Introduction
Capecitabine is an oral fluorouracil (FU) prodrug commonly used in patients with colorectal cancer, particularly as adjuvant and palliative chemotherapy in colon cancer (1). The most common gastrointestinal adverse events include nausea, vomiting and diarrhea. Capecitabine may also cause serious gastrointestinal adverse events, such as intestinal perforation or obstruction (1).
We treated 2 patients with ileitis associated with capecitabine administration. In one of the patients, ileitis occurred during palliative second-line combination chemotherapy for metastatic colon cancer, despite good tolerance to capecitabine during previous chemotherapy. A literature search identified no previous reported cases among Chinese adults who had received capecitabine as second-line chemotherapy. The other patient developed ileitis while on single-agent adjuvant therapy with capecitabine for sigmoid colon cancer. The purpose of this study was to present the case histories, pathophysiology, imaging findings and literature review for this uncommon condition.
Discussion
The two patients developed ileitis associated with capecitabine. Previously reported cases of capecitabine-associated ileitis included 1 patient who had received adjuvant capecitabine monotherapy for colon cancer, 1 patient who had received capecitabine, oxaliplatin and bevacizumab for metastatic rectal cancer, and 1 patient who had received capecitabine and oxaliplatin for metastatic rectal cancer (2–4). In these previous cases, the ileitis dveloped early, between the first and third cycle of chemotherapy, and none of the patients in these reports had previous exposure to capecitabine. Case 1 highlights the fact that small bowel complications may occur during later cycles of chemotherapy, despite previous good tolerance to capecitabine.
In both presented cases, it was difficult to confirm the diagnosis, as the initial clinical findings were non-specific, the patients were on combination chemotherapy plus targeted therapy, and this type of toxicity is rare. The CT scan was an important tool for diagnosis and monitoring. The radiographic findings were comparable in the two cases, and ileitis was observed as diffuse submucosal edema of the small bowel wall, which was consistent with previous case reports and confirmed the diagnosis.
It was important to closely monitor serum electrolyte levels during the acute phase of the ileitis. Adequate hydration was also important, as capecitabine is excreted primarily by the kidneys.
Capecitabine is administered as an oral prodrug; it is metabolized in successive enzymatic steps to 5-FU, which is metabolized into two active metabolites that exert the cytotoxic effect. The step of conversion to 5-FU preferentially occurs in tumor tissues (1). 5-FU may cause vasospasm in the coronary vessels and cardiotoxicity (5). Furthermore, the vascular endothelium is susceptible to 5-FU via the generation of free radicals. The endothelial damage may cause a procoagulant state and thrombosis (6,7). These vascular effects of 5-FU may also affect intestinal vessels. A previous case of 5-FU-associated small bowel vasculitis due to arterial ischemia has been reported (8). Another study demonstrated that proinflammatory cytokines may contribute to 5-FU-associated intestinal mucosal injury (9).
In our cases, the contribution of bevacizumab and irinotecan to ileitis was unlikely. According to a previous case series, the most common clinical findings in bevacizumab-associated bowel perforation include abdominal pain and tenderness, vomiting, fever and leukocytosis. Diarrhea has been less frequently reported in most bevacizumab studies and is not a typical symptom of bowel perforation (10). A literature search identified no reported cases of small bowel ileitis associated with bevacizumab and irinotecan administration. The patient in case 1 did not have another episode of ileitis during subsequent cycles of irinotecan and bevacizumab treatment following discontinuation of capecitabine.
In summary, we presented two cases of adult Chinese patients who developed ileitis associated with capecitabine treatment. Ileitis may occur despite previous good tolerance to capecitabine. A high index of suspicion is crucial for prompt diagnosis. Ileitis may be reversible with early recognition, close monitoring and proper supportive treatment.