The present study included 536 patients (256 with gastric cancer and 280 with colorectal cancer), the clinical characteristics of whom are presented in Table 1. The most common types of fluoropyrimidines administered were S-1 (70%) for gastric cancer and 5-FU (72%) for colorectal cancer. Both groups had low frequency of capecitabine use. The chemotherapy regimen consisted of fluoropyrimidine alone and combination chemotherapy in 77 (14%) and 459 (86%) patients, respectively, while molecular-targeted drug therapy consisted of fluoropyrimidine and cisplatin plus trastuzumab in 35 patients with HER2-positive gastric cancer. Patients with colorectal cancer received molecular-targeted drugs in combination with fluoropyrimidine and oxaliplatin or irinotecan. Bevacizumab and cetuximab/panitumumab were administered in 25 and 116 patients, respectively.
Among 536 patients, diarrhea with grade 1 or 2 and grade 3 or 4 were observed in 174 (32%) and 10 (2%) patients, respectively. A total of 32 (6%) patients developed complicated CID, among whom 23 and 9 had gastric and colorectal cancer, respectively. Most of the patients developed the condition within a month (Figs. 1 and 2). Complicating symptoms were noted in 78% (25/32) patients, 76% (19/25) of whom were with oral fluoropyrimidine and 24% (6/25) of whom were with infusional fluoropyrimidine. Accordingly, cramping, vomiting, fever and sepsis were observed in 15 (60%), 8 (32%), 6 (24%), and 3 (12%) patients.
Among the 32 patients with complicated CID, 6% (2/32) and 94% (30/32) developed the condition after receiving single-agent chemotherapy and combination chemotherapy, respectively. All patients, except one who died after developing grade 4 neutropenia and sepsis, recovered from complicated CID through infusion and antibiotic therapy. The median duration to recovery from complicated CID to grade 1 diarrhea was 6 days (range, 1–59 days).
Small bowel findings of CT scan and CE
Among 32 patients who developed complicated CID, 13 patients underwent CE (10 gastric and 3 colon cancer; 11 oral fluoropyrimidine and 2 infusional 5-FU based chemotherapy). Table 2 summarizes the characteristics of patients with complicated CID who underwent CE. 59% (19/32) patients did not undergo CE because of following reasons. Eleven patients had the risk of retention: due to primary tumours in 8, peritoneal dissemination in 2, and massive ascites in 1. Seven patients refused the examination despite extensive explanation. Another patient was unable to undergo CE due to the severity of the underlying medical condition. Six patients received a patency capsule, and all of them were confirmed to have intestinal patency. The mean duration between the onset of complicated CID and small bowel CE was 9 days (range, 2–21 days). Among the 13 patients who underwent CE, the capsule passed through their small intestine within the scheduled timeframe in 10 patients. Capsule excretion was ultimately confirmed in all 13 patients with no adverse events including capsule retention.
Among the 13 patients who underwent CE, CT scans were performed in 12 at the onset of complicated CID. Increased thickness of the wall of the small intestines was identified in 7 patient cases; however, no abnormalities associated with the large intestines were detected. Moreover, of the four patients with mucosal injury of the small intestine, 2 patients (#2 and #6) underwent esophagogastroduodenoscopy and the other 2 patients (#5 and #11) underwent colonoscopy. No abnormal findings were detected in either of these studies except for previously-identified primary tumors or mucosal injury of small intestine. Among those who underwent CE, abnormal findings were identified in 85% (11/13) patients; multiple red spots, erosions, and ulcers were noted in 91% (10/11), 64% (7/11), and 27% (3/11) patients, respectively (Fig. 3). Of the 11 patients who presented with abnormal findings, mucosal lesions were detected in the ileum in six patients (#1, #3, #7, #9, #12, and #13), in the jejunum in four patients (#2, #4, #5, and #6), and in entire small intestine in one patient (#11). Colonoscopy was performed in patient #5 on day 13 after CE (see Table 2), which revealed sparsely-distributed small ulcers and erosions that were amenable for biopsy. Histology of an ileal biopsy specimen revealed ulceration with granulation tissue with acute and chronic inflammatory changes (Fig. 4). Of the 536 patients enrolled in this study, 349 patients (65%) experienced no diarrhea. Capsule endoscopy (CE) was performed in five of these patients (2 diagnosed with gastric cancer and 3 with colon cancer; 3 had undergone treatment with oral fluoropyrimidine and 2 with intravenous 5-FU). No abnormal findings were detected in any of the patients in this cohort.
Clinical factors associated with the incidence of complicated CID
Univariate and multivariate analyses were performed to identify clinical or treatment factors associated with the incidence of complicated CID (Table 3) given that small intestinal mucosal injury was observed in most of the patients with complicated CID. Univariate analysis involving the entire patient cohort indicated that gastric cancer (p = 0.01) and oral fluoropyrimidine (p = 0.003) were significantly associated with the incidence of complicated CID, whereas sex, age, performance status, primary site resection, number of metastatic sites; however, any combination of drugs including platinum, irinotecan, taxane, trastuzumab, cetuximab or panitumumab, and bevacizumab were not. Multivariate analysis revealed that oral fluoropyrimidine (OR 2.95; 95% CI 1.06–8.19) was independent risk factor associated with the incidence of complicated CID.
The incidence of diarrhea of all grades was 38% (101/274) and 31% (82/262) among the patients treated with oral fluoropyrimidine and intravenous 5-FU, respectively; this difference did not reach statistical significance (p = 0.09). By contrast, the incidence of complicated CID in the patients treated with oral fluoropyrimidine and intravenous 5-FU was 9% (25/276) and 3% (7/260), respectively, a finding that was highly significant (p = 0.001).