Radiation injury of the GI tract has been the most extensively studied cause of fibrosis and enteritis. According to data from cohorts of adults treated with radiation for abdominopelvic tumors, radiation complications typically develop within 5 years after treatment in individuals who experienced acute GI toxicity [24]. However, primary presentations of strictures or inflammatory lesions may occur as late as 20 years after radiation [17, 25]. The risk of radiation injury to the GI tract is related to the cumulative radiation dose, daily fraction dose, and extent of treatment volume [26, 27]. Fixed loops of the duodenum and terminal ileum are more prone to radiation injury than the esophagus or other intestinal sites [6, 25]. The incidence of small bowel fibrosis is about 5 % after 40–50 Gy and rises to 40 % when doses exceed 60 Gy [26, 28]. Chronic GI tract injury is uncommon after treatment doses below 42 Gy given over 4–4.5 weeks.

Limited studies are available describing the chronic effects of GI radiation therapy in children [17]. Many of the data on the risk of bowel adhesions and obstruction in this population are confounded by the fact that most of the cancer survivors had prior abdominal surgery as a risk factor for late gastrointestinal effects [17]. Donaldson et al. comprehensively evaluated intestinal symptoms in 44 children with Wilms tumor, teratoma, or lymphoma (including Hodgkin lymphoma) treated with whole abdominal (10–40 Gy) and involved field (25–40 Gy) radiation [1]. Additional interventions predisposing to GI tract toxicity in the group included abdominal laparotomy in 43(98 %) and chemotherapy in 25 (57 %). Late small bowel obstruction was observed in 36 % of patients surviving 19 months to 7 years, which was uniformly preceded by small bowel toxicity during therapy. Infants and children younger than 2 years appeared to experience more acute and chronic GI toxicity following intensive radiation or combined modality therapy compared to older children.

Several reports document GI toxicity in long-term survivors of genitourinary rhabdomyosarcoma [2, 3, 29]. Investigators from the Intergroup Rhabdomyosarcoma Study evaluated late effects in long-term survivors of paratesticular and bladder/prostate rhabdomyosarcoma [5]. Radiation-related complications occurred in approximately 10 % of patients and included intraperitoneal adhesions with bowel obstruction, chronic diarrhea, and stricture or enteric fistula formation. Similar findings were observed in another small cohort of survivors of paratesticular rhabdomyosarcoma treated at a single institution [29]. A report on long-term survivors of germ cell tumors reported up to 25 % had gastrointestinal dysfunction in patients who had received 25–30 Gy to the abdomen and pelvis. The late effects included chronic diarrhea or constipation, stool incontinence, bowel obstruction, rectal prolapse, strictures, or fistula formation [30]. The small number of patients and GI events reported in these studies precluded correlation of host and treatment factors predicting GI toxicity.

Radiation can enhance the risk of late postsurgical small bowel obstruction in long-term childhood survivors, but this complication has been rarely observed with contemporary techniques and doses. Donaldson reported only one case of late bowel obstruction in 79 surgically staged pediatric patients with Hodgkin lymphoma treated with radiation (35–44 Gy) [31]. Similarly, high-dose radiation used in earlier protocols for Hodgkin lymphoma in adolescents and young adults has been associated with a 1 % incidence of late onset nonspecific abdominal pain attributable to retroperitoneal fibrosis involving the genitourinary tract rather than the GI tract [32]. However, children irradiated at lower doses for Wilms tumor less commonly develop chronic small bowel obstruction [17].

Thoracic radiation, particularly when administered to young children at high cumulative doses (40 Gy or more), predisposes to the development of esophageal strictures [4, 33]. The frequency of stricture formation after mediastinal radiation has ranged from 17 % to 42 % in older series [34–36]. This complication is uncommonly observed following contemporary treatment for pediatric tumors which have reduced or eliminated radiation in many frontline therapies. Acute radiation esophagitis developing during radiation administration is likely the nidus for stricture formation or tracheoesophageal fistulas; fungal esophagitis may also enhance the risk of this complication [33, 37]. Subacute or chronic candidal esophagitis may predispose to stricture formation that usually involves the upper third of the esophagus [37, 38] (Figure 12.2). Strictures developing in individuals with chronic candidal esophagitis have been seen in association with intramucosal pseudodiverticulitis, an inflammatory disorder characterized by digitation of excretory ducts of the submucosal glands. Another characteristic histopathology includes the development of mucosal bridges that may result in webs. Similarly, the administration of radiation-enhancing chemotherapeutic agents like doxorubicin may augment the risk of stricture formation by inducing recurrent episodes of esophagitis through a “recall” phenomenon [39–41]. This premise concurs with the increased frequency of strictures observed in patients treated with combined modality therapy including radiation and radiomimetic chemotherapy.

In general, chemotherapy plays a less prominent role in the development of chronic enteritis. Multiple chemotherapeutic agents produce acute GI toxicity and typically manifest as mucositis; complete resolution of symptoms after completion of therapy is the usual clinical course. Anthracyclines and dactinomycin have potent radiomimetic effects that enhance acute GI toxicity and likely contribute to late onset radiation-related GI toxicity [40–42]. Rapid chemotherapy-induced tumor lysis has been associated with intestinal necrosis and fistula formation [43]. Both alkylating agents and anthracyclines were associated with dose-dependent risk of upper GI and liver complications in the CCSS cohort. Vincristine exposure is associated with late liver and lower GI complications [7].

Abdominal surgery is associated with a lifelong risk of developing adhesive and obstructive complications involving the GI tract. Numerous pediatric studies describe adhesive or obstructive complications that most commonly develop within the acute or subacute postoperative period [44–46]. In contrast, information about very late onset adhesive and obstructive complications in childhood cancer survivors are more likely to be found in manuscripts describing global long-term outcome after pediatric sarcomas, in which the incidence of complications related to adhesions and obstructions is approximately 10 % [3, 5, 29]. Notably, in addition to laparotomy, risk factors for postoperative complications included intensive combination chemotherapy including radiomimetic agents and radiation therapy. Investigators from the National Wilms Tumor Study Group observed small bowel obstruction in 7 % of patients; however, the incidence of late onset obstruction (more than 1 year from laparotomy) occurred in fewer than 2 % of patients, with events rarely reported more than 5 years postoperatively [44]. Jockovich et al. evaluated long-term complications of laparotomy in a cohort of 133 pediatric and adult patients who had undergone staging laparotomy with splenectomy before treatment of Hodgkin lymphoma [45]. At a median follow-up of 15.7 years (range, 2.5–28 years) after laparotomy, the most frequent surgical complication was small bowel obstruction, which occurred in 9.8 % and required surgical intervention in 6.8 %. Patients younger than 15 years of age at the time of laparotomy had a higher risk of small bowel obstruction compared to older patients, perhaps related to the increased intensity of the pediatric surgical staging protocols. An increased frequency of obstructive complications is also anticipated in survivors who have undergone multiple laparotomies for staging and assessment of tumor response [31, 42].

Rarely, a temporary or permanent enterostomy is required for the management of cancer-related GI toxicity, for example, after resection of ischemic bowel, for a refractory GI tract stricture or fistula, or for chronic fecal incontinence. Affected survivors must cope with physical and psychological issues related to stoma maintenance. Finally, excess gastrointestinal bicarbonate loss associated with ureterosigmoidostomy or ileal or jejunal loop procedures predisposes to hyperchloremic metabolic acidosis [47]. These individuals are also at increased risk of developing adenocarcinoma of the large bowel [48].

The incidence and severity of delayed GI tract toxicity following allogeneic hematopoietic stem cell transplantation are related to the cumulative radiation dose used in the conditioning regimen, the presence of GVHD, or a combination of both. Whereas GI tract toxicity is frequent in the acute transplant setting, chronic late problems affecting GI tissues are relatively uncommon. Xerostomia may result from sclerodermatous changes of the mucous membranes and salivary glands and predispose to accelerated tooth decay and periodontal disease [49]. Esophageal stricture formation is the most common form of delayed GI toxicity and may require dilation procedures to maintain satisfactory oral intake [50, 51]. Affected tissues show characteristic weblike intraluminal membranes that form strictures; some patients also demonstrate perimuscular fibrosis similar to that seen in scleroderma [50, 51]. GVHD of the small bowel may result in chronic diarrhea from malabsorption (Fig. 12.3). Steatorrhea and diarrhea may also signal the presence of bacterial overgrowth with stasis syndrome. As a result, many individuals with chronic GVHD involving the GI tract are anorexic and undernourished. Endoscopic evaluation with biopsy is generally required to identify the specific GI pathology and provide appropriate therapeutic interventions.

Liver injury related to treatment for childhood cancer is most often subclinical and may develop without a history of prior acute toxicity. Asymptomatic abnormalities of serum transaminases (alanine aminotransferase and aspartate aminotransferase) are most commonly observed. In the setting of chronic GVHD, alkaline phosphatase and bilirubin may also be elevated. However, bilirubin elevation is variable and does not correlate with clinical outcome. Patients with chronic liver dysfunction frequently report constitutional complaints like pruritus, fatigue, and weight loss. In contrast, hepatic sinusoidal obstruction syndrome (or venoocclusive disease) is characterized by the acute onset of jaundice, right upper quadrant pain, hepatomegaly, ascites, liver dysfunction, and thrombocytopenia. The clinical course of sinusoidal obstruction syndrome varies from mild and reversible to life threatening with progressive hepatic failure. The impact of acute sinusoidal obstruction syndrome on long-term hepatic function has not been established. Chronic progressive hepatic fibrosis associated with cirrhosis may cause portal hypertension and resulting sequelae like hypersplenism and variceal bleeding. If cirrhosis leads to liver decompensation, clinical signs and symptoms of hepatic synthetic dysfunction appear including ascites and coagulopathy. As hepatic failure ensues, affected individuals manifest progressive metabolic derangements and encephalopathy.