both subacute and, even more markedly, chronic injury in the intestine. With the fractionation regimens used here, the chronic radiation enteropathy develops as a combined consequential and primary late effect, but the primary mechanism predominates.